bluuebunny/crossref_metadata_2025 huggingface dataset:
Bacterial surface motility is modulated by colony-scale flow and granular jamming
Authors: Rhodeland Ben , Hoeger Kentaro , Ursell Tristan
Published: June 2020

Microbes routinely face the challenge of acquiring territory and resources on wet surfaces. Cells move in large groups inside thin, surface-bound water layers, often achieving speeds of 30 µm s
−1
within this environment, where viscous forces dominate over inertial forces (low Reynolds number). The canonical Gram-positive bacterium
Bacillus subtilis
is a model organism for the study of collective migration over surfaces with groups exhibiting motility on length-scales three orders of magnitude larger than themselves within a few doubling times. Genetic and chemical studies clearly show that the secretion of endogenous surfactants and availability of free surface water are required for this fast group motility. Here, we show that: (i) water availability is a sensitive control parameter modulating an abiotic jamming-like transition that determines whether the group remains fluidized and therefore collectively motile, (ii) groups self-organize into discrete layers as they travel, (iii) group motility does not require proliferation, rather groups are pulled from the front, and (iv) flow within expanding groups is capable of moving material from the parent colony into the expanding tip of a cellular dendrite with implications for expansion into regions of varying nutrient content. Together, these findings illuminate the physical structure of surface-motile groups and demonstrate that physical properties, like cellular packing fraction and flow, regulate motion from the scale of individual cells up to length scales of centimetres.
Cancer biomarker profiling using nanozyme containing iron oxide loaded with gold particles
Authors: Akpe Victor , Shiddiky Muhammad J. A. , Kim Tak H. , Brown Christopher L. , Yamauchi Yusuke , Cock Ian E.
Published: June 2020

Nanozymes are nanomaterials with intrinsic magnetism and superparamagnetic properties. In the presence of an external magnet, nanozyme particles aggregate and redisperse without a foreign attraction. We evaluated the performances of nanozyme by changing the biosensing platforms and substituting other biological variants for a complete cancer assay detection. We investigated the expression of morphological variants in the transmission of signals using an electrochemical method. The signal responses, including signal enhancement with the nanozyme (Au-Fe
2
O
3
), showed a wide capturing range (greater than 80%, from 10
2
to 10
5
cells ml
−1
in phosphate-buffered saline buffer, pH 7.4). The platform showed a fast response time within a dynamic range of 10–10
5
cells ml
−1
for the investigated T47D cancer cell line. We also obtained higher responses for anti-HER2 (human epidermal receptor 2)/streptavidin interface as the biosensing electrode in the presence of T47D cancer cells. The positive assay produced a sixfold increase in current output compared to the negative target or negative biological variant. We calculated the limit of detection at 0.4 U ml
−1
, and of quantitation at 4 U ml
−1
(units per millilitre). However, blood volume amounts in clinical settings may constrain diagnosis and increase detection limit value significantly.
Critical adsorption of multiple polyelectrolytes onto a nanosphere: splitting the adsorption–desorption transition boundary
Authors: Caetano Daniel L. Z. , de Carvalho Sidney J. , Metzler Ralf , Cherstvy Andrey G.
Published: June 2020

Employing extensive Monte Carlo computer simulations, we investigate in detail the properties of multichain adsorption of charged flexible polyelectrolytes (PEs) onto oppositely charged spherical nanoparticles (SNPs). We quantify the conditions of critical adsorption—the phase-separation curve between the adsorbed and desorbed states of the PEs—as a function of the SNP surface-charge density and the concentration of added salt. We study the degree of fluctuations of the PE–SNP electrostatic binding energy, which we use to quantify the emergence of the phase subtransitions, including a series of partially adsorbed PE configurations. We demonstrate how the phase-separation adsorption–desorption boundary shifts and splits into multiple subtransitions at low-salt conditions, thereby generalizing and extending the results for critical adsorption of a single PE onto the SNP. The current findings are relevant for finite concentrations of PEs around the attracting SNP, such as the conditions for PE adsorption onto globular proteins carrying opposite electric charges.
The reverse flight of a monarch butterfly (Danaus plexippus) is characterized by a weight-supporting upstroke and postural changes
Authors: Bode-Oke Ayodeji T. , Dong Haibo
Published: June 2020

Butterflies are agile fliers which use inactive and active upstrokes (US). The active US plays a secondary role to the downstroke (DS), generating both thrust and negative vertical force. However, whether their active halfstroke function is fixed or facultative has not been clarified. We showed that during multiple backward flights of an individual, postural adjustments via body angles greater than 90°, with pitch-down and pitch-up motions in the DS and US, respectively, reoriented the stroke plane and caused the reversal of the aerodynamic functions of the halfstrokes compared with forward flight. The US and DS primarily provided weight support and horizontal force, respectively, and a leading edge vortex (LEV) was formed in both halfstrokes. The US's LEV was a Class II LEV extending from wingtip to wingtip, previously reported albeit during the DS in forward flight. The US's net force contribution increased from 32% in forward to 60% in backward flight. Likewise, US weight support increased from 8 to 85%. Despite different trajectories, body postures and force orientations among flight sequences in the global frame, the halfstroke-average forces pointed in a uniform direction relative to the body in both forward and backward flight.
Predicting re-emergence times of dengue epidemics at low reproductive numbers: DENV1 in Rio de Janeiro, 1986–1990
Authors: Subramanian Rahul , Romeo-Aznar Victoria , Ionides Edward , Codeço Claudia T. , Pascual Mercedes
Published: June 2020

