bluuebunny/crossref_metadata_2025 huggingface dataset:
AGE IS ASSOCIATED WITH INCREASED EXPRESSION OF PATTERN RECOGNITION RECEPTOR GENES ANDACE2, THE RECEPTOR FOR SARS-COV-2: IMPLICATIONS FOR THE EPIDEMIOLOGY OF COVID-19 DISEASE
Authors: Bickler Stephen W. , Cauvi David M. , Fisch Kathleen M. , Prieto James M. , Gaidry Alicia D. , Thangarajah Hariharan , Lazar David , Ignacio Romeo , Gerstmann Dale R. , Ryan Allen F. , Bickler Philip E. , De Maio Antonio
Published: June 2020

Older aged adults and those with pre-existing conditions are at highest risk for severe COVID-19 associated outcomes. Using a large dataset of genome-wide RNA-seq profiles derived from human dermal fibroblasts (GSE113957) we investigated whether age affects the expression of pattern recognition receptor (PRR) genes andACE2, the receptor for SARS-CoV-2. Older age was associated with increased expression of PRR genes,ACE2and four genes that encode proteins that have been shown to interact with SAR2-CoV-2 proteins. Assessment of PRR expression might provide a strategy for stratifying the risk of severe COVID-19 disease at both the individual and population levels.
Constitutive overexpression of RAM1 increases arbuscule density during arbuscular mycorrhizal symbiosis in Brachypodium distachyon
Authors: Müller Lena M. , Campos-Soriano Lidia , Levesque-Tremblay Veronique , Bravo Armando , Daniels Dierdra A. , Pathak Sunita , Park Hee-Jin , Harrison Maria J.
Published: June 2020

Arbuscular mycorrhizal (AM) symbiosis is a mutually beneficial association of plants and fungi of the sub-phylum Glomeromycotina. The endosymbiotic AM fungi colonize the inner cortical cells of the roots, where they form branched hyphae called arbuscules that function in nutrient exchange with the plant. To support arbuscule development and subsequently bidirectional nutrient exchange, the root cortical cells undergo substantial transcriptional re-programming.REDUCED ARBUSCULAR MYCORRHIZA 1 (RAM1), studied in several dicot plant species, is a major regulator of this cortical cell transcriptional program. Here, we generatedram1mutants andRAM1overexpressors in a monocot,Brachypodium distachyon. The AM phenotypes of tworam1linesrevealed thatRAM1is only partly required to enable arbuscule development inB. distachyon. Transgenic lines constitutively overexpressingBdRAM1showed constitutive expression of AM-inducible genes even in the shoots. Following inoculation with AM fungi,BdRAM1-overexpressing roots showed higher arbuscule densities relative to controls, indicating the potential to manipulate the relative proportion of symbiotic interfaces via modulation ofRAM1. However, the overexpressors also show altered expression of hormone biosynthesis genes and aberrant growth patterns including stunted bushy shoots and poor seed set. While these phenotypes possibly provide additional clues aboutBdRAM1’s scope of influence, they also indicate that directed approaches to increase the density of symbiotic interfaces will require a more focused, potentially cell-type specific manipulation of transcription factor gene expression.
Virus survival in evaporated saliva microdroplets deposited on inanimate surfaces
Authors: Fedorenko Aliza , Grinberg Maor , Orevi Tomer , Kashtan Nadav
Published: June 2020

