bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphisms in the ACE2 Locus Associate with Severity of COVID-19 Infection
Authors: Wooster Luke , Nicholson Christopher J. , Sigurslid Haakon H. , Lino Cardenas Christian L. , Malhotra Rajeev
Published: June 2020

Data from clinical studies suggests a strong association between underlying cardiometabolic disease and worse outcomes in COVID-19. Given that the SARS-CoV-2 virus has a unique marked affinity to the human angiotensin-converting enzyme 2 (ACE2) receptor, one potential explanation behind this phenomenon may involve the higher expression of ACE2 receptor in these patients. Here, we analyzed association between polymorphisms in the ACE2 locus and COVID-19 severity in 62 patients found to be COVID-19 positive by polymerase chain reaction. Of these patients, 23 required hospitalization due to COVID-19 infection. Of 61 ACE2 single nucleotide polymorphisms (SNPs) genotyped in this patient cohort, 10 were significantly associated with tissue expression of ACE2. Logistic regression adjusted for age and for sex identified six of these ten SNPs to be significantly associated with hospitalization. These results provide preliminary evidence of a genetic link between the ACE2 genotype and COVID-19 disease severity and suggest that the ACE2 genotype may inform COVID-19 risk stratification and need for more intense therapy.
Universality in COVID-19 spread in view of the Gompertz function
Authors: Ohnishi Akira , Namekawa Yusuke , Fukui Tokuro
Published: June 2020

We demonstrate that universal scaling behavior is observed in the current coronavirus (SARS-CoV-2) spread, the COVID-19 pandemic, in various countries. We analyze the numbers of infected people who tested positive (cases) in selected eleven countries (Japan, USA, Russia, Brazil, China, Italy, Indonesia, Spain, South Korea, UK, and Sweden). By using the double exponential function called the Gompertz function, fG(x) = exp(−e−x), the number of cases is well described as N(t) = N0fG(γ(t − t0)), where N0, 7 and t0 are the final number of cases, the damping rate of the infection probability and the peak time of the daily number of new cases, dN(t)/dt, respectively. The scaled data of cases in most of the analyzed countries are found to collapse onto a common scaling function fG(x) with x = γ(t − t0) being the scaling variable in the range of fG(x) ± 0.05. The recently proposed indicator so-called the K value, the increasing rate of cases in one week, is also found to show universal behavior. The mechanism for the Gompertz function to appear is discussed from the time dependence of the produced pion numbers in nucleus-nucleus collisions, which is also found to be described by the Gompertz function.
An integrated multi-omics analysis identifies clinically relevant molecular subtypes of non-muscle-invasive bladder cancer
Authors: Lindskrog Sia Viborg , Prip Frederik F. , Lamy Philippe , Taber Ann , Groeneveld Clarice S. , Birkenkamp-Demtröder Karin , Jensen Jørgen Bjerggaard , Strandgaard Trine , Nordentoft Iver , Christensen Emil , Sokac Mateo , Birkbak Nicolai J. , Maretty Lasse , Hermann Gregers G. , Petersen Astrid C. , Weyerer Veronika , Grimm Marc-Oliver , Horstmann Marcus , Sjödahl Gottfrid , Höglund Mattias , Steiniche Torben , Mogensen Karin , de Reyniès Aurélien , Nawroth Roman , Jordan Brian , Lin Xiaoqi , Dragicevic Dejan , Ward Douglas G. , Goel Anshita , Hurst Carolyn D. , Raman Jay D. , Warrick Joshua I. , Segersten Ulrika , Sikic Danijel , van Kessel Kim E.M. , Maurer Tobias , Meeks Joshua J. , DeGraff David J. , Bryan Richard T. , Knowles Margaret A. , Simic Tatjana , Hartmann Arndt , Zwarthoff Ellen C. , Malmström Per-Uno , Malats Núria , Real Francisco X. , Dyrskjøt Lars
Published: June 2020

The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we performed a large integrative multi-omics analysis of patients diagnosed with NMIBC (n=834). Transcriptomic analysis identified four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provided independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations were significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration was associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirmed the higher infiltration of class 2b tumors and demonstrated an association between higher immune cell infiltration and lower recurrence rates. Finally, a single-sample classification tool was built and the independent prognostic value of the transcriptomic classes was documented in 1306 validation samples. The classifier provides a framework for novel biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
The Covid-19 epidemic in the UK
Authors: Faggio Giulia , Peracchi Franco
Published: June 2020

In this note we present some stylised facts about the Covid-19 epidemic in the UK using daily time-series data published by Public Health England and the UK Department of Health and Social Care. We model the data on confirmed new cases using standard count-data models estimated at the country and national levels using a fixed rolling window to capture changes in the model parameters over time. We then use the most recent estimated models to carry out a simple real-time forecasting exercise aimed at predicting the date when the number of confirmed new cases will be approximately zero.
A Standard Virus Load Function
Authors: Hillen Thomas
Published: June 2020