Predicting arbovirus re-emergence remains challenging in regions with limited off-season transmission and intermittent epidemics. Current mathematical models treat the depletion and replenishment of susceptible (non-immune) hosts as the principal drivers of re-emergence, based on established understanding of highly transmissible childhood diseases with frequent epidemics. We extend an analytical approach to determine the number of ‘skip’ years preceding re-emergence for diseases with continuous seasonal transmission, population growth and under-reporting. Re-emergence times are shown to be highly sensitive to small changes in low
R
0
(secondary cases produced from a primary infection in a fully susceptible population). We then fit a stochastic Susceptible–Infected–Recovered (SIR) model to observed case data for the emergence of dengue serotype DENV1 in Rio de Janeiro. This aggregated city-level model substantially over-estimates observed re-emergence times either in terms of skips or outbreak probability under forward simulation. The inability of susceptible depletion and replenishment to explain re-emergence under ‘well-mixed’ conditions at a city-wide scale demonstrates a key limitation of SIR aggregated models, including those applied to other arboviruses. The predictive uncertainty and high skip sensitivity to epidemiological parameters suggest a need to investigate the relevant spatial scales of susceptible depletion and the scaling of microscale transmission dynamics to formulate simpler models that apply at coarse resolutions.
Fresh Fish: Observation up Close in Late Seventeenth-Century England
Authors: van Trijp Didi
Published: June 2020

The traditional view of London's Royal Society as a closed circle has been subject to revision in the past decades. Historians have shown the considerable extent to which the Fellows of the Society drew on a broad range of men of practice for their respective skill sets. This article offers an in-depth analysis of the contributions of fishermen and fishmongers to the creation of natural knowledge. It centres on the
Historia piscium
(Oxford, 1686), written by Francis Willughby and John Ray, and its surrounding sources. This natural history of fishes aspired to give a concise and precise overview of species, and to uncover the divine order in which they were created. While men of practice contributed to this project in multiple ways, their first-hand observations carried particular weight. Through their cumulative experience of working with fish they saw a great number of living species, rather than the dried exemplars that naturalists would usually consult in cabinets of curiosities, or the indirect evidence that images might present. This article examines what kind of exchanges took place between fishermen and fishmongers on the one hand and Fellows on the other, and where, how and why these were incorporated into the fish book. In so doing, it also aims to qualify the value attached to direct (natural historical) observation in the socio-cultural context of late seventeenth-century England.
A DEAD BOX RNA helicase fromMedicago truncatulais hijacked by an RNA-binding effector from the root pathogenAphanomyces euteichesto facilitate host infection
Authors: Camborde L. , Kiselev A. , Pel M.J.C. , Leru A. , Jauneau A. , Pouzet C. , Dumas B. , Gaulin E.
Published: June 2020

Microbial effectors from plant pathogens are molecules that target host components to facilitate colonization. While eukaryotic pathogens are virtually able to produce hundreds of effectors, the molecular mechanisms allowing effectors to promote infection are still largely unexplored. Here we show that the effector AeSSP1256 from the soilborne oomycete pathogenAphanomyces euteichesis able to interact with plant RNA. Heterologous expression of AeSSP1256 delaysMedicago truncatulahost roots development and facilitate pathogen colonization. Transcriptomic analyses of AeSSP1256-expressing roots show a downregulation of genes implicated in ribosome biogenesis pathway. A yeast-two hybrid approach reveals that AeSSP1256 associates with a nucleolar L7 ribosomal protein and aM. truncatulaRNA helicase (MtRH10) orthologous to the Arabidopsis RNA helicase RH10. Association of AeSSP1256 with MtRH10 impaired the capacity of MtRH10 to bind nucleic acids. Promoter:GUS composite plants revealed that MtRH10 is expressed preferentially in the meristematic root cells. Missense MtRH10 plants displayed shorter roots with developmental delay and are more susceptible toA. euteichesinfection. These results show that the effector AeSSP1256 facilitates pathogen infection by causing stress on plant ribosome biogenesis and by hijacking a host RNA helicase involved in root development and resistance to root pathogens.
Intracranial recordings reveal ubiquitous in-phase and in-antiphase functional connectivity between homotopic brain regions in humans
Authors: O’Reilly Christian , Elsabbagh Mayada
Published: June 2020

Whether neuronal populations exhibit zero-lag (in-phase or in-antiphase) functional connectivity is a fundamental question when conceptualizing communication between cell assemblies. It also has profound implications on how we assess such interactions. Given that the brain is a delayed network due to the finite conduction velocity of the electrical impulses traveling across its fibers, the existence of long-distance zero-lag functional connectivity may be considered improbable. However, in this study, using human intracranial recordings we demonstrate that most interhemispheric connectivity between homotopic cerebral regions is zero-lagged and that this type of connectivity is ubiquitous. Volume conduction can be safely discarded as a confounding factor since it is known to drop almost completely within short inter-electrode distances (< 20 mm) in intracranial recordings. This finding should guide future electrophysiological connectivity studies and highlight the importance of considering the role of zero-lag connectivity in our understanding of communication between cell assemblies.

Significance statement

By analysing the functional connectivity between pairs of intracranial electrodes, we demonstrate that corresponding regions from the two cerebral hemispheres show oscillatory activity synchronized without any delay. Most often, these synchronized oscillations have an inverted amplitude, suggesting that the hemispheres inhibit one another in alternance. The existence of such synchronous activity between homotopic brain regions has important implications on how we understand communication between brain regions and on how we assess neuronal functional connectivity. Our results show that controlling the confounding effect of volume conduction by discarding instantaneous synchrony may result in missing important brain dynamics.