The novel coronavirus respiratory syndrome (COVID-19) has now spread worldwide. The relative contribution of viral transmission via fomites is still unclear. SARS-CoV-2 has been shown to survive on inanimate surfaces for several days, yet the factors that determine its survival on surfaces are not well understood. Here we combine microscopy imaging with virus viability assays to study survival of three bacteriophages suggested as good models for human respiratory pathogens: the enveloped Phi6 (a surrogate for SARS-CoV-2), and the non-enveloped PhiX174 and MS2. We measured virus viability in human saliva microdroplets, SM buffer, and water following deposition on glass surfaces at various relative humidities (RH). Although saliva microdroplets dried out rapidly at all tested RH levels (unlike SM that remained hydrated at RH ≥ 57%), survival of all three viruses in dry saliva microdroplets was significantly higher than in water or SM. Thus, RH and hydration conditions are not sufficient to explain virus survival, indicating that the suspended medium, and association with saliva components in particular, likely affect physicochemical properties that determine virus survival. The observed high virus survival in dry saliva deposited on surfaces, under a wide range of RH levels, can have profound implications for human public health, specifically the COVID-19 pandemic.
Mutation density changes in SARS-CoV-2 are related to the pandemic stage but to a lesser extent in the dominant strain with mutations in spike and RdRp
Authors: Eskier Doğa , Suner Aslı , Karakülah Gökhan , Oktay Yavuz
Published: June 2020

Since its emergence in Wuhan, China in late 2019, the origin and evolution of SARS-CoV-2 have been among the most debated issues related to COVID-19. Throughout its spread around the world, the viral genome continued acquiring new mutations and some of them became widespread. Among them, 14408 C>T and 23403 A>G mutations in RdRp and S, respectively, became dominant in Europe and the US, which led to debates regarding their effects on the mutability and transmissibility of the virus. In this study, we aimed to investigate possible differences between time-dependent variation of mutation densities (MDe) of viral strains that carry these two mutations and those that do not. Our analyses at the genome and gene level led to two important findings: First, time-dependent changes in the average MDe of circulating SARS-CoV-2 genomes showed different characteristics before and after the beginning of April, when daily new case numbers started levelling off. Second, this pattern was much delayed or even non-existent for the “mutant” (MT) strain that harbored both 14408 C>T and 23403 A>G mutations. Although these differences were not limited to a few hotspots, it is intriguing that the MDe increase is most evident in two critical genes, S and Orf1ab, which are also the genes that harbor the defining mutations of the MT genotype. The nature of these unexpected relationships warrant further research.
The Integrin Binding Peptide, ATN-161, as a Novel Therapy for SARS-CoV-2 Infection
Authors: Beddingfield Brandon , Iwanaga Naoki , Chapagain Prem , Zheng Wenshu , Roy Chad J. , Hu Tony Y. , Kolls Jay , Bix Gregory
Published: June 2020

Many efforts to design and screen therapeutics for severe acute respiratory syndrome coronavirus (SARS-CoV-2) have focused on inhibiting viral cell entry by disrupting ACE2 binding with the SARS-CoV-2 spike protein. This work focuses on inhibiting SARS-CoV-2 entry through a hypothesized α5β1 integrin-based mechanism, and indicates that inhibiting the spike protein interaction with α5β1 integrin (+/− ACE2), and the interaction between α5β1 integrin and ACE2 using a molecule ATN-161 represents a promising approach to treat COVID-19.
Fatty acid composition and parasitism of European sardine (Sardina pilchardus) and European anchovy (Engraulis encrasicolus) populations in the northern Catalan Sea in the context of changing environmental conditions
Authors: Biton-Porsmoguer Sebastian , Bou Ricard , Lloret Elsa , Alcaide Manuel , Lloret Josep
Published: June 2020