The idea is to design a simple function that can describe typical virus-load curves without solving a full virus load dynamic model. We present such a standard virus load function and validate it on data from influenza A as well as SARS-CoV-2 infection data for Macaque monkeys and humans. Further, we compare the virus load function to an established target model of virus dynamics as presented by A. Smith in [1]. This virus-load function can be used as input to higher level models for the physiological effects of a virus infection, for models for tissue damage, and to develop treatment strategies.
Hospitalized COVID-19 Patients treated with Convalescent Plasma in a Mid-size City in the Midwest
Authors: Hartman William , Hess Aaron S , Connor Joseph P
Published: June 2020

Background

SARS-CoV-2 and its associated disease, COVID-19, has infected over seven million people world-wide, including two million people in the United States. While many people recover from the virus uneventfully, a subset of patients will require hospital admission, some with intensive care needs including intubation, and mechanical ventilation. To date there is no cure and no vaccine is available. Passive immunotherapy by the transfusion of convalescent plasma donated by COVID-19 recovered patients might be an effective option to combat the virus, especially if used early in the course of disease. Here we report our experience of using convalescent plasma at a tertiary care center in a mid-size, midwestern city that did not experience an overwhelming patient surge.

Methods

Hospitalized COVID-19 patients categorized as having Severe or Life-Threatening disease according to the Mayo Clinic Emergency Access Protocol were screened, consented, and treated with convalescent plasma collected from local donors recovered from COVID-19 infection. Clinical data and outcomes were collected retrospectively.

Results

31 patients were treated, 16 severe patients and 15 life-threatened patients. Overall mortality was 27% (4/31) but only patients with life-threatening disease died. 94% of transfused patients with severe disease avoided escalation to ICU care and mechanical ventilation. 67% of patients with life-threatening disease were able to be extubated. Most transfused patients had a rapid decrease in their respiratory support requirements on or about day 7 following convalescent plasma transfusion.

Conclusion

Our results demonstrate that convalescent plasma is associated with reducing ventilatory requirements in patients with both severe and life-threatening disease, but appears to be most beneficial when administered early in the course of disease when patients meet the criteria for severe illness.
Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study
Authors: Chen Lan , Zhang Zhen-Yu , Fu Jian-Guo , Feng Zhi-Peng , Zhang Su-Zhen , Han Qiu-Ying , Zhang Xiao-Bin , Xiao Xiong , Chen Hui-Min , Liu Li-Long , Chen Xian-Li , Lan Yu-Pei , Zhong De-Jin , Hu Lan , Wang Jun-Hui , Yu Xing-Hua , She Dan-Yang , Zhu Yong-Hong , Yin Zhen-Yu
Published: June 2020

The outbreak of novel coronavirus disease 2019 (COVID-19) has become a pandemic. Drug repurposing may represent a rapid way to fill the urgent need for effective treatment. We evaluated the clinical utility of chloroquine and hydroxychloroquine in treating COVID-19.

Forty-eight patients with moderate COVID-19 were randomized to oral treatment with chloroquine (1000 mg QD on Day 1, then 500 mg QD for 9 days; n=18), hydroxychloroquine (200 mg BID for 10 days; n=18), or control treatment (n=12).

Adverse events were mild, except for one case of Grade 2 ALT elevation. Adverse events were more commonly observed in the chloroquine group (44.44%) and the hydroxychloroquine group (50.00%) than in the control group (16.67%). The chloroquine group achieved shorter time to clinical recovery (TTCR) than the control group (P=0.019). There was a trend toward reduced TTCR in the hydroxychloroquine group (P=0.049). The time to reach viral RNA negativity was significantly faster in the chloroquine group and the hydroxychloroquine group than in the control group (P=0.006 and P=0.010, respectively). The median numbers of days to reach RNA negativity in the chloroquine, hydroxychloroquine, and control groups was 2.5 (IQR: 2.0-3.8) days, 2.0 (IQR: 2.0-3.5) days, and 7.0 (IQR: 3.0-10.0) days, respectively. The chloroquine and hydroxychloroquine groups also showed trends toward improvement in the duration of hospitalization and findings on lung computerized tomography (CT). This study provides evidence that (hydroxy)chloroquine may be used effectively in treating moderate COVID-19 and supports larger trials.
U2AF1is a haplo-essential gene required for cancer cell survival
Authors: Wadugu Brian A. , Heard Amanda , Srivatsan Sridhar N. , Alberti Michael O. , Ndonwi Matthew , Grieb Sarah , Bradley Joseph , Shao Jin , Ahmed Tanzir , Shirai Cara L. , Khanna Ajay , Fei Dennis L. , Miller Christopher A. , Graubert Timothy A. , Walter Matthew J.
Published: June 2020