Graphical abstract

Graphical abstract text

Offset PLI and standard PLI (sensitive and insensitive to zero-lag connectivity, respectively) for pairs of electrodes separated by more than 105 mm, plotted against their homotopic distance. Significant connectivity (dots above the red dashed line) is found only between homotopic regions and mostly for zero-lag connectivity (offset-PLI).
Female reproductive tract has low concentration of SARS-CoV2 receptors
Authors: Goad Jyoti , Rudolph Joshua , Rajkovic Aleksandar
Published: June 2020

There has been significant concern regarding fertility and reproductive outcomes during the SARS-CoV2 pandemic. Recent data suggests a high concentration of SARS-Cov2 receptors,ACE2orTMPRSS2, in nasal epithelium and cornea, which explains person-to-person transmission. We investigated the prevalence of SARS-CoV2 receptors among reproductive tissues by exploring the single-cell sequencing datasets from uterus, myometrium, ovary, fallopian tube, and breast epithelium. We did not detect significant expression of eitherACE2orTMPRSS2in the normal human myometrium, uterus, ovaries, fallopian tube, or breast. Furthermore, none of the cell types in the female reproductive organs we investigated, showed the co-expression ofACE2with proteases,TMPRSS2, Cathepsin B (CTSB), and Cathepsin L (CTSL) known to facilitate the entry of SARS2-CoV2 into the host cell. These results suggest that myometrium, uterus, ovaries, fallopian tube, and breast are unlikely to be susceptible to infection by SARS-CoV2. Our findings suggest that COVID-19 is unlikely to contribute to pregnancy-related adverse outcomes such as preterm birth, transmission of COVID-19 through breast milk, oogenesis and female fertility.
Compassionate Use of Opaganib For Patients with Severe COVID-19
Authors: Kurd Ramzi , Ben-Chetrit Eli , Karameh Hani , Bar-Meir Maskit
Published: June 2020

Background

Opaganib is a selective sphingosine-kinase (SK)-2 inhibitor with anti-inflammatory and anti-viral properties.

Methods

We provided opaganib on a compassionate-use basis to patients with severe COVID-19. Patients who required oxygen support via high-flow nasal cannula (HFNC) were offered the treatment. For comparison, we used a control group with same-sex, same-severity patients.

Results

Seven patients received at least one dose of opaganib since April 2, 2020. One patient, who received both hydroxychloroquine and azithromycin, developed diarrhea and all his medications were stopped. This was the only adverse effect possibly related to opaganib. A second patient was weaned of oxygen and discharged after receiving two doses of opaganib. Therefore, five patients were included in this analysis. Baseline characteristics were not significantly different between cases and controls. Patients treated with opaganib had significantly faster increase in lymphocyte count. All other clinical outcomes had a non-statistically significant trend in favor of the treatment group: median time to weaning from HFNC was 10 and 15 days in cases vs. controls (HR= 0.3, 95% CI: 0.07-1.7, p=0.2), time to ambient air was 13 vs.14.5 days (HR=0.4, 95% CI: 0.15-1.5), none of the cases required mechanical ventilation compared with 33% of controls.

Conclusion

In this small cohort of severe COVID-19 patients, opaganib was safe and well tolerated with improvement in both clinical and laboratory parameters in all treated patients. The efficacy of opaganib for COVID-19 infection should be further tested in randomized placebo-controlled trials.
Distinct antibody repertoires against endemic human coronaviruses in children and adults
Authors: Khan Taushif , Rahman Mahbuba , Ali Fatima Al , Huang Susie S. Y. , Ata Manar , Zhang Qian , Bastard Paul , Liu Zhiyong , Jouanguy Emmanuelle , Béziat Vivien , Cobat Aurélie , Nasrallah Gheyath K. , Yassine Hadi , Smatti Maria , Sayeed Amira , Vandernoot Isabelle , Goffard Jean-Christophe , Smits Guillaume , Migeotte Isabelle , Haerynck Filomeen , Meyts Isabelle , Abel Laurent , Casanova Jean-Laurent , Hasan Mohammad R. , Marr Nico
Published: June 2020

Four endemic human coronaviruses (HCoVs) are commonly associated with acute respiratory infection in humans. B cell responses to these “common cold” viruses remain incompletely understood. Here we report a comprehensive analysis of CoV-specific antibody repertoires in 231 children and 1168 adults using phage-immunoprecipitation sequencing. Seroprevalence of antibodies to endemic HCoVs ranged between ~4 and 27% depending on the species and cohort. We identified at least 136 novel linear B cell epitopes. Antibody repertoires against endemic HCoVs were qualitatively different between children and adults in that anti-HCoV IgG specificities more frequently found among children targeted functionally important and structurally conserved regions of the spike, nucleocapsid and matrix proteins. Moreover, antibody specificities targeting the highly conserved fusion peptide region and S2’ cleavage site of the spike protein were broadly cross-reactive with peptides of epidemic human and non-human coronaviruses. In contrast, an acidic tandem repeat in the N-terminal region of the Nsp3 subdomain of the HCoV-HKU1 polyprotein was the predominant target of antibody responses in adult donors. Our findings shed light on the dominant species-specific and pan-CoV target sites of human antibody responses to coronavirus infection, thereby providing important insights for the development of prophylactic or therapeutic monoclonal antibodies and vaccine design.
New insights on the interaction mechanism of rhTNFα with its antagonists Adalimumab and Etanercept
Authors: Contreras María Angélica , Macaya Luis , Neira Pedro , Camacho Frank , González Alaín , Acosta Jannel , Montesino Raquel , Toledo Jorge Roberto , Sánchez Oliberto
Published: June 2020

