bluuebunny/crossref_metadata_2025 huggingface dataset:
Apnea Testing Using Continuous Positive Airway Pressure When Determining Death by Neurologic Criteria in Children: Retrospective Analysis of Potential Adverse Events*
Authors: Puccetti Deirdre F. , Morrison Wynne , Francoeur Conall , Mai Mark , Kirschen Matthew P.
Published: July 2020

Objectives:

To determine the prevalence of adverse events during apnea testing for determination of death by neurologic criteria using continuous positive airway pressure in children.

Design:

Single-center retrospective descriptive study.

Setting:

Academic children’s hospital.

Patients:

Children evaluated for death by neurologic criteria in the PICU from 2013 to 2018.

Interventions:

None.

Measurements and Main Results:

For each patient evaluated for death by neurologic criteria, we abstracted the number of apnea tests performed, vital signs and arterial blood gases during apnea testing, and outcome from the medical record. Adverse events were defined as oxygen-hemoglobin desaturation (arterial oxygen saturation < 85%), hypotension, or other significant event (e.g. arrhythmia, cardiac arrest) based on documentation in the medical record. We determined which adverse events resulted in early termination of the apnea test. We used oxygenation index, ventilator variables, and presence of vasopressors to determine preapnea test cardiopulmonary dysfunction. Seventy-two patients (age 7 yr [2.7–13.2 yr]; 48% male) underwent 121 apnea tests. Nine patients (12%) had 13 potential apnea tests deferred due to concern for cardiopulmonary instability as determined by the attending physician. Patients who underwent apnea testing had an oxygenation index of 3.5 (2.5–4.8) and were receiving vasopressors at the time of 108 apnea tests (89%). Hypotension was reported during seven apnea tests (6%) and resulted in the early termination of one apnea test (<1%). No other adverse events were reported. One hundred and twenty apnea tests (99%) were consistent with death by neurologic criteria.

Conclusions:

Apnea testing following a protocol that uses continuous positive airway pressure for apneic oxygenation has a low rate of adverse events in children meeting prerequisite criteria and determined by a pediatric intensivist to be physiologically appropriate for testing.
Association Between Elevated RBC Distribution Width and Multiple Organ Dysfunction in Pediatric Critical Illness
Authors: Matehuala Sonia , Pasala Sanjiv , Goudie Anthony , Fiser Richard , Weiss Scott , Irby Katherine , Crary Shelley , Wang Angela , Sanders Ronald
Published: July 2020

Objectives:

RBC distribution width, a part of the complete blood count, has been shown in several published studies to be a strong biomarker of adverse outcomes. We sought to determine the association between admission RBC distribution width value and clinical outcomes including multiple organ dysfunction, mechanical ventilation days, PICU length of stay, and hospital length of stay in children admitted to the PICU.

Design:

Single center, retrospective study.

Setting:

A tertiary pediatric hospital in the United States.

Patients:

All subjects admitted to the PICU from 2016 to 2017. Exclusions: Greater than 21 years old, pregnancy, and history of packed RBC transfusion within 120 days prior to admission.

Interventions:

None.

Measurements and Main Results:

One-thousand five-hundred one subjects were screened and 856 were included in data analysis. RBC distribution width value was categorized into four separate groups: group I (RBC distribution width < 13.4%), group II (13.4–14.3%), group III (14.4–15.7%), and group IV (RBC distribution width > 15.7%). Increased RBC distribution width at admission was associated with multiple organ dysfunction syndrome in the first 7 days (group I = 11.8% vs group IV = 30.1%; p < 0.0001) (odds ratio, 3.22; 95% CI, 1.95–5.30; p < 0.0001). Increased RBC distribution width was associated with increased median mechanical ventilation duration (group IV = 7 d vs group I = 5 d; p = 0.001), median hospital length of stay (group IV = 13 d vs group I = 5 d; p < 0.0001), and median PICU length of stay (group IV = 4 d vs group I = 3 d; p = 0.01). Mortality was not statistically associated with admission RBC distribution width (p = 0.12).

Conclusions:

PICU admission RBC distribution width values greater than 15.7% obtained upon admission to the PICU in patients who have not received a RBC transfusion are associated with multiple organ dysfunction syndrome in the first 7 days of admission, increased duration of mechanical ventilation, and increased hospital length of stay.
Age-Specific Risk Scores Do Not Improve HIV-1 Prediction Among Women in South Africa
Authors: Peebles Kathryn , Palanee-Phillips Thesla , Balkus Jennifer E. , Beesham Ivana , Makkan Heeran , Deese Jennifer , Smit Jennifer , Heffron Renee , Morrison Charles S. , Philip Neena M. , Malahleha Mookho , Kasaro Margaret , Naidoo Yuthika , Nielson Tanya , Reddy Krishnaveni , Kotze Philip , Ahmed Khatija , Rees Helen , Baeten Jared M. , Barnabas Ruanne V. ,   for the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium
Published: July 2020

Background:

HIV-1 risk scoring tools could help target provision of prevention modalities such as pre-exposure prophylaxis. Recent research suggests that risk scores for women aged 18–45 may not predict risk well among young women aged 18–24. We evaluated the predictive performance of age-specific risk scores compared with the existing non–age-specific VOICE risk score, developed for women aged 18–45.