Somatic mutations in the spliceosome geneU2AF1are common in patients with myelodysplastic syndromes.U2AF1mutations that code for the most common amino acid substitutions are always heterozygous, and the retained wild-type allele is expressed, suggesting that mutant hematopoietic cells may require the residual wild-type allele to be viable and cause disease. We show that hematopoiesis and RNA splicing inU2af1heterozygous knock-out mice was similar to control mice, but that deletion of the wild-type allele in U2AF1(S34F) heterozygous mutant expressing hematopoietic cells (i.e., hemizygous mutant) was lethal. These results confirm that U2AF1 mutant hematopoietic cells are dependent on the expression of wild-type U2AF1 for survivalin vivoand thatU2AF1is a haplo-essential cancer gene. Mutant U2AF1 (S34F) expressing cells were also more sensitive to reduced, but not absent, expression of wild-type U2AF1 than non-mutant cells. Furthermore, mice transplanted with leukemia cells expressing mutant U2AF1 had significantly reduced tumor burden and improved survival after the wild-typeU2af1allele was deleted compared to when it was not deleted. These results suggest that selectively targeting the wild-typeU2AF1allele in heterozygous mutant cells could induce cancer cell death and be a therapeutic strategy for patients harboringU2AF1mutations.
Characterizing super-spreading events and age-specific infectiousness of SARS-CoV-2 transmission in Georgia, USA
Authors: Lau Max SY , Grenfell Bryan , Thomas Michael , Bryan Michael , Nelson Kristin , Lopman Ben
Published: June 2020

It is imperative to advance our understanding of heterogeneities in the transmission of SARS-CoV-2 such as age-specific infectiousness and super-spreading. To this end, it is important to exploit multiple data streams that are becoming abundantly available during the pandemic. In this paper, we formulate an individual-level spatio-temporal mechanistic framework to integrate individual surveillance data with geo-location data and aggregate mobility data, enabling a more granular understanding of the transmission dynamics of SARS-CoV-2. We analyze reported cases, between March and early May 2020, in five (urban and rural) counties in the State of Georgia USA. First, our results show that the reproductive number reduced to below 1 in about two weeks after the shelter-in-place order. Super-spreading appears to be widespread across space and time, and it may have a particularly important role in driving the outbreak in rural areas and an increasing importance towards later stages of outbreaks in both urban and rural settings. Overall, about 2% of cases were directly responsible for 20% of all infections. We estimate that the infected non-elderly cases (<60) may be 2.78 [2.10, 4.22] times more infectious than the elderly, and the former tend to be the main driver of super-spreading. Our results improve our understanding of the natural history and transmission dynamics of SARS-CoV-2. More importantly, we reveal the roles of age-specific infectiousness and characterize systematic variations and associated risk factors of super-spreading. These have important implications for the planning of relaxing social distancing and, more generally, designing optimal control measures.

Significance Statement

There is still considerable scope for advancing our understanding of the epidemiology and ecology of COVID-19. In particular, much is unknown about individual-level transmission heterogeneities such as super-spreading and age-specific infectiousness. We statistically synthesize multiple valuable datastreams, including surveillance data and mobility data, that are available during the current COVID-19 pandemic. We show that age is an important factor in the transmission of the virus. Super-spreading is ubiquitous over space and time, and has particular importance in rural areas and later stages of an outbreak. Our results improve our understanding of the natural history the virus and have important implications for designing optimal control measures.
Comparison of primer-probe sets among different master mixes for laboratory screening of Severe Acute Respiratory Syndrome - Coronavirus 2 (SARS-CoV-2)
Authors: Cuong Hoang Quoc , Hai Nguyen Duc , Linh Hoang Thuy , Anh Nguyen Hoang , Hieu Nguyen Trung , Thang Cao Minh , Thao Nguyen Thi Thanh , Lan Phan Trong
Published: June 2020

Background

There is a shortage of chemical reagents for severe acute respiratory syndrome - coronavirus 2 (SARS-CoV-2) diagnosis and a surge of SARS-CoV-2cases, especially in limited-resource settings. Therefore, the combination of an optimal assay kit is necessary.

Methods

We compared the ability to screen SARS-CoV-2 among three primer-probe sets in two different master mixes, Invitrogen™ SuperScript™ III One-Step RT-PCR and LightCycler Multiplex RNA Virus Master.

Results

The assay with TIB-Molbiol, IDT, and Phu Sa sets for LightCycler Multiplex RNA Virus Master or Invitrogen™ SuperScript™ III One-Step RT-PCR showed positive results from a single reaction of triplicate in the three days of 4.8 copies per reaction. R-squared and amplification efficiency were 0.97 and ranged from 107 to 108%, respectively.

Conclusions

Our findings indicated that TIB-Molbiol, IDT, and Phu Sa primer-probe sets could be beneficial for the laboratory screening of SARS-CoV-2 by RT-qPCR assay of E gene. There is a need to consider the combination of these reagent sets as a new strategy to increase the testing capacity of screening programs for COVID-19.
Spring Weather and COVID-19 Deaths in the U.S.
Authors: Karimi Seyed M. , Majbouri Mahdi , White Kelsey , Little Bert , McKinney W. Paul , DuPre Natalie
Published: June 2020

This study used statistically robust regression models to control for a large set of confounders (including county-level time-invariant factors and time trends, regional-level daily variation, state-level social distancing measures, ultraviolet light, and levels of ozone and fine particulate matter, PM2.5) to estimate a reliable rather than simple regression for the impact of weather on the most accurately measured outcome of COVID-19, death. When the average minimum temperature within a five-day window increased by one degree Fahrenheit in spring 2020, daily death rates in northern U.S. counties increased by an estimated 5.1%. When ozone concentration over a five-day window rose by one part per billion, daily death rates in southern U.S. counties declined by approximately 2.0%. Maximum temperature, precipitation, PM2.5, and ultraviolet light did not significantly associate with COVID-19 mortality. The mechanism that may drive the observed association of minimum temperature on COVID-19 deaths in spring months may be increased mobility and contacts. The effect of ozone may be related to its disinfectant properties, but this requires further confirmation.
Arsenic trioxide resistance in acute promyelocytic leukemia: More to it than PML mutations
Authors: Balasundaram Nithya , Ganesan Saravanan , Chendamarai Ezhilarasi , Palani Hamenth Kumar , Venkatraman Arvind , Alex Ansu Abu , David Sachin , Krishna Sanjeev , Korula Anu , Janet Nancy Beryl , Balasubramanian Poonkuzhali , Mathews Vikram
Published: June 2020