TNFα is a pro-inflammatory cytokine that is a therapeutic target for inflammatory autoimmune disorders. Thus, TNFα antagonists are successfully used for the treatment of these disorders. Here, new association patterns of rhTNFα and its antagonists Adalimumab and Etanercept are disclosed. Active rhTNFα was purified by IMAC from the soluble fraction of transformedE. coli.Protein detection was assessed by SDS-PAGE and western blot. The KDvalues for rhTNFα interactions with their antagonists were obtained by non-competitive ELISA and by microscale thermophoresis. Molecular sizes of the complexes were characterized by SEC-HPLC. Surprisingly, both antagonists recognized the monomeric form of rhTNFα under reducing and non-reducing conditions, indicating unexpected bindings of the antagonists to lineal epitopes and to one protomer of rhTNFα. Binding curves of two phases with low and high KDvalues (<10−9M and >10−8M) were observed during thermophoresis experiments, suggesting the generation of complexes with different stoichiometry, which were confirmed by SEC-HPLC. This pioneer investigation revealed interactions of rhTNFα with Adalimumab and Etanercept never described before, which constitute valuable data for future approaches into the study of their interaction mechanism.
3d Virtual Pathohistology of Lung Tissue from Covid-19 Patients based on Phase Contrast X-ray Tomography
Authors: Eckermann M. , Frohn J. , Reichardt M. , Osterhoff M. , Sprung M. , Westermeier F. , Tzankov A. , Werlein C. , Kühnel M. , Jonigk D. , Salditt T.
Published: June 2020

We present a new approach of three-dimensional (3d) virtual histology and histopathology based on multi-scale phase contrast x-ray tomography, and use this to investigate the parenchymal architecture of unstained lung tissue from patients who succumbed to Covid-19. Based on this first proof-of-concept study, we propose multi-scale phase contrast x-ray tomography as a novel tool to unravel the pathophysiology of Covid-19, extending conventional histology by a third dimension and allowing for full quantification of tissue remodeling. By combining parallel and cone beam geometry, autopsy samples with a maximum cross section of 4 mm are scanned and reconstructed at a resolution and image quality which allows for the segmentation of individual cells. Using the zoom capability of the cone beam geometry, regions-of-interest are reconstructed with a minimum voxel size of 167 nm. We exemplify the capability of this approach by 3d visualisation of the diffuse alveolar damage with its prominent hyaline membrane formation, by mapping the 3d distribution and density of lymphocytes infiltrating the tissue, and by providing histograms of characteristic distances from tissue interior to the closest air compartment.
Bayesian approach for modelling the dynamic of COVID-19 outbreak on the Diamond Princess Cruise Ship
Authors: Lai Chao-Chih , Hsu Chen-Yang , Jen Hsiao-Hsuan , Yen Amy Ming-Fang , Chan Chang-Chuan , Chen Hsiu-Hsi
Published: June 2020

The outbreaks of acute respiratory infectious disease with high attack rates on cruise ships were rarely studied. The outbreak of COVID-19 on the Diamond Princess Cruise Ship provides an unprecedented opportunity to estimate its original transmissibility with basic reproductive number (R0) and the effectiveness of containment measures. The traditional deterministic approach for estimating R0 is based on the outbreak of a large population size rather than that a small cohort of cruise ship. The parameters are therefore fraught with uncertainty. To tackle this problem, we developed a Bayesian Susceptible-Exposed-Infected-Recovery (SEIR) model with ordinary differential equation (ODE) to estimate three parameters, including transmission coefficients, the latent period, and the recovery rate given the uncertainty implicated the outbreak of COVID-19 on cruise ship with modest population size. Based on the estimated results on these three parameters before the introduction of partial containment measures, the natural epidemic curve after intervention was predicted and compared with the observed curve in order to assess the efficacy of containment measures. With the application of the Bayesian model to the empirical data on COVID-19 outbreak on the Diamond Princess Cruise Ship, the R0 was estimated as high as 5.71(95% credible interval: 4.08-7.55) because of its aerosols and fomite transmission mode. The simulated trajectory shows the entire epidemic period without containment measurements was approximately 47 days and reached the peak one month later after the index case. The partial containment measure reduced 34% (95% credible interval: 31-36%) infected passengers. Such a discovery provides an insight into timely evacuation and early isolation and quarantine with decontamination for containing other cruise ships and warship outbreaks.
Chest X-ray classification using Deep learning for automated COVID-19 screening
Authors: Shelke Ankita , Inamdar Madhura , Shah Vruddhi , Tiwari Amanshu , Hussain Aafiya , Chafekar Talha , Mehendale Ninad
Published: June 2020