Methods:

We conducted a secondary analysis of the Evidence for Contraceptive Options and HIV Outcomes Trial to develop and internally validate HIV-1 risk scores for women aged 18–24 and 25–35 in South Africa. Candidate predictors included baseline demographic, clinical, behavioral, and contextual characteristics readily available in clinical settings. The VOICE risk score was applied to women aged 18–35. We evaluated predictive performance of each risk score by area under the receiver operating characteristic curve (AUC).

Results:

Predictive performance of all risk scores was moderate, with AUC (95% confidence interval) of 0.64 (0.60 to 0.67) among women aged 18–24, 0.68 (0.62 to 0.73) among those aged 25–35, and 0.61 (0.58 to 0.65) for the VOICE risk score applied to women aged 18–35; The AUC was similar in internal validation. Among women aged 18–24, HIV-1 incidence was high even at low risk scores, at 3.9 per 100 person-years (95% confidence interval: 3.2 to 4.7).

Conclusions:

All risk scores were moderately predictive of HIV-1 acquisition, and age-specific risk scores performed only marginally better than the VOICE non–age-specific risk score. Approaches for targeted pre-exposure prophylaxis provision to women in South Africa may require more extensive data than are currently available to improve prediction.
Sir Anthony Seymour Laughton. 29 April 1927—27 September 2019
Authors: Searle Roger C.
Published: July 2020

Anthony (Tony) Laughton was an oceanographer who promoted the science of oceanograpy in Britain. Focusing on the shape of the seafloor, his work included underwater photography, ocean drilling, long-range side-scan sonar and scientific charting of the ocean floor. Following undergraduate studies at King's College, Cambridge, he joined Maurice Hill (FRS 1962) at the Cambridge Department of Geodesy and Geophysics, beginning a career in marine geophysics. Following his PhD, he spent a year at Lamont Geological Observatory, USA, where he met many leading US workers, and became interested in deep-seafloor photography and bathymetric mapping. Returning to the UK, he joined the National Institute of Oceanography (Institute of Oceanographic Sciences from 1973) at Wormley, Surrey, and became director in 1978. He developed the first UK seafloor camera, was an enthusiastic supporter and user of the revolutionary Precision Echo Sounder and later of the GLORIA long-range side-scan sonar. He played a significant part in the International Indian Ocean Expedition, subsequently developing a new understanding of the Gulf of Aden. A consummate committee man, he had a vital role in reviving the General Bathymetric Chart of the Oceans and promoted UK involvement in the international Deep-Sea Drilling Project. He was an accomplished amateur musician (playing French horn), small-boat sailor and handyman.
Reconciling early-outbreak estimates of the basic reproductive number and its uncertainty: framework and applications to the novel coronavirus (SARS-CoV-2) outbreak
Authors: Park Sang Woo , Bolker Benjamin M. , Champredon David , Earn David J. D. , Li Michael , Weitz Joshua S. , Grenfell Bryan T. , Dushoff Jonathan
Published: July 2020

A novel coronavirus (SARS-CoV-2) emerged as a global threat in December 2019. As the epidemic progresses, disease modellers continue to focus on estimating the basic reproductive numberR0—the average number of secondary cases caused by a primary case in an otherwise susceptible population. The modelling approaches and resulting estimates ofR0during the beginning of the outbreak vary widely, despite relying on similar data sources. Here, we present a statistical framework for comparing and combining different estimates ofR0across a wide range of models by decomposing the basic reproductive number into three key quantities: the exponential growth rate, the mean generation interval and the generation-interval dispersion. We apply our framework to early estimates ofR0for the SARS-CoV-2 outbreak, showing that manyR0estimates are overly confident. Our results emphasize the importance of propagating uncertainties in all components ofR0, including the shape of the generation-interval distribution, in efforts to estimateR0at the outset of an epidemic.
Symmetry structures in dynamic models of biochemical systems
Authors: Ohlsson Fredrik , Borgqvist Johannes , Cvijovic Marija
Published: July 2020

Understanding the complex interactions of biochemical processes underlying human disease represents the holy grail of systems biology. When processes are modelled in ordinary differential equation (ODE) fashion, the most common tool for their analysis is linear stability analysis where the long-term behaviour of the model is determined by linearizing the system around its steady states. However, this asymptotic behaviour is often insufficient for completely determining the structure of the underlying system. A complementary technique for analysing a system of ODEs is to consider the set of symmetries of its solutions. Symmetries provide a powerful concept for the development of mechanistic models by describing structures corresponding to the underlying dynamics of biological systems. To demonstrate their capability, we consider symmetries of the nonlinear Hill model describing enzymatic reaction kinetics and derive a class of symmetry transformations for each order of the model. We consider a minimal example consisting of the application of symmetry-based methods to a model selection problem, where we are able to demonstrate superior performance compared to ordinary residual-based model selection. Moreover, we demonstrate that symmetries reveal the intrinsic properties of a system of interest based on a single time series. Finally, we show and propose that symmetry-based methodology should be considered as the first step in a systematic model building and in the case when multiple time series are available it should complement the commonly used statistical methodologies.
Riddles in the cold: Antarctic endemism and microbial succession impact methane cycling in the Southern Ocean
Authors: Thurber Andrew R. , Seabrook Sarah , Welsh Rory M.
Published: July 2020