Acquired genetic mutations can confer resistance to arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL). However, such resistance-conferring mutations are rare and do not explain the majority of disease recurrence seen in the clinic. We have generated a stable ATO resistant promyelocytic cell from a ATO sensitive NB4 cell line. We also noted that another ATRA resistant cell line (UF1) was cross resistant to ATO. We have characterized these resistant cell lines and observed that they significantly differed in their immunophenotype, drug transporter expression, drug resistance mutation profile and were also cross-resistant to other conventional chemotherapeutic agents. The NB4 derived resistant cell line had the classical A216VPML-B2domain mutation while the UF1 cell line did not. Gene expression profiling revealed prominent dysregulation of the cellular metabolic pathways in the resistant cell lines. Glycolytic inhibition by 2-DG was efficient and comparable to the standard of care (ATO) in targeting the sensitive APL cell lines and was also effective in the in vivo transplantable APL mouse model; however, it did not affect the ATO resistant cell lines. The survival of the resistant cell lines was significantly affected by compounds targeting the mitochondrial respiration irrespective of the existence of ATO resistance-conferring genetic mutations. Our data demonstrate the addition of mitocans can overcome ATO resistance. We further demonstrated that the combination of ATO and mitocans has the potential in the treatment of non-M3 AML and the translation of this approach in the clinic needs to be explored further.

Key points

Metabolic rewiring promotes ATO resistance, which can be overcome by targeting mitochondrial oxidative phosphorylation.

Combination of ATO and mitocans can be exploited as a potential therapeutic option for relapsed APL and in non-M3 AML patients.
ADA2 is a lysosomal DNase regulating the type-I interferon response
Authors: Greiner-Tollersrud Ole Kristian , Boehler Vincent , Bartok Eva , Krausz Máté , Polyzou Aikaterini , Schepp Johanna , Seidl Maximilian , Olsen Jan Ole , Smulski Cristian R. , Raieli Salvatore , Hübscher Katrin , Trompouki Eirini , Link Regina , Ebersbach Hilmar , Srinivas Honnappa , Marchant Martine , Staab Dieter , Guerini Danilo , Baasch Sebastian , Henneke Philipp , Kochs Georg , Hartmann Gunther , Geiger Roger , Grimbacher Bodo , Warncke Max , Proietti Michele
Published: June 2020

Deficiency of adenosine deaminase 2 (DADA2) is a severe, congenital syndrome, which manifests with hematologic, immunologic and inflammatory pathologies. DADA2 is caused by biallelic mutations inADA2, but the function of ADA2, and the mechanistic link between ADA2 deficiency and the severe inflammatory phenotype remains unclear. Here, we show that monocyte-derived proteomes from DADA2 patients are highly enriched in interferon response proteins. Using immunohistochemistry and detailed glycan analysis we demonstrate that ADA2 is post-translationally modified for sorting to the lysosomes. At acidic, lysosomal pH, ADA2 acts as a novel DNase that degrades cGAS/Sting-activating ligands. Furthermore, we define a clear structure-function relationship for this acidic DNase activity. Deletion of ADA2 increased the production of cGAMP and type I interferons upon exposure to dsDNA, which was reverted by ADA2 overexpression or deletion ofSTING.Our results identify a new level of control in the nucleic acid sensing machinery and provide a mechanistic explanation for the pathophysiology of autoinflammation in DADA2.

One Sentence Summary

ADA2 is a lysosomal nuclease controlling nucleic acid sensing and type I interferon production.
Lift observation conveys object weight distribution but partly enhances predictive lift planning
Authors: Rens Guy , de Xivry Jean-Jacques Orban , Davare Marco , van Polanen Vonne
Published: June 2020

Observation of object lifting allows updating of internal object representations for object weight, in turn enabling accurate scaling of fingertip forces when lifting the same object. Here, we investigated whether lift observation also enables updating of internal representations for an object’s weight distribution. We asked participants to lift an inverted T-shaped manipulandum, of which the weight distribution could be changed, in turns with an actor. Participants were required to minimize object roll (i.e., ‘lift performance’) during lifting and were allowed to place their fingertips at self-chosen locations. The center of mass changed unpredictably every third to sixth trial performed by the actor and participants were informed that they would always lift the same weight distribution as the actor. Participants observed either erroneous (i.e., object rolling towards its heavy side) or skilled (i.e., minimized object roll) lifts. Lifting performance after observation was compared to lifts without prior observation and to lifts after active lifting, which provided haptic feedback about the weight distribution. Our results show that observing both skilled and erroneous lifts convey an object’s weight distribution similar to active lifting, resulting in altered digit positioning strategies. However, minimizing object roll on novel weight distributions was only improved after observing error lifts and not after observing skilled lifts. In sum, these findings suggest that although observing motor errors and skilled motor performance enables updating of digit positioning strategy, only observing error lifts enables changes in predictive motor control when lifting objects with unexpected weight distributions.