In today’s world, we find ourselves struggling to fight one of the worst pandemics in the history of humanity known as COVID-2019 caused by a coronavirus. If we detect the virus at an early stage (before it enters the lower respiratory tract), the patient can be treated quickly. Once the virus reaches the lungs, we observe ground-glass opacity in the chest X-ray due to fibrosis in the lungs. Due to the significant differences between X-ray images of an infected and non-infected person, artificial intelligence techniques can be used to identify the presence and severity of the infection. We propose a classification model that can analyze the chest X-rays and help in the accurate diagnosis of COVID-19. Our methodology classifies the chest X-rays into 4 classes viz. normal, pneumonia, tuberculosis (TB), and COVID-19. Further, the X-rays indicating COVID-19 are classified on severity-basis into mild, medium, and severe. The deep learning model used for the classification of pneumonia, TB, and normal is VGG16 with an accuracy of 95.9 %. For the segregation of normal pneumonia and COVID-19, the DenseNet-161 was used with an accuracy of 98.9 %. ResNet-18 worked best for severity classification achieving accuracy up to 76 %. Our approach allows mass screening of the people using X-rays as a primary validation for COVID-19.
LONGITUDINAL OVARIAN RESERVE CHANGES IN WOMEN WITH BREAST CANCER RECEIVING ADJUVANT CHEMOTHERAPY OR TAMOXIFEN-ALONE
Authors: Goldfarb Shari B , Turan Volkan , Bedoschi Giuliano , Taylan Enes , Abdo Nadia , Cigler Tessa , Bang Heejung , Patil Sujita , Dickler Maura N , Oktay Kutluk H
Published: June 2020

Background

To determine the longitudinal impact of adjuvant chemotherapy and tamoxifen-only treatments on ovarian reserve by serum anti-Mullerian hormone (AMH) levels in women with breast cancer.

Methods

One-hundred-and-forty-two women with a primary diagnosis of breast cancer were prospectively followed with serum AMH assessments before the initiation, and 12, 18 and 24 months after the completion of adjuvant chemotherapy or the start of tamoxifen-only treatment. The chemotherapy regimens were classified into Anthracycline-Cyclophosphamide-based (AC-based) and Cyclophosphamide-Methotrexate+5-Fluorouracil (CMF). Longitudinal data were analyzed by mixed effects model for treatment effects over time, adjusting for baseline age and BMI.

Results

Both chemotherapy regimens resulted in significant decline in ovarian reserve compared to the tamoxifen-only treatment (p<0.0001 either regimen vs. tamoxifen for overall trend). AMH levels sharply declined at 12 months but did not show a significant recovery from 12 to 18 and 18 to 24 months after the completion of AC-based or CMF regimens. The degree of decline did not differ between the two chemotherapy groups (p=0.53). In contrast, tamoxifen-only treatment did not significantly alter the age-adjusted serum AMH levels over the 24-month follow up. Likewise, the use of adjuvant tamoxifen following AC-based regimens did not affect AMH recovery.

Conclusions

Both AC-based and CMF regimens significantly compromise ovarian reserve, which does not recover during the 12-24-month post-chemotherapy follow up. In contrast, tamoxifen treatment does not seem to alter ovarian reserve. This novel information should be valuable for fertility preservation counselling and in assessing future reproductive potential of breast cancer survivors.
Derivation and Validation of Clinical Prediction Rule for COVID-19 Mortality in Ontario, Canada
Authors: Fisman David N. , Greer Amy L. , Tuite Ashleigh R.
Published: June 2020

Background

SARS-CoV-2 is currently causing a high mortality global pandemic. However, the clinical spectrum of disease caused by this virus is broad, ranging from asymptomatic infection to cytokine storm with organ failure and death. Risk stratification of individuals with COVID-19 would be desirable for management, prioritization for trial enrollment, and risk stratification. We sought to develop a prediction rule for mortality due to COVID-19 in individuals with diagnosed infection in Ontario, Canada.

Methods

Data from Ontario’s provincial iPHIS system were extracted for the period from January 23 to May 15, 2020. Both logistic regression-based prediction rules, and a rule derived using a Cox proportional hazards model, were developed in half the study and validated in remaining patients. Sensitivity analyses were performed with varying approaches to missing data.

Results

21,922 COVID-19 cases were reported. Individuals assigned to the derivation and validation sets were broadly similar. Age and comorbidities (notably diabetes, renal disease and immune compromise) were strong predictors of mortality. Four point-based prediction rules were derived (base case, smoking excluded as a predictor, long-term care excluded as a predictor, and Cox model based). All rules displayed excellent discrimination (AUC for all rules > 0.92) and calibration (both by graphical inspection and P > 0.50 by Hosmer-Lemeshow test) in the derivation set. All rules performed well in the validation set and were robust to random replacement of missing variables, and to the assumption that missing variables indicated absence of the comorbidity or characteristic in question.

Conclusions

We were able to use a public health case-management data system to derive and internally validate four accurate, well-calibrated and robust clinical prediction rules for COVID-19 mortality in Ontario, Canada. While these rules need external validation, they may be a useful tool for clinical management, risk stratification, and clinical trials.
Quantifying Costs of Urbanisation: Wetland Loss and Impacts in a Rapidly Developing Global City
Authors: Gabites Harriet , Spencer Ricky-John
Published: June 2020

As cities grow, natural ecosystems decline through conversion to urban environments. Cities are often viewed as biodiversity wastelands, but they can be hotspots of global biodiversity. Urban biodiversity emphasises two fundamentals. First, people living in cities enjoy wildlife and second, there is virtually no planning for species that co-inhabit our cities. If urban biodiversity was a significant part of planning, then we would be far better at integrating green infrastructure into expanding urban environments.