Antarctica is estimated to contain as much as a quarter of earth's marine methane, however we have not discovered an active Antarctic methane seep limiting our understanding of the methane cycle. In 2011, an expansive (70 m × 1 m) microbial mat formed at 10 m water depth in the Ross Sea, Antarctica which we identify here to be a high latitude hydrogen sulfide and methane seep. Through 16S rRNA gene analysis on samples collected 1 year and 5 years after the methane seep formed, we identify the taxa involved in the Antarctic methane cycle and quantify the response rate of the microbial community to a novel input of methane. One year after the seep formed, ANaerobic MEthane oxidizing archaea (ANME), the dominant sink of methane globally, were absent. Five years later, ANME were found to make up to 4% of the microbial community, however the dominant member of this group observed (ANME-1) were unexpected considering the cold temperature (−1.8°C) and high sulfate concentrations (greater than 24 mM) present at this site. Additionally, the microbial community had not yet formed a sufficient filter to mitigate the release of methane from the sediment; methane flux from the sediment was still significant at 3.1 mmol CH4m−2d−1. We hypothesize that this 5 year time point represents an early successional stage of the microbiota in response to methane input. This study provides the first report of the evolution of a seep system from a non-seep environment, and reveals that the rate of microbial succession may have an unrealized impact on greenhouse gas emission from marine methane reservoirs.
Analogue gravity on a superconducting chip
Authors: Blencowe Miles P. , Wang Hui
Published: July 2020

We describe how analogues of a Hawking evaporating black hole as well as the Unruh effect for an oscillatory, accelerating photodetector in vacuum may be realized using superconducting, microwave circuits that are fashioned out of Josephson tunnel junction and film bulk acoustic resonator elements.

This article is part of a discussion meeting issue ‘The next generation of analogue gravity experiments’.
Polariton fluids for analogue gravity physics
Authors: Jacquet M. J. , Boulier T. , Claude F. , Maître A. , Cancellieri E. , Adrados C. , Amo A. , Pigeon S. , Glorieux Q. , Bramati A. , Giacobino E.
Published: July 2020

Analogue gravity enables the study of fields on curved space–times in the laboratory. There are numerous experimental platforms in which amplification at the event horizon or the ergoregion has been observed. Here, we demonstrate how optically generating a defect in a polariton microcavity enables the creation of one- and two-dimensional, transsonic fluid flows. We show that this highly tuneable method permits the creation of horizons. Furthermore, we present a rotating geometry akin to the water-wave bathtub vortex. These experiments usher in the possibility of observing stimulated as well as spontaneous amplification by the Hawking, Penrose and Zeld’ovich effects in fluids of light.

This article is part of a discussion meeting issue ‘The next generation of analogue gravity experiments’.
The case for a Casimir cosmology
Authors: Leonhardt Ulf
Published: July 2020

The cosmological constant, also known as dark energy, was believed to be caused by vacuum fluctuations, but naive calculations give results in stark disagreement with fact. In the Casimir effect, vacuum fluctuations cause forces in dielectric media, which is very well described by Lifshitz theory. Recently, using the analogy between geometries and media, a cosmological constant of the correct order of magnitude was calculated with Lifshitz theory (Leonhardt 2019
Ann. Phys.
(
New York
)
411
, 167973. (
doi:10.1016/j.aop.2019.167973
)). This paper discusses the empirical evidence and the ideas behind the Lifshitz theory of the cosmological constant without requiring prior knowledge of cosmology and quantum field theory.

This article is part of a discussion meeting issue ‘The next generation of analogue gravity experiments’.
Estimate of the superradiance spectrum in dispersive media
Authors: Torres Theo
Published: July 2020

In 2016, the Nottingham group detected the rotational superradiance effect. While this experiment demonstrated the robustness of the superradiance process, it still lacks a complete theoretical description due to the many effects at stage in the experiment. In this paper, we shine new light on this experiment by deriving an estimate of the reflection coefficient in the dispersive regime by means of a Wentzel–Kramers–Brillouin analysis. This estimate is used to evaluate the reflection coefficient spectrum of counter-rotating modes in the Nottingham experiment. Our finding suggests that the vortex flow in the superradiance experiment was not purely absorbing, contrary to the event horizon of a rotating black hole. While this result increases the gap between this experimental vortex flow and a rotating black hole, it is argued that it is in fact this gap that is the source of novel ideas.

This article is part of a discussion meeting issue ‘The next generation of analogue gravity experiments’.
Epidemiological profile of Neisseria meningitidis in Casablanca, Morocco: 2010–2019
Authors: Ait Mouss Khadija , Razki Aziza , Hong Eva , Zaki Bahija , Maaloum Fakhreddine , Nzoyikorera Néhémie , Belabbes Houria , Elmdaghri Naima , Zerouali Khalid
Published: July 2020

Surveillance of invasive meningococcal diseases (IMD) must be carried out regularly and continuously in order to detect the emergence of strains of reduced susceptibility to antibiotics for therapeutic and prophylactic use and the appearance of new invasive clones. Molecular-typing approaches allow reliable traceability and powerful epidemiological analysis. This is an epidemiological study of Neisseria meningitidis causing meningitis in Casablanca, Morocco. The grouping was confirmed by PCR mainly on the isolates from cerebrospinal fluid (CSF). A total of 245 confirmed isolates of N .meningitidis were obtained between 2010 and 2019 of which 93 % are of group B. Overall, 24 % of all the isolates have a reduced susceptibility to penicillin G, but no resistance to penicillin G has been reported. All the isolated strains are susceptible to third-generation cephalosporins (3GCs). Genotyping by multilocus sequence typing (MLST) of a selection of 18 strains showed that the majority of isolates belong to the invasive clonal complex CC 32(9/18) followed by the CC 41/44(3/18).
Isachenkonia alkalipeptolytica gen. nov. sp. nov., a new anaerobic, alkaliphilic proteolytic bacterium capable of reducing Fe(III) and sulfur
Authors: Zavarzina Daria G. , Zhilina Tatyana N. , Kostrikina Nadegda A. , Toshchakov Stepan V. , Kublanov Ilya V.
Published: July 2020