New and noteworthy

Individuals are able to extract an object’s size and weight by observing interactions with objects and subsequently integrate this information in their own motor repertoire. Here, we show that this ability extrapolates to weight distributions. Specifically, we highlighted that individuals can perceive an object’s weight distribution during lift observation but can only partially embody this information when planning their own actions.
Live imaging of chromatin distribution in muscle nuclei reveals novel principles of nuclear architecture and chromatin compartmentalization
Authors: Amiad-Pavlov Daria , Lorber Dana , Bajpai Gaurav , Safran Samuel , Volk Talila
Published: June 2020

Packaging of the chromatin within the nucleus serves as an important factor in the regulation of transcriptional output. However, information on chromatin architecture on nuclear scale in fully differentiated cells, under physiological conditions and in live organisms, is largely unavailable. Here, we imaged nuclei and chromatin in muscle fibers of live, intactDrosophilalarvae. In contrast to the common view that chromatin is distributed throughout the nuclear volume, we show that the entire chromatin, including active and repressed regions, forms a peripheral layer underneath the nuclear lamina, leaving a chromatin-devoid compartment at the nucleus center. Importantly, visualization of nuclear compartmentalization required imaging of un-fixed nuclei embedded within their intrinsic tissue environment, with preserved nuclear volume. Upon fixation of similar muscle nuclei, we observed an average of three-fold reduction in nuclear volume caused by dehydration and evidenced by nuclear flattening. In these conditions, the peripheral chromatin layer was not detected anymore, demonstrating the importance of preserving native biophysical tissue environment. We further show that nuclear compartmentalization is sensitive to the levels of lamin C, since over-expression of lamin C-GFP in muscle nuclei resulted in detachment of the peripheral chromatin layer from the lamina and its collapse into the nuclear center. Computer simulations of chromatin distribution recapitulated the peripheral chromatin organization observed experimentally, when binding of lamina associated domains (LADs) was incorporated with chromatin self-attractive interactions. Reducing the number of LADs led to collapse of the chromatin, similarly to our observations following lamin C over-expression. Taken together, our findings reveal a novel mode of mesoscale organization of chromatin within the nucleus in a live organism, in which the chromatin forms a peripheral layer separated from the nuclear interior. This architecture may be essential for robust transcriptional regulation in fully differentiated cells.
Vegetative phase change inPopulus tremula x alba
Authors: Lawrence Erica H. , Leichty Aaron R. , Doody Erin E. , Ma Cathleen , Strauss Steven H. , Poethig R. Scott
Published: June 2020

Plants transition through juvenile and adult phases of vegetative development in a process known as vegetative phase change (VPC). In poplars (genusPopulus) the differences between these stages are subtle, making it difficult to determine when this transition occurs. Previous studies of VPC in poplars have relied on plants propagatedin vitro, leaving the natural progression of this process unknown.

We examined developmental morphology of seed-grown andin vitroderivedPopulus tremula x alba(clone 717-1B4), and compared the phenotype of these, to transgenics with manipulated miR156 expression, the master regulator of VPC.

In seed-grown plants, most traits changed from node-to-node during the first 3 months of development but remained constant after node 25. Many traits remained unchanged in clones over-expressing miR156, or were enhanced when miR156 was lowered, demonstrating their natural progression is regulated by the miR156/SPL pathway. The characteristic leaf fluttering ofPopulusis one of these miR156-regulated traits.

Vegetative development in plants grown from culture mirrored that of seed-grown plants, allowing direct comparison between plants often used in research and those found in nature. These results provide a foundation for further research on the role of VPC in the ecology and evolution of this economically important genus.
Diametric Property of Rotational and Spiral Doppler Effect in Human Heart Atrial Fibrillation
Authors: Rubenstein D
Published: June 2020

Compass mapping of moving rotors during atrial fibrillation unveiled unique properties of a different form of Doppler phenomenon. New rotational (RDE) and spiral Doppler effect (SDE) equations are derived and explain the diverging frequency changes (increasing and decreasing) that occur simultaneously on either side of passing rotor. These equations confirm that regions of maximal frequency are shifted 90° compared to moving sources that exhibit classical doppler effects. The new SDE equation predicts sequence reversal, side-dependent frequency changes, and an unpaired strong-side wave front strike previously observed in patients with persistent atrial fibrillation. Conclusion: The diametric property of SDE is a mechanism behind dysynchrony of atrial fibrillation when a spinning source of wave fronts moves between two stationary electrodes. The diametric property of SDE in other fields of science are discussed.