Wetlands are among the most important and productive ecosystems in the world. They are the main suppliers of fresh water for human use and provide habitat to critical fauna and flora. In urban areas they are a vital link to nature and social cohesion. Currently, there is an absence of wetland inventory quantifying loss and changes overtime. Hence the broad impacts of urbanisation on wetland loss are difficult to assess.

We explored wetland loss and created a wetland inventory for Western Sydney, Australia, one of the world’s fastest growing urban regions. We used satellite imagery to determine wetland number and type, and calculated changes in wetland surface area from 2010-2017. Broad changes to land use were also quantified. We developed species distribution models of a common urban wetland turtle (Chelodina longicollis) that people interact with regularly or have as pets.Chelodina longicollisutilises both aquatic and terrestrial environments, and we determined if changes in distribution were associated with changes in the wetland inventory and urbanisation.

Most local government areas (LGA) experienced a decrease in wetland surface area from 2010-2017, ranging from -1% (Cumberland) to -21% (Blacktown). Majority of LGAs experienced a decrease in wetland density, with wetland densities declining by 25% (Blacktown). All LGAs experienced an increase in urban land use, ranging from 3-12%, which was associated with high rates of wetland loss.

Changes in turtle distribution over the decade reflects a southern distribution shift away from where wetland losses were concentrated. We estimated that ∼40,000 individual turtles were displaced or killed due to wetland loss and urbanisation.

Urbanisation was the leading cause of wetland loss and degradation in Western Sydney between 2010 and 2017. Wetlands provide critical green infrastructure and significant green space for social cohesion in urban areas. Integration of current wetlands, or the creation of functional wetlands, is key for sustainable development of urban landscapes. Urban wetlands (natural and constructed) may provide “biodiversity arks” for endangered species and facilitate community led conservation programs.
Monitoring the collective behavior of enzymatic nanomotors in vitro and in vivo by PET-CT
Authors: Hortelao Ana C. , Simó Cristina , Guix Maria , Guallar-Garrido Sandra , Julián Esther , Vilela Diana , Rejc Luka , Ramos-Cabrer Pedro , Cossío Unai , Gómez-Vallejo Vanessa , Patiño Tania , Llop Jordi , Sánchez Samuel
Published: June 2020

Enzyme powered nanomotors hold great potential for biomedical applications, as they show improved diffusion and navigation within biological environments using endogenous fuels. Yet, understanding their collective behavior and tracking themin vivois paramount for their clinical translation. Here, we report on thein vitroandin vivostudy of swarms of self-propelled enzyme-nanomotors and the effect of collective behavior on the nanomotors distribution within the bladder. For that purpose, mesoporous silica nanomotors were functionalized with urease enzymes and gold nanoparticles. Two radiolabeling strategies, i.e. absorption of124I on gold nanoparticles and covalent attachment of an18F-labeled prosthetic group to urease, were assayed.In vitroexperiments using optical microscopy and positron emission tomography (PET) showed enhanced fluid mixing and collective migration of nanomotors in phantoms containing complex paths. Biodistribution studies after intravenous administration in mice confirmed the biocompatibility of the nanomotors at the administered dose, the suitability of PET to quantitatively track nanomotorsin vivo, and the convenience of the18F-labeling strategy. Furthermore, intravesical instillation of nanomotors within the bladder in the presence of urea resulted in a homogenous distribution after the entrance of fresh urine. Control experiments using BSA-coated nanoparticles or nanomotors in water resulted in sustained phase separation inside the bladder, demonstrating that the catalytic decomposition of urea can provide urease-nanomotors with active motion, convection and mixing capabilities in living reservoirs. This active collective dynamics, together with the medical imaging tracking, constitutes a key milestone and a step forward in the field of biomedical nanorobotics, paving the way towards their use in theranostic applications.
Composite modeling of leaf shape across shoots discriminatesVitisspecies better than individual leaves
Authors: Bryson Abigail E. , Brown Maya Wilson , Mullins Joey , Dong Wei , Bahmani Keivan , Bornowski Nolan , Chiu Christina , Engelgau Philip , Gettings Bethany , Gomezcano Fabio , Gregory Luke M. , Haber Anna C. , Hoh Donghee , Jennings Emily E. , Ji Zhongjie , Kaur Prabhjot , Raju Sunil K. Kenchanmane , Long Yunfei , Lotreck Serena G. , Mathieu Davis T. , Ranaweera Thilanka , Ritter Eleanore J. , Sadohara Rie , Shrote Robert Z. , Smith Kaila E. , Teresi Scott J. , Venegas Julian , Wang Hao , Wilson McKena L. , Tarrant Alyssa R. , Frank Margaret H. , Migicovsky Zoë , Kumar Jyothi , VanBuren Robert , Londo Jason P. , Chitwood Daniel H.
Published: June 2020

Premise of study

Leaf morphology is dynamic, continuously deforming during leaf expansion and among leaves within a shoot. We measured leaf morphology from over 200 vines over four years, and modeled changes in leaf shape along the shoot to determine if a composite “shape of shapes” can better capture variation and predict species identity compared to individual leaves.

Methods

Using homologous universal landmarks found in grapevine leaves, we modeled various morphological features as a polynomial function of leaf node. The resulting functions are used to reconstruct modeled leaf shapes across shoots, generating composite leaves that comprehensively capture the spectrum of possible leaf morphologies.

Results

We found that composite leaves are better predictors of species identity than individual leaves from the same plant. We were able to use composite leaves to predict species identity of previously unassigned vines, which were verified with genotyping.