An obligately alkaliphilic, anaerobic, proteolytic bacterium was isolated from a sample of Tanatar III soda lake sediment (Altai region, Russia) and designated as strain Z-1701T. Cells of strain Z-1701Twere short, straight, motile Gram-stain-positive rods. Growth of Z-1701Tobligately depended on the presence of sodium carbonate. Strain Z-1701Tcould utilize various peptides mixtures, such as beef and yeast extracts, peptone, soytone, trypticase and tryptone, as well as such proteins as albumin, gelatin and sodium caseinate. It was able to grow oligotrophically with 0.02 g l−1yeast extract as the sole energy and carbon source. Carbohydrates did not support the growth of strain Z-1701T. The main products released during the growth of strain Z-1701Ton tryptone were formate, acetate and ammonium. Strain Z-1701Twas able to reduce ferrihydrite, Fe(III)-EDTA, anthraquinone-2,6-disulfonate and elemental sulfur, using proteinaceous substrates as electron donors. In all cases the presence of the electron acceptor in the medium stimulated growth. The main cellular fatty acids were iso-C15 : 0, iso-C15 : 0aldehyde, iso-C15 : 1 ω6, C16 : 0, iso-C17 : 0aldehyde, C16 : 0aldehyde and C14 : 0. The DNA G+C content of the isolate was 43.9 mol%. Phylogenetic analysis based on the concatenated alignment of 120 protein-marker sequences revealed that strain Z-1701Tfalls into a cluster with the genusTindallia, familyClostridiaceae. 16S rRNA gene sequence identity between strain Z-1701TandTindalliaspecies were 88.3–89.75 %. On the basis of its phenotypic characteristics and phylogenetic position, the novel isolate is considered to be a representative of a novel genus and species for which the nameIsachenkonia alkalipeptolyticagen. nov., sp. nov. is proposed, with Z-1701T(=JCM 32929Т=DSM 109060Т=VKM B-3261Т) as its type strain.
Enzyme activities and volatile compounds of Rhizopus
oligosporus ‘Koji’
Authors: Jeon Sung-Hee , Youn Young , Jeong Do-Youn , Kim Young-Soo
Published: July 2020

This study was performed to verify the possibility of manufacturing
Rhizopus oligosporus ‘Koji’, which is
cultured using a range of different substrates. The growth characteristics of
R. oligosporus were therefore investigated for the
preparation of R. oligosporus ‘Koji’, and the
optimal incubation conditions were determined to be 30 °C for 24 h, with
an optimal NaCl concentration were 5%. Based on these results, R.
oligosporus was incubated using three substrates, namely beans,
rice and a mixture of beans and rice, for 6 d, and the enzyme activities and
volatile compounds of the fermentation products were investigated. On the fourth
day of incubation, the α-amylase activities of the rice and the mixed
substrates were 155 and 42 unit/mL, respectively, while on the fifth day of
incubation, the neutral protease activities of the beans and the mixed substrate
were 14 and 15 unit/mL, respectively. In terms of the lipase activity, the mixed
substrate resulted in a higher activity than the other substrates. Various
volatile flavor compounds, including alcohols, ketones, esters, aldehydes, and
pyrazines, were identified in R. oligosporus
‘Koji’ cultured using the mixed substrate.
Clinical and functional connectivity outcomes of 5-Hz repeated transcranial magnetic stimulation as an add-on treatment in cocaine use disorder: a double-blind randomized controlled trial
Authors: Garza-Villarreal Eduardo A. , Alcala-Lozano Ruth , Fernandez-Lozano Sofia , Morelos-Santana Erik , Dávalos Alan , Villicaña Viviana , Alcauter Sarael , Castellanos F. Xavier , Gonzalez-Olvera Jorge J.
Published: July 2020

BACKGROUND

Cocaine use disorder (CUD) is a global condition lacking effective treatment. Repeated magnetic transcranial stimulation (rTMS) may reduce craving and frequency of cocaine use, but little is known about its efficacy and neural effects.

METHODS

Using a double-blind placebo-controlled randomized clinical trial (RCT) [NCT02986438], we sought to elucidate short- and long-term clinical benefits of 5-Hz rTMS as an add-on to standard treatment in CUD patients and discern underlying functional connectivity effects using magnetic resonance imaging. Forty-four randomly assigned CUD patients completed the 2-week double-blind acute phase [Sham (n=20, 2f/18m) and Active (n=24, 4f/20m)], in which they received 2 daily sessions of rTMS (5,000 pulses) on the left dorsolateral prefrontal cortex. Subsequently, n=20 CUD patients continued to open-label maintenance (2 weekly sessions for up to 6 months). Measures were acquired at baseline, 2 weeks, 3 months and 6 months.

RESULTS

Overall, 5-Hz rTMS plus standard treatment for 2 weeks significantly reduced craving and impulsivity in the Active group; decreased impulsivity correlated with improvements in functional connectivity in executive control and default mode networks. Clinical and functional connectivity effects were maintained for 3 months but they dissipated by 6 months. We did not observe reduction of positive cocaine urine tests, however, self-reported frequency and grams consumed for 6 months were reduced.