The status of sardine and anchovy populations in the northern Mediterranean Sea has been declining in recent decades. In this study, fatty acids and parasitism at different reproductive and feeding stages in these two species were assessed using specimens caught along the northern Catalan coast, in order to assess the links between lipid dynamics, reproduction and feeding in these two species, and to contribute towards an explanation of the potential causes of the current situation of the stocks. The results support the use of fatty acid levels as indicators of the body condition of sardine and anchovy at different reproductive and feeding stages, as well as that of the pelagic environmental conditions. In particular, the relatively low n-3 PUFA levels (which are crucial for reproductive success) found in spawning sardines compared to spawning anchovies indicate a poorer reproductive health status of sardine. By comparing the current total lipid content values with those recorded in other Mediterranean and North Atlantic areas, and, others from more than ten years ago, in the adjacent area of the Gulf of Lion, our study reveals the persistent poor condition of sardine and anchovy in the northern Catalan Sea. Furthermore, the low levels of diatom fatty acid markers observed throughout the spawning and non-spawning seasons in both sardine and anchovy, indicate a diet poor in diatoms. Moreover, the results indicate that it is very unlikely that parasitism is a significant factor in the decline in condition of sardine and anchovy in the northern Catalan Sea. In fact, the results suggest that the current poor condition of sardine and anchovy in the northern Catalan Sea has been exacerbated by a decrease in plankton productivity and/or a shift in the taxonomic composition of phytoplankton communities, adding to the ongoing effects of overfishing.
Cascade of care, awareness and treatment of Chronic Hepatitis B in Malaysia- findings from a community-based screening campaign
Authors: Lim ZZ , Teo JS , Tan AC , Siam Tan Soek , Mohamed Rosmawati , Goh KL , Lee YY , Lai WH , Lim TO
Published: June 2020

Introduction

In 2016 the World Health Organization (WHO) had adopted a global strategy to eliminate Hepatitis B (HBV) by 2030 through five core interventions, the first four were preventive while the fifth is the “cascade of care”, the continuum of services that persons with chronic HBV should receive as they progress from screening to diagnosis to treatment to chronic care. We determined the prevalence of the awareness and treatment of chronic HBV in Malaysia based on a large sample data from a screening campaign.

Methods

A total of 10,436 subjects participated in the HBV screening campaign organized by the Hepatitis Free Pahang Malaysia (HFPM) in 2018 and 2019. All screen-positive subjects were recalled to undergo laboratory-based HBsAg and HBV DNA tests. Patients with confirmed chronic HBV were referred to local health services, while continued being monitored by HFPM.

Results

We estimated 13.1% of Malaysian adults aged 20 or older with chronic HBV were aware of their HBV status, and of those only 0.7% had received prior anti-viral treatment, but among those with baseline HBV DNA level>20,000 IU/ml, 15.6% were subsequently treated. Tenofovir disoproxil fumarate was the only medicine used on all treated patients. The linkage to care post-screening was broken in substantial number of patients, only 108 (54%) subjects had returned to have their HBV DNA measured and only 115 (58%) patients had subsequently sought care and were on still follow-up.

Conclusion

Few Malaysian adults with HBV were aware of their infection and even less received anti-viral therapy. Concerted public health efforts are urgently needed to improve HBV screening and care cascade in order to meet WHO’s targets for HBV elimination.
Automatic phenotyping of electronical health record: PheVis algorithm
Authors: Ferté Thomas , Cossin Sébastien , Schaeverbeke Thierry , Barnetche Thomas , Jouhet Vianney , Hejblum Boris P
Published: June 2020

Electronic Health Records (EHRs) often lack reliable annotation of patient medical conditions. Yu et al. recently proposed PheNorm, an automated unsupervised algorithm to identify patient medical conditions from EHR data. PheVis extends PheNorm at the visit resolution. PheVis combines diagnosis codes together with medical concepts extracted from medical notes, incorporating past history in a machine learning approach to provide an interpretable “white box” predictor of the occurrence probability for a given medical condition at each visit. PheVis is applied to two real-world use-cases using the datawarehouse of the University Hospital of Bordeaux: i) rheumatoid arthritis, a chronic condition; ii) tuberculosis, an acute condition (cross-validated AUROC were respectively 0.947 [0.944; 0.948] and 0.987 [0.983; 0.990]). PheVis performs well for chronic conditions, though absence of exclusion of past medical history by natural language processing tools limits its performance in French for acute conditions. It achieves significantly better performance than state-of-the-art methods especially for chronic diseases.
The effect of serological screening for SARS-CoV-2 antibodies to participants’ attitudes and risk behaviour: a study on a tested population sample of industry workers in Split-Dalmatia County, Croatia
Authors: Ljubić Toni , Banovac Ana , Buljan Ivan , Jerković Ivan , Bašić Željana , Kružić Ivana , Kolić Andrea , Kolombatović Rino Rivi , Marušić Ana , Anđelinović Šimun
Published: June 2020