Discussion

Observations of individual leaf shape fail to capture the true diversity between species. Composite leaf shape—an assemblage of modeled leaf snapshots across the shoot—is a better representation of the dynamic and essential shapes of leaves, as well as serving as a better predictor of species identity than individual leaves.
Global analysis of a cancer model with drug resistance due to Lamarckian induction and microvesicle transfer
Authors: Dénes Attila , Röst Gergely
Published: June 2020

Development of resistance to chemotherapy in cancer patients strongly effects the outcome of the treatment. Due to chemotherapeutic agents, resistance can emerge by Darwinian evolution. Besides this, acquired drug resistance may arise via changes in gene expression. A recent discovery in cancer research uncovered a third possibility, indicating that this phenotype conversion can occur through the transfer of microvesicles from resistant to sensitive cells, a mechanism resembling the spread of an infectious agent. We present a model describing the evolution of sensitive and resistant tumour cells considering Darwinian selection, Lamarckian induction and microvesicle transfer. We identify three threshold parameters which determine the existence and stability of the three possible equilibria. Using a simple Dulac function, we give a complete description of the dynamics of the model depending on the three threshold parameters. We demonstrate the possible effects of increasing drug concentration, and characterize the possible bifurcation sequences. Our results show that the presence of microvesicle transfer cannot ruin a therapy that otherwise leads to extinction, however it may doom a partially successful therapy to failure.
Keratins couple with the nuclear lamina and regulate proliferation in colonic epithelial cells
Authors: Stenvall Carl-Gustaf A. , Nyström Joel H. , Butler-Hallissey Ciarán , Adam Stephen A. , Foisner Roland , Ridge Karen M. , Goldman Robert D. , Toivola Diana M.
Published: June 2020

Keratin intermediate filaments (IFs) convey mechanical stability and protection against stress to epithelial cells, and may participate in nuclear structure and organization. Keratins are important for colon health as observed in keratin 8 knockout (K8−/−) mice, which exhibit colonic inflammation and epithelial hyperproliferation. Here, using a full body and two intestinal epithelial-specific K8−/−knockout mouse models, we determine if cytoplasmic keratins affect the nuclear structure and lamina in epithelial colonocytes. K8−/−colonocytes in vivo and in organoid cultures exhibit significantly decreased levels of the major lamins A/C, B1 and B2 in a colon-specific and cell-intrinsic manner independent of major changes in colonic inflammation or microbiota. Downregulation of K8 by siRNA in Caco-2 cells similarly decreases lamin A levels, which recover after re-expression of K8. K8 loss is associated with reduced plectin, LINC complex proteins and lamin-associated proteins, indicating a dysfunctional keratin-nuclear lamina coupling. Immunoprecipitation identifies complexes of colonocyte keratins with the LINC protein SUN2 and lamin A. Hyperphosphorylation of the lamin A-associated cell cycle regulator pRb in K8−/−colonocytes together with increased nuclear localization of the mechanosensor YAP provide a molecular mechanism for the hyperproliferation phenotype. These findings identify a novel, colonocyte-specific role for K8 in nuclear function.
Evaluation ofstaA,viaBandsopEgenes inSalmonelladetection using conventional polymerase chain reaction (PCR)
Authors: Kariuki Francis , Getanda Pauline , Nyachieo Atunga , Juma Gerald , Kinyanjui Peter , Kamau Joseph
Published: June 2020

Typhoid fever is caused by the bacteriaSalmonella entericasubspeciesentericaserovar Typhi (S. Typhi) and remains a significant health problem in many developing countries. The lack of adequate diagnostic capabilities in these poor resource settings have contributed greatly in making typhoid fever endemic in these regions. Reliable and inexpensive diagnostic tests are needed to improve the management of this disease burden. This study evaluated the ability ofstaA, viaBandsopEgenes to detectSalmonellaspp. Conventional polymerase chain reaction (PCR) amplification ofstaA,viaBandsopEgenes ofSalmonellawas used to detect and differentiate between the three most prevalentSalmonellaspp. in Kenya (S. Typhi,S.Typhimurium andS.Enteritidis). ThestaAprimers (StaA-Forward / StaA-Reverse) andviaBprimers (vi-Forward / vi-Reverse) were found to be specific only for the different strains ofS. Typhi, producing PCR products of 585 bp and 540 bp respectively. No amplification was observed withS.Typhimurium,S.Enteritidis,E. coli andS. boydii bacterial strains. ThesopEprimers (SopE-Forward / SopE-Reverse) was demonstrated to be specific for allSalmonellaspp. producing a 465 bp PCR product with no amplification observed with theE. coli andS. boydii bacterial strains. Conventional PCR using thesestaAandviaBprimers for detection ofS. Typhi shows great potential for diagnosis of typhoid fever however, further studies need to be carried out with actual food samples and human samples (blood, stool or saliva) to determine the effectiveness of this method in the detection of common Salmonella spp. in Kenya.