CONCLUSIONS

With this RCT we show that 5-Hz rTMS has potential promise as an adjunctive treatment for CUD and merits further research.
Bibliometric analysis of COVID-19 literature
Authors: Al-Zaman Md. Sayeed
Published: July 2020

This study analyzesN=16384 COVID-19-related literature published between December 2019 to June 2020. The data were extracted from the Web of Science database using four keywords: “COVID-19”, “Coronavirus”, “2019-nCoV”, and “SARS-CoV-2”. The analysis found that almost all but a tiny number of the papers are published in 2020 (95.16%). Of the 15 types of publications,article(40.015%) is on the top of the list. All publications are in 19 different languages where English (95.313%) is the dominant one. A total of 159 countries produce COVID-19-related researches, and the USA (25.433%) is in the leading position. According to the findings, Wang Y (n=94) is the top author, and the British Medical Journal (BMJ) (n=488) is the top source. Also, the University of London (n=488) is the leading organization with the highest number of papers, and medicine-related papers (n=2259) are the highest in numbers. Apart from these novel findings, this study is perhaps the largest COVID-19-related bibliometric analysis to date.
Rheumatoid arthritis synovial fluid neutrophils drive inflammation through production of chemokines, reactive oxygen species and neutrophil extracellular traps
Authors: Wright Helen L , Lyon Max , Chapman Elinor A , Moots Robert J , Edwards Steven W
Published: July 2020

Rheumatoid arthritis (RA) is a chronic inflammatory disorder affecting synovial joints. Neutrophils are believed to play an important role in both the initiation and progression of RA, and large numbers of activated neutrophils are found within both synovial fluid (SF) and synovial tissue from RA joints. In this study we analysed paired blood and SF neutrophils from patients with severe, active RA (DAS28> 5.1, n=3) using RNA-seq. 772 genes were significantly different between blood and SF neutrophils. IPA analysis predicted that SF neutrophils had increased expression of chemokines and ROS production, delayed apoptosis, and activation of signalling cascades regulating the production of NETs. This activated phenotype was confirmed experimentally by incubating healthy control neutrophils in cell-free RA SF, which was able to delay apoptosis and induce ROS production in both unprimed and TNFαprimed neutrophils (p< 0.05). RA SF significantly increased neutrophil migration through 3mM transwell chambers (p< 0.05) and also increased production of NETs by healthy control neutrophils, including exposure of myeloperoxidase (MPO) and citrullinated histone-H3-positive DNA NETs. IPA analysis predicted NET production was mediated by signalling networks including AKT, RAF1, SRC and NF-κB. Our results expand the understanding of the molecular changes that take place in the neutrophil transcriptome during migration into inflamed joints in RA, and the altered phenotype in RA SF neutrophils. Specifically, RA SF neutrophils lose their migratory properties, residing within the joint to generate signals that promote joint damage, as well as inflammation via recruitment and activation of both innate and adaptive immune cells. We propose that this activated SF neutrophil phenotype contributes to the chronic inflammation and progressive damage to cartilage and bone observed in patients with RA.
Distinct signatures of calcium activity in brain pericytes
Authors: Glück Chaim , Ferrari Kim David , Keller Annika , Saab Aiman S. , Stobart Jillian L. , Weber Bruno
Published: July 2020

Even though pericytes have been implicated in various neurological disorders, little is known about their function and signaling pathways in the healthy brain. Here, we characterized cortical pericyte calcium dynamics using two-photon imaging ofPdgfrβ-CreERT2;GCaMP6s mice under anesthesiain vivoand in brain slicesex vivo. We found distinct differences between pericyte subtypesin vivo: Ensheathing pericytes exhibited smooth muscle cell-like calcium dynamics, while calcium signals in capillary pericytes were irregular, higher in frequency and occurred in cellular microdomains. In contrast to ensheathing pericytes, capillary pericytes retained their spontaneous calcium signals during prolonged anesthesia and in the absence of blood flowex vivo. Chemogenetic activation of neuronsin vivoand acute increase of extracellular potassium in brain slices strongly decreased calcium activity in capillary pericytes. We propose that neuronal activity-induced elevations in extracellular potassium suppress calcium activity in capillary pericytes, likely mediated by Kir2.2 and KATPchannel activation.
PARP and PI3K inhibitor combination therapy eradicates c-MYC-driven murine prostate cancers via cGAS/STING pathway activation within tumor-associated macrophages
Authors: Gupta Priyanka Dutta , Chaudagar Kiranj , Sharma-Saha Sweta , Bynoe Kaela , Maillat Lea , Heiss Brian , Stadler Walter M , Patnaik Akash
Published: July 2020

The majority of metastatic, castrate-resistant prostate cancer (mCRPC) patients arede novoresistant to immune checkpoint blockade (ICB), so therapeutic strategies to enhance immune-responsiveness are urgently needed. Here we performed a co-clinical trial of PARP inhibitor (PARPi) in combination with PD-1 or PDL-1 antibody in genomically unselected mCRPC patients or homologous-recombination proficient murine models, respectively, which demonstrated lack of efficacy. In contrast, PARPi in combination with PI3K inhibitor (PI3Ki), induced tumor regression via macrophage STING-dependent innate immune activationin vivo, and enhanced T-cell infiltration/activation in c-myc driven murine prostate cancer models, which was augmented by PD-L1 blockade.Ex vivomechanistic studies revealed that PARPi-induced DNA double strand break-associated microvesicles released from tumor cells, coupled with PI3Ki-mediated c-GAS de-repression, were both required for macrophage cGAS/STING pathway activation. These data demonstrate that PARPi/PI3Ki combination triggers macrophage STING-mediated anti-cancer innate immunity, which is sufficient to induce tumor regression in ICB-refractory c-myc-driven prostate cancer.