Statement of Significance

Spinning sources of periodic wave fronts during atrial fibrillation do NOT exhibit classical Doppler effects when they approach and pass between 2 adjacent equidistant electrodes. The wave front is a spinning single spiral arm and frequency of wave front strikes is not only dependent upon distance between successive WF crests, but it is also dependent upon changes in rotation. Rotational and spiral math were developed and to derive new rotational and spiral wave front Doppler effect equations in two dimensions. These equations predict the unique and profound diametric property that have been observed clinically in which the strong side electrodes record an approaching increasing frequency while the weak side electrodes record an approaching decreasing frequency. The solution opens up many new avenues of research, not only into atrial fibrillation, but at all levels of nature, into objects that spin.
NMR spectroscopy analysis reveals an altered metabolic homeostasis in Arabidopsis seedlings treated with a cytokinesis inhibitor
Authors: Wilkop Thomas E. , Wang Minmin , Heringer Angelo , Zakharov Florence , Krishnan Viswanathan V. , Drakakaki Georgia
Published: June 2020

In plant cytokinesis,de novoformation of a cell plate evolving into the new cell wall partitions the cytoplasm of the dividing cell. Cell plate formation involves highly orchestrated vesicle accumulation, fusion, and membrane network maturation supported by the temporary integration of elastic and pliable callose. The small molecule, Endosidin 7 (ES7) arrests late cytokinesis in Arabidopsis by inhibiting callose deposition at the cell plate. Its effect is specific, as it does not broadly affect endomembrane trafficking or cytoskeletal organization. It has emerged as a very valuable tool for dissecting this essential plant process. In order to gain deeper insights regarding its mode of action and the effects of cytokinesis inhibition on overall plant growth, we investigated the effect of ES7 through a nuclear magnetic resonance spectroscopy metabolomics approach. In this case study, profiles of Arabidopsis leaf and root tissues were analyzed at different growth stages and ES7 exposure levels. The results show tissue-specific changes in the plant metabolic profile across a developmental gradient, and the effect that ES7 treatment has on the corresponding metabolome. The ES7 induced profile suggests metabolic compensations in central metabolism pathways in response to cytokinesis inhibition. Further, this study shows that long-term treatment of ES7 disrupts the homeostasis of primary metabolism in Arabidopsis seedlings, likely via alteration of hormonal regulation.
ATP induces protein folding, inhibits aggregation and antagonizes destabilization by effectively mediating water-protein-ion interactions, the heart of protein folding and aggregation
Authors: Kang Jian , Lim Liangzhong , Song Jianxing
Published: June 2020

Many, particularly β-dominant proteins, are prone to misfolding/aggregation in the crowded cells, a hallmark of ageing and neurodegenerative diseases including ALS. ATP provides energy to drive supramolecular machineries to control protein hemostasis in modern cells. Recently ATP was decoded to hydrotropically inhibit/dissolve liquid-liquid phase separation (LLPS) and aggregation/fibrillation at millimolar concentrations. We also found that by specific binding, ATP induces and subsequently dissolves LLPS, as well as inhibits fibrillation. Nevertheless, no report shows that ATP can directly induce protein folding. Here, by selecting two aggregation-prone ALS-causing proteins with the unfolded states, we successfully visualized the effects of ATP and 11 molecules with NMR directly on their folding and aggregation. The study reveals for the first time that ATP can induce folding at molar ratios of 2-8, the highest efficiency known so far. Intriguingly, this inducing-capacity comes from triphosphate, a key intermediate in prebiotic chemistry, which, however, also triggers aggregation. Most unexpectedly, upon joining with adenosine, the ability of triphosphate to trigger aggregation is shielded. Marvelously, ATP emerged to manifest three integrated abilities: to induce folding, inhibit aggregation and increase stability, that are absent in ATPP, AMP-PCP and AMP-PNP. Our study sheds the first light on previously-unknown roles of ATP in energy-independently controlling protein folding and aggregation by effectively mediating water-protein-ion interactions. Therefore, ATP might be not just irreplaceable for solving protein folding and aggregation problems simultaneously in primitive cells for Origin of Life, but also energy-independently operating in modern cells to regulate protein homeostasis fundamentally critical for physiology and pathology.
Rapid screening and detection of inter-type viral recombinants using phylo-k-mers
Authors: Scholz Guillaume E. , Linard Benjamin , Romashchenko Nikolai , Rivals Eric , Pardi Fabio
Published: June 2020

Motivation

Novel recombinant viruses may have important medical and evolutionary significance, as they sometimes display new traits not present in the parental strains. This is particularly concerning when the new viruses combine fragments coming from phylogenetically-distinct viral types. Here, we consider the task of screening large collections of sequences for such novel recombinants. A number of methods already exist for this task. However, these methods rely on complex models and heavy computations that are not always practical for a quick scan of a large number of sequences.

Results

We have developed SHERPAS, a new program to detect novel recombinants and provide a first estimate of their parental composition. Our approach is based on the precomputation of a large database of “phylogenetically-informedk-mers”, an idea recently introduced in the context of phylogenetic placement in metagenomics. Our experiments show that SHERPAS is hundreds to thousands of times faster than existing software, and enables the analysis of thousands of whole genomes, or long sequencing reads, within minutes or seconds, and with limited loss of accuracy.