Author summary

Typhoid fever is a severe disease caused by the bacteriaSalmonellaTyphi (S. Typhi) and is a significant health problem in many developing countries. The lack of adequate diagnostic capabilities in poor resource settings common in most public health facilities in Kenya and Africa in general, hinder prompt diagnosis of typhoid fever. Currently, the available diagnostic tests are often expensive and more so not readily available in most resource poor endemic areas. This has often led to misdiagnosis of the disease, thereby delaying appropriate treatment and making typhoid fever widespread in most resource poor areas. This study examines the ability of three different genes to detect and differentiate between the three most prevalentSalmonellastrains in Kenya using a readily available and widely used genetic test known as conventional polymerase chain reaction (PCR). This research found thatstaAandviaBgenes were specific only forS. Typhi, while thesopEgene was specific for allSalmonellastrains. Consequently, conventional PCR using thesestaAandviaBgenes for detection ofS. Typhi shows great potential to be used as a readily available diagnostic tool to detect the presence of theS. Typhi organism in individuals or foods sample in Kenya.
MYC regulates ribosome biogenesis and mitochondrial gene expression programs through interaction with Host Cell Factor-1
Authors: Popay Tessa M. , Wang Jing , Adams Clare M. , Codreanu Simona G. , Sherrod Stacy , McClean John A. , Thomas Lance R. , Lorey Shelly L. , Machida Yuichi J. , Weissmiller April M. , Eischen Christine M. , Liu Qi , Tansey William. P.
Published: June 2020

The oncoprotein transcription factor MYC is a major driver of malignancy and a highly-validated but challenging target for development of anti-cancer therapies. Novel strategies to inhibit MYC may come from understanding the co-factors it uses to drive pro-tumorigenic gene expression programs, providing their role in MYC activity is understood. Here, we interrogate how one MYC co-factor, Host Cell Factor (HCF)-1, contributes to MYC activity in a Burkitt lymphoma setting. We identify genes connected to mitochondrial function and ribosome biogenesis as direct MYC/HCF-1 targets, and demonstrate how modulation of the MYC–HCF-1 interaction influences cell growth, metabolite profiles, global gene expression patterns, and tumor growthin vivo. This work defines HCF-1 as a critical MYC co-factor, places the MYC–HCF-1 interaction in biological context, and highlights HCF-1 as a focal point for development of novel anti-MYC therapies.
Somatotopic Arrangement of Eight Distinct Skin Areas in the Human Primary Somatosensory Cortex Derived from Functional Magnetic Resonance Imaging
Authors: Willoughby W. R. , Thoenes Kristina , Bolding Mark
Published: June 2020

Abstract

Blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to investigate cortical activity associated with peripheral tactile stimuli in a small cohort of healthy humans. MR-safe automated pneumatic stimulators modeled after the Wartenberg pinwheel were used to generate tactile stimuli at regular intervals on eight disparate areas of skin. The phase-encoded BOLD responses of voxels in the cerebral cortex were characterized by the maximal normalized cross-correlation coefficients at time delays between an idealized response and the measure time course. Overall at the group level, the somatotopic organization of the somatosensory cortex (SI) follows the accepted homunculus model, but a noticeable amount of variation was observed between individual study participants. The surface areas of cortical regions in SI activated by tactile stimulation of different body parts were calculated, giving an estimate of cortical magnification factors. Data collected with the participant actively attending the stimuli were compared to data collected before the attention task. No significant attention-related changes were observed in the somatotopic maps or in time courses of voxels well-correlated to stimuli.
Three-dimensional morphodynamics simulations of macropinocytic cups
Authors: Saito Nen , Sawai Satoshi
Published: June 2020

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Macropinocytosis is non-specific uptake of the extracellular fluid playing ubiquitous roles in cell growth, immune-surveillance as well as virus entry. Despite its widespread occurrence, it remains unclear how its initial cup-shaped plasma membrane extensions forms without external physical support as in phagocytosis or curvature inducing proteins as in clathrin-mediated endocytosis. Here, by developing a novel computational framework that describes the coupling between bistable reaction-diffusion processes of active signaling patches and membrane deformation, we demonstrate that protrusive force localized to the edge of the patches can give rise to the self-enclosing cup structure without further assumption of local bending or contraction. Efficient uptake requires an appropriate balance between the patch size and the magnitude of protrusive force relative to the cortical tension. Furthermore, our model exhibits a variety of known morphology dynamics including cyclic cup formation, coexistence and competition between multiple cups and cup splitting indicating that these complex morphologies self-organize through mutually dependent dynamics between the reaction-diffusion process and membrane deformation.
A dual role for H2A.Z.1 in modulating the dynamics of RNA Polymerase II initiation and elongation
Authors: Mylonas Constantine , Auld Alexander L. , Lee Choongman , Cisse Ibrahim I. , Boyer Laurie A.
Published: June 2020

RNAPII pausing immediately downstream of the transcription start site (TSS) is a critical rate limiting step at most metazoan genes that allows fine-tuning of gene expression in response to diverse signals1–5. During pause-release, RNA Polymerase II (RNAPII) encounters an H2A.Z.1 nucleosome6–8, yet how this variant contributes to transcription is poorly understood. Here, we use high resolution genomic approaches2,9(NET-seq and ChIP-nexus) along with live cell super-resolution microscopy (tcPALM)10to investigate the role of H2A.Z.1 on RNAPII dynamics in embryonic stem cells (ESCs). Using a rapid, inducible protein degron system11combined with transcriptional initiation and elongation inhibitors, our quantitative analysis shows that H2A.Z.1 slows the release of RNAPII, impacting both RNAPII and NELF dynamics at a single molecule level. We also find that H2A.Z.1 loss has a dramatic impact on nascent transcription at stably paused, signal-dependent genes. Furthermore, we demonstrate that H2A.Z.1 inhibits re-assembly and re-initiation of the PIC to reinforce the paused state and acts as a strong additional pause signal at stably paused genes. Together, our study suggests that H2A.Z.1 fine-tunes gene expression by regulating RNAPII kinetics in mammalian cells.