STATEMENT OF SIGNIFICANCE

Co-targeting of PARP and PI3K signaling pathways activates c-GAS/STING pathway within tumor-associated macrophages, thereby enhancing T cell recruitment/activation and cancer clearance in c-myc-driven murine prostate cancer models. PARPi/PI3Ki combination therapy could markedly increase the fraction of mCRPC patients responsive to ICB, independent of germline or tumor homologous recombination status.
Preparing For the Next Pandemic: Learning Wild Mutational Patterns At Scale For Analyzing Sequence Divergence In Novel Pathogens
Authors: Li Jin , Li Timmy , Chattopadhyay Ishanu
Published: July 2020

As we begin to recover from the COVID-19 pandemic, a key question is if we can avert such disasters in future. Current surveillance protocols generally focus on qualitative impact assessments of viral diversity 1. These efforts are primarliy aimed at ecosystem and human impact monitoring, and do not help to precisely quantify emergence. Currently, the similarity of biological strains is measured by the edit distance or the number of mutations that separate their genomic sequences 2–6, e.g. the number of mutations that make an avian flu strain human-adapted. However, ignoring the odds of those mutations in the wild keeps us blind to the true jump risk, and gives us little indication of which strains are more risky. In this study, we develop a more meaningful metric for comparison of genomic sequences. Our metric, the q-distance, precisely quantifies the probability of spontaneous jump by random chance. Learning from patterns of mutations from large sequence databases, the q-distance adapts to the specific organism, the background population, and realistic selection pressures; demonstrably improving inference of ancestral relationships and future trajectories. As important application, we show that the q-distance predicts future strains for seasonal Influenza, outperforming World Health Organization (WHO) recommended flu-shot composition almost consistently over two decades. Such performance is demonstrated separately for Northern and Southern hemisphere for different subtypes, and key capsidic proteins. Additionally, we investigate the SARS-CoV-2 origin problem, and precisely quantify the likelihood of different animal species that hosted an immediate progenitor, producing a list of related species of bats that have a quantifiably high likelihood of being the source. Additionally, we identify specific rodents with a credible likelihood of hosting a SARS-CoV-2 ancestor. Combining machine learning and large deviation theory, the analysis reported here may open the door to actionable predictions of future pandemics.
Sample Adequacy Controls for Infectious Disease Diagnosis by Oral Swabbing
Authors: Deviaene Meagan , Weigel Kris M. , Wood Rachel C. , Luabeya Angelique K. K. , Jones-Engel Lisa , Hatherill Mark , Cangelosi Gerard A.
Published: July 2020

Oral swabs are emerging as a non-invasive sample type for diagnosing infectious diseases including Ebola, tuberculosis (TB), and COVID-19. To assure proper sample collection, sample adequacy controls (SACs) are needed that detect substances indicative of samples collected within the oral cavity. This study evaluated two candidate SACs for this purpose. One detected representative oral microbiota (Streptococcus species DNA) and the other, human cells (human mitochondrial DNA, mtDNA). Quantitative PCR (qPCR) assays for the two target cell types were applied to buccal swabs (representing samples collected within the oral cavity) and hand swabs (representing improperly collected samples) obtained from 51 healthy U.S. volunteers. Quantification cycle (Cq) cutoffs that maximized Youden’s index were established for each assay. The streptococcal target at a Cq cutoff of ≤34.9 had 99.0% sensitivity and specificity for oral swab samples, whereas human mtDNA perfectly distinguished between hand and mouth swabs with a Cq cutoff of 31.3. The human mtDNA test was then applied to buccal, tongue, and gum swabs that had previously been collected from TB patients and controls in South Africa, along with “air swabs” collected as negative controls (total N = 292 swabs from 71 subjects). Of these swabs, 287/292 (98%) exhibited the expected Cq values. In a paired analysis the three oral sites yielded indistinguishable amounts of human mtDNA, however PurFlock™ swabs collected slightly more human mtDNA than did OmniSwabs™ (p = 0.012). The results indicate that quantification of human mtDNA cannot distinguish swabs collected from different sites within the mouth. However, it can reliably distinguish oral swabs from swabs that were not used orally., which makes it a useful SAC for oral swab-based diagnosis.
Geographic access to COVID-19 healthcare in Brazil using a balanced float catchment area approach
Authors: Pereira Rafael H. M. , Braga Carlos Kauê Vieira , Servo Luciana Mendes , Serra Bernardo , Amaral Pedro , Gouveia Nelson , Paez Antonio
Published: July 2020