Availability and Implementation

The source code is freely available for download athttps://github.com/phylo42/sherpas

Contact

pardi@lirmm.fr,gllm.scholz@gmail.com

Supplementary information

Supplementary Materials are available online.
HSC70, HSPA1A, and HSP90AB1 Facilitate Ebola Virus trVLPs to Induce Autophagy
Authors: Yu Dong-Shan , Yao Shu-Hao , Xi Wen-Na , Cheng Lin-Fang , Liu Fu-Min , Wu Hai-Bo , Lu Xiang-Yun , Wu Nan-Ping , Sun Shui-Lin , Yao Hang-Ping
Published: June 2020

Ebola virus (EBOV) can induce autophagy to benefit the virus life cycle, but detailed mechanisms remain to be elucidated. We previously found that EBOV GP and VP40 proteins interact with HSC70 (HSPA8), HSPA1A, and HSP90AB1. Thus, we presumed that EBOV likely induced autophagy by virus protein-host HSC70 or co-chaperon interactions via chaperone-mediated autophagy (CMA). We developed EBOV-trVLPs to model the EBOV life cycle, infected 293T cells with trVLPs, evaluated CMA by GFP-LC3 and RFP-LAMP1 co-localization, transmission electron microscopy (TEM) observation, and immunoblot analysis. The results demonstrated that EBOV-trVLPs induce autophagy which could not be inhibited by 3-MA significantly; autophagosomes and autolysosomes are obviously in the cytoplasm confirming CMA in cells infected with trVLPs. Meanwhile, a knockdown of HSC70 and relevant co-chaperones could inhibit trVLPs-associated autophagy, but no effort to Akt/mTOR/PHLPP1 pathway. These data indicate that EBOV-trVLPs could induce autophagy by CMA but was not limited by the CMA pathway. HSC70, HSPA1A, and HSP90AB1 participate and regulate CMA induced by EBOV-trVLPs. This was the first study about EBOV-trVLPs-induction of CMA and provides insight into the viral protein-host protein interaction, which is probably associated with CMA.

Highlights

EBOV-trVLPs induce chaperone-mediated autophagy (CMA) but are not limit by CMA.

HSC70, HSPA1A, and HSP90AB1 facilitate EBOV-trVLPs to induce autophagy

Knockdown of HSC70, HSPA1A, and HSP90AB1 inhibit EBOV-trVLPs-induced CMA.
Spatially and cell-type resolved quantitative proteomic atlas of healthy human skin
Authors: Dyring-Andersen Beatrice , Løvendorf Marianne Bengtson , Coscia Fabian , Santos Alberto , Møller Line Bruun Pilgaard , Colaço Ana R. , Niu Lili , Bzorek Michael , Doll Sophia , Andersen Jørgen Lock , Clark Rachael A. , Skov Lone , Teunissen Marcel B.M. , Mann Matthias
Published: June 2020

Human skin provides both physical integrity and immunological protection from the external environment using functionally distinct layers, cell types and extracellular matrix. Despite its central role in human health and disease, the constituent proteins of skin have not been systematically characterized. Here, we combined advanced tissue dissection methods, flow cytometry and state-of-the-art proteomics to describe a spatially-resolved quantitative proteomic atlas of human skin. We quantified 10,701 proteins as a function of their spatial location and cellular origin. The resulting protein atlas and our initial data analyses demonstrate the value of proteomics for understanding cell-type diversity within the skin. We describe the quantitative distribution of structural proteins, known and novel proteins specific to cellular subsets and those with specialized immunological functions such as cytokines and chemokines. We anticipate that this proteomic atlas of human skin will become an essential community resource for basic and translational research (www.skin.science).
Spatio-temporal Characteristics of Noun and Verb Processing during Sentence Comprehension in the Brain
Authors: Jat Sharmistha , Laing Erika J C , Talukdar Partha , Mitchell Tom
Published: June 2020

The human brain is very effective at integrating new words one by one into the composed representation of a sentence as it is read left-to-right. This raises the important question of what happens to the neural representations of words present earlier in the sentence? For example, do the strength of word representations encountered earlier on in the sentence remain constant or do they evolve as additional words are processed? Representation of words by neural activity in the brain has been the subject of several previous studies. We perform the experiment with a naturalistic task in which the subjects read simple active and passive sentences. Naturalistic studies have tended to explore words in isolation or in a very limited context (e.g., adjective-noun phrases). Representation of previously encountered words during incremental sentence reading, and how such representation evolve as more parts of a sentence are read, is a fundamental but unexplored problem – we take a first step in this direction. In particular, we examine the spatio-temporal characteristics of neural activity encoding nouns and verbs encountered in a sentence as it is read word-by-word. We use Magnetoencephalography (MEG) to passively observe neural activity, providing 1 ms temporal resolution.