The rapid spread of the new coronavirus across the world has raised concerns about the responsiveness of cities and healthcare systems during pandemics. Recent studies try to model how the number of COVID-19 infections will likely grow and impact the demand for hospitalization services at national and regional levels. However, less attention has been paid to the geographic access to COVID-19 healthcare services and to the response capacity of hospitals at the local level, particularly in urban areas in the Global South. This paper shows how transport accessibility analysis can provide actionable information to help improve healthcare coverage and responsiveness. It analyzes accessibility to COVID-19 healthcare at high spatial resolution in the 20 largest cities of Brazil. Using network-distance metrics, we estimate the vulnerable population living in areas with poor access to healthcare facilities that could either screen or hospitalize COVID-19 patients. We then use a new balanced floating catchment area (BFCA) indicator to estimate spatial, income and racial inequalities in access to hospitals with intensive care unit (ICU) beds and mechanical ventilators while taking into account congestion effects. Based on this analysis, we identify substantial social and spatial inequalities in access to health services during the pandemic. The availability of ICU equipment varies considerably between cities and it is substantially lower among black and poor communities. The study maps territorial inequalities in healthcare access and reflects on different policy lessons that can be learned for other countries based on the Brazilian case.
Large-scale Multi-omic Analysis of COVID-19 Severity
Authors: Overmyer Katherine A. , Shishkova Evgenia , Miller Ian J. , Balnis Joseph , Bernstein Matthew N. , Peters-Clarke Trenton M. , Meyer Jesse G. , Quan Qiuwen , Muehlbauer Laura K. , Trujillo Edna A. , He Yuchen , Chopra Amit , Chieng Hau C. , Tiwari Anupama , Judson Marc A. , Paulson Brett , Brademan Dain R. , Zhu Yunyun , Serrano Lia R. , Linke Vanessa , Drake Lisa A. , Adam Alejandro P. , Schwartz Bradford S. , Singer Harold A. , Swanson Scott , Mosher Deane F. , Stewart Ron , Coon Joshua J. , Jaitovich Ariel
Published: July 2020

We performed RNA-Seq and high-resolution mass spectrometry on 128 blood samples from COVID-19 positive and negative patients with diverse disease severities. Over 17,000 transcripts, proteins, metabolites, and lipids were quantified and associated with clinical outcomes in a curated relational database, uniquely enabling systems analysis and cross-ome correlations to molecules and patient prognoses. We mapped 219 molecular features with high significance to COVID-19 status and severity, many involved in complement activation, dysregulated lipid transport, and neutrophil activation. We identified sets of covarying molecules, e.g., protein gelsolin and metabolite citrate or plasmalogens and apolipoproteins, offering pathophysiological insights and therapeutic suggestions. The observed dysregulation of platelet function, blood coagulation, acute phase response, and endotheliopathy further illuminated the unique COVID-19 phenotype. We present a web-based tool (covid-omics.app) enabling interactive exploration of our compendium and illustrate its utility through a comparative analysis with published data and a machine learning approach for prediction of COVID-19 severity.
Quantifying SARS-CoV-2 infection risk within the Google/Apple exposure notification framework to inform quarantine recommendations
Authors: Wilson Amanda M. , Aviles Nathan , Petrie James I. , Beamer Paloma I. , Szabo Zsombor , Xie Michelle , McIllece Janet , Chen Yijie , Son Young-Jun , Halai Sameer , White Tina , Ernst Kacey C. , Masel Joanna
Published: July 2020

Most Bluetooth-based exposure notification apps use three binary classifications to recommend quarantine following SARS-CoV-2 exposure: a window of infectiousness in the transmitter, ≥15 minutes duration, and Bluetooth attenuation below a threshold. However, Bluetooth attenuation is not a reliable measure of distance, and infection risk is not a binary function of distance, nor duration, nor timing. We model uncertainty in the shape and orientation of an exhaled virus-containing plume and in inhalation parameters, and measure uncertainty in distance as a function of Bluetooth attenuation. We calculate expected dose by combining this with estimated infectiousness based on timing relative to symptom onset. We calibrate an exponential dose-response curve based on infection probabilities of household contacts. The probability of current or future infectiousness, conditioned on how long post-exposure an exposed individual has been symptom-free, decreases during quarantine, with shape determined by incubation periods, proportion of asymptomatic cases, and asymptomatic shedding durations. It can be adjusted for negative test results using Bayes Theorem. We capture a 10-fold range of risk using 6 infectiousness values, 11-fold range using 3 Bluetooth attenuation bins, ∼6-fold range from exposure duration given the 30 minute duration cap imposed by the Google/Apple v1.1, and ∼11-fold between the beginning and end of 14 day quarantine. Public health authorities can either set a threshold on initial infection risk to determine 14-day quarantine onset, or on the conditional probability of current and future infectiousness conditions to determine both quarantine and duration.
Novel features of centriole polarity and cartwheel stacking revealed by cryo-tomography
Authors: Nazarov Sergey , Bezler Alexandra , Hatzopoulos Georgios N , Villímová Veronika Nemčíková , Demurtas Davide , Le Guennec Maeva , Guichard Paul , Gönczy Pierre
Published: July 2020

Centrioles are polarized microtubule-based organelles that seed the formation of cilia, and which assemble from a cartwheel containing stacked ring oligomers of SAS-6 proteins. A cryo-tomography map of centrioles from the termite flagellateTrichonymphaspp. was obtained previously, but higher resolution analysis is likely to reveal novel features. Using sub-tomogram averaging (STA) inT.spp. andTrichonympha agilis, we delineate the architecture of centriolar microtubules, pinhead and A-C-linker. Moreover, we report ∼25 Å resolution maps of the central cartwheel, revealing notably polarized cartwheel inner densities (CID). Furthermore, STA of centrioles from the distant flagellateTeranympha mirabilisuncovers similar cartwheel architecture and a distinct filamentous CID. Fitting the CrSAS-6 crystal structure into the flagellate maps and analyzing cartwheels generatedin vitroindicates that SAS-6 rings can directly stack onto one another in two alternating configurations: with a slight rotational offset and in register. Overall, improved STA maps in three flagellates enabled us to unravel novel architectural features, including of centriole polarity and cartwheel stacking, thus setting the stage for an accelerated elucidation of underlying assembly mechanisms.
Assessing the impact of grassland management on landscape multifunctionality
Authors: Neyret M. , Fischer M. , Allan E. , Hölzel N. , Klaus V.H. , Kleinebecker T. , Krauss J. , Le Provost G. , Peter S. , Schenk N. , Simons N.K. , van der Plas F. , Binkenstein J. , Börschig C. , Jung K. , Prati D. , Schäfer D. , Schäfer M. , Schöning I. , Schrumpf M. , Tschapka M. , Westphal C. , Manning P.
Published: July 2020

Land-use intensification has contrasting effects on different ecosystem services, often leading to land-use conflicts. While multiple studies have demonstrated how landscape-scale strategies can minimise the trade-off between agricultural production and biodiversity conservation, little is known about which land-use strategies maximise the landscape-level supply of multiple ecosystem services (landscape multifunctionality), a common goal of stakeholder communities.

We combine comprehensive data collected from 150 German grassland sites with a simulation approach to identify landscape compositions, with differing proportions of low-, medium-, and high-intensity grasslands, that minimise trade-offs between the six main grassland ecosystem services prioritised by local stakeholders: biodiversity conservation, aesthetic value, productivity, carbon storage, foraging, and regional identity. Results are made accessible through an online tool that provides information on which compositions best meet any combination of user-defined priorities (https://neyret.shinyapps.io/landscape_composition_for_multifunctionality/).

Results show that an optimal landscape composition can be identified for any pattern of ecosystem service priorities. However, multifunctionality was similar and low for all landscape compositions in cases where there are strong trade-offs between services (e.g. aesthetic value and fodder production), where many services were prioritised, and where drivers other than land use played an important role. We also found that if moderate service levels are deemed acceptable, then strategies in which both high and low intensity grasslands are present can deliver landscape multifunctionality. The tool presented can aid informed decision-making by predicting the impact of future changes in landscape composition, and by allowing for the relative roles of stakeholder priorities and biophysical trade-offs to be understood by scientists and practitioners alike.

Highlights

An online tool identifies optimal landscape compositions for desired ecosystem services

When the desired services are synergic, the optimum is their common best landscape composition

When the desired services trade-off, a mix of grassland intensity is most multifunctional

Such tools could support decision-making processes and aid conflict resolution

Graphical abstract
Comparative genomics analyses of lifestyle transitions at the origin of an invasive fungal pathogen in the genusCryphonectria
Authors: Stauber Lea , Prospero Simone , Croll Daniel
Published: July 2020

Emerging fungal pathogens are a threat to forest and agroecosystems, as well as animal and human health. How pathogens evolve from non-pathogenic ancestors is still poorly understood making the prediction of future outbreaks challenging. Most pathogens have evolved lifestyle adaptations, which were enabled by specific changes in the gene content of the species. Hence, understanding transitions in the functions encoded by genomes gives valuable insight into the evolution of pathogenicity. Here, we studied lifestyle evolution in the genusCryphonectria, including the prominent invasive pathogenC. parasitica, the causal agent of chestnut blight onCastaneaspecies. We assembled and compared the genomes of pathogenic and putatively non-pathogenicCryphonectriaspecies, as well as sister group pathogens in the family Cryphonectriaceae (Diaporthales, Ascomycetes) to investigate the evolution of genome size and gene content. We found a striking loss of genes associated with carbohydrate metabolism (CAZymes) inC. parasiticacompared to other Cryphonectriaceae. Despite substantial CAZyme gene loss, experimental data suggests thatC. parasiticahas retained wood colonization abilities shared with otherCryphonectriaspecies. Putative effectors substantially varied in number, cysteine content and protein length among species. In contrast, secondary metabolite gene clusters show a high degree of conservation within the genus. Overall, our results underpin the recent lifestyle transition ofC. parasiticatowards a more pathogenic lifestyle. Our findings suggest that a CAZyme loss may have promoted pathogenicity ofC. parasiticaon chestnuts. Analyzing gene complements underlying key nutrition modes can facilitate the detection of species with the potential to emerge as pathogens.
Structural basis for the inhibition of the papain-like protease of SARS-CoV-2 by small molecules
Authors: Fu Ziyang , Huang Bin , Tang Jinle , Liu Shuyan , Liu Ming , Ye Yuxin , Liu Zhihong , Xiong Yuxian , Cao Dan , Li Jihui , Niu Xiaogang , Zhou Huan , Zhao Yong Juan , Zhang Guoliang , Huang Hao
Published: July 2020

SARS-CoV-2 is the pathogen responsible for the COVID-19 pandemic. The SARS-CoV-2 papain-like cysteine protease has been implicated in virus maturation, dysregulation of host inflammation and antiviral immune responses. We showed that PLpro preferably cleaves the K48-ubiquitin linkage while also being capable of cleaving ISG15 modification. The multiple functions of PLpro render it a promising drug target. Therefore, we screened an FDA-approved drug library and also examined available inhibitors against PLpro. Inhibitor GRL0617 showed a promising IC50of 2.1 μM. The co-crystal structure of SARS-CoV-2 PLpro-C111S in complex with GRL0617 suggests that GRL0617 is a non-covalent inhibitor. NMR data indicate that GRL0617 blocks the binding of ISG15 to PLpro. The antiviral activity of GRL0617 reveal that PLpro is a promising drug target for therapeutically treating COVID-19.

One Sentence Summary

Co-crystal structure of PLpro in complex with GRL0617 reveals the druggability of PLpro for SARS-CoV-2 treatment.