Our experiments reveal that nouns and verbs read early in the sentence have a varying influence on neural activity while reading subsequent words, decreasing and increasing at particular word positions in active and passively voiced sentences, with particularly important contributions to activity in frontal and temporal cortical regions. We find the noun and verb information to be decodable from the neural activity for several seconds after sentence reading has completed. Our exploration is also the first to study the effect of question-answering task on the neural representation of the words post-sentence. We are releasing our 300 sentence MEG dataset to encourage further research in this important area.
Global discovery of bacterial RNA-binding proteins by RNase-sensitive gradient profiles reports a new FinO domain protein
Authors: Gerovac Milan , Mouali Youssef El , Kuper Jochen , Kisker Caroline , Barquist Lars , Vogel Jörg
Published: June 2020

RNA-binding proteins (RBPs) play important roles in bacterial gene expression and physiology but their true number and functional scope remain little understood even in model microbes. To advance global RBP discovery in bacteria, we here establish glycerol gradient sedimentation with RNase treatment and mass spectrometry (GradR). Applied toSalmonella enterica, GradR confirms many known RBPs such as CsrA, Hfq and ProQ by their RNase-sensitive sedimentation profiles, and discovers the FopA protein as a new member of the emerging family of FinO/ProQ-like RBPs. FopA, encoded on resistance plasmid pCol1B9, primarily targets a small RNA associated with plasmid replication. The target suite of FopA dramatically differs from the related global RBP ProQ, revealing context-dependent selective RNA recognition by FinO-domain RBPs. Numerous other unexpected RNase-induced changes in gradient profiles suggest that cellular RNA helps to organize macromolecular complexes in bacteria. By enabling poly(A)-independent generic RBP discovery, GradR provides an important element in the quest to build a comprehensive catalogue of microbial RBPs.
Gas-phase endstation of electron, ion and coincidence spectroscopies for diluted samples at the FinEstBeAMS beamline of the MAX IV 1.5 GeV storage ring
Authors: Kooser Kuno , Kivimäki Antti , Turunen Paavo , Pärna Rainer , Reisberg Liis , Kirm Marco , Valden Mika , Huttula Marko , Kukk Edwin
Published: June 2020

Since spring 2019 an experimental setup consisting of an electron spectrometer and an ion time-of-flight mass spectrometer for diluted samples has been available for users at the FinEstBeAMS beamline of the MAX IV Laboratory in Lund, Sweden. The setup enables users to study the interaction of atoms, molecules, (molecular) microclusters and nanoparticles with short-wavelength (vacuum ultraviolet and X-ray) synchrotron radiation and to follow the electron and nuclear dynamics induced by this interaction. Test measurements of N2 and thiophene (C4H4S) molecules have demonstrated that the setup can be used for many-particle coincidence spectroscopy. The measurements of the Ar 3p photoelectron spectra by linear horizontal and vertical polarization show that angle-resolved experiments can also be performed. The possibility to compare the electron spectroscopic results of diluted samples with solid targets in the case of Co2O3 and Fe2O3 at the Co and Fe L
2,3-absorption edges in the same experimental session is also demonstrated. Because the photon energy range of the FinEstBeAMS beamline extends from 4.4 eV up to 1000 eV, electron, ion and coincidence spectroscopy studies can be executed in a very broad photon energy range.
A self-supervised workflow for particle picking in cryo-EM
Authors: McSweeney Donal M. , McSweeney Sean M. , Liu Qun
Published: June 2020

High-resolution single-particle cryo-EM data analysis relies on accurate particle picking. To facilitate the particle picking process, a self-supervised workflow has been developed. This includes an iterative strategy, which uses a 2D class average to improve training particles, and a progressively improved convolutional neural network for particle picking. To automate the selection of particles, a threshold is defined (%/Res) using the ratio of percentage class distribution and resolution as a cutoff. This workflow has been tested using six publicly available data sets with different particle sizes and shapes, and can automatically pick particles with minimal user input. The picked particles support high-resolution reconstructions at 3.0 Å or better. This workflow is a step towards automated single-particle cryo-EM data analysis at the stage of particle picking. It may be used in conjunction with commonly used single-particle analysis packages such as Relion, cryoSPARC, cisTEM, SPHIRE and EMAN2.
Judgments about sexual assault vary depending on whether an affirmative consent policy or a “no means no” policy is applied
Authors: Miller Monica K.
Published: June 2020

Purpose

Affirmative consent (AC) policies require potential sexual partners to clearly and positively confirm that they want to engage in sexual behavior – in contrast to standard “no means no” policies, which typically define consent through resistance. AC policies might not be effective because they do not align well with typical scripts of how consent is given in practice. This study aims to compare participants’ judgments as to what constitutes sexual assault, using either an AC policy or a standard “no means no” policy.

Design/methodology/approach

Participants read 16 scenarios depicting various male-female sexual encounters and applied either an AC or a standard “no means no” policy to determine whether the encounter was consensual.

Findings

When an AC policy was used, participants were more likely to judge the scenario as sexual assault. Aspects of the scenario (which reflect AC policy criteria), such as the type of communication (verbal or nonverbal), clarity of communication (clear or unclear) and resistance (high or low) also affected judgments of the scenario. Relationship type (stranger vs acquaintance) did not affect judgments. Students were more likely to perceive the scenarios as sexual assault than community members; they also perceived differences between scenarios based on verbal communication and clarity more than community members. Finally, there was no main effect of participant gender, however, men perceived differences between scenarios based on verbal communication type, whereas women did not.

Research limitations/implications

Findings indicate that participants are generally able to apply AC policies correctly, even though AC criteria do not generally align with common sexual scripts.

Originality/value

This is the first study known to test whether decision-makers can properly apply criteria outlined in AC policies and whether the application of these policies affect decisions-makers judgments as to whether a sexual encounter is consensual or assault.