Rapid serological tests for SARS-CoV-2 antibodies have been questioned by scientists and the public because of unexplored effects of negative test results on behaviour and attitudes, that could lower the level of adherence to protective measures. Therefore, our study aimed to investigate the changes in personal attitudes and behaviour before and after negative serological test results for SARS-CoV-2 antibodies. We conducted a survey questionnaire on 200 industry workers (69% males and 31% females) that have been previously tested negative. The survey examined participants’ self-reported general attitudes towards COVID-19, sense of fear, as well as their behaviour related to protective measures before and after the testing. The participants perceived the disease as a severe health threat and acknowledged the protective measures as appropriate. They reported a high level of adherence to measures and low level of fear both before and after the testing. Although those indicators were statistically significantly reduced after the test (P < 0.004), they did not result in risk behaviour. Therefore, the serological tests are not an additional threat regarding the risk behaviour in an environment where protective measures are efficient. In contrast, they might contribute to reducing the fear in the society and working environment.
Causes of Death and Comorbidities in Patients with COVID-19
Authors: Elezkurtaj Sefer , Greuel Selina , Ihlow Jana , Michaelis Edward , Bischoff Philip , Kunze Catarina Alisa , Sinn Bruno Valentin , Gerhold Manuela , Hauptmann Kathrin , Ingold-Heppner Barbara , Miller Florian , Herbst Hermann , Corman Victor Max , Martin Hubert , Radbruch Helena , Heppner Frank L. , Horst David
Published: June 2020

Infection by the new corona virus strain SARS-CoV-2 and its related syndrome COVID-19 has caused several hundreds of thousands of deaths worldwide. Patients of higher age and with preexisting chronic health conditions are at an increased risk of fatal disease outcome. However, detailed information on causes of death and the contribution of comorbidities to death yet is missing. Here, we report autopsy findings on causes of death and comorbidities of 26 decedents that had clinically presented with severe COVID-19. We found that septic shock and multi organ failure was the most common immediate cause of death, often due to suppurative pulmonary infection. Respiratory failure due to diffuse alveolar damage presented as the most immediate cause of death in fewer cases. Several comorbidities, such as hypertension, ischemic heart disease, and obesity were present in the vast majority of patients. Our findings reveal that causes of death were directly related to COVID-19 in the majority of decedents, while they appear not to be an immediate result of preexisting health conditions and comorbidities. We therefore suggest that the majority of patients had died of COVID-19 with only contributory implications of preexisting health conditions to the mechanism of death.
Diagnostic accuracy of six commercial SARS-CoV-2 IgG/total antibody assays and identification of SARS-CoV-2 neutralizing antibodies in convalescent sera
Authors: Strömer Annabelle , Grobe Olaf , Rose Ruben , Fickenscher Helmut , Lorentz Thomas , Krumbholz Andi
Published: June 2020

The reliable detection of immunoglobulin G (IgG) or total antibodies directed against the novel severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is important for clinical diagnostics and epidemiological studies.

Here, we compare the diagnostic accuracy of six commercially available SARS-CoV-2 IgG (Abbott SARS-CoV-2 IgG; Diasorin Liaison® SARS-CoV-2 S1/2 IgG; Epitope EDI™ Novel Coronavirus COVID-19 IgG ELISA Kit; Euroimmun Anti-SARS-CoV-2 ELISA (IgG); Mikrogen recomWell SARS-CoV-2 IgG) or total SARS-CoV-2 antibody assays (Roche Elecsys Anti-SARS-CoV-2).

The test sensitivities were analyzed with a set of 34 sera obtained from 26 patients after PCR-confirmed SARS-CoV-2 infection and varied from 76.9% (Euroimmun) to 96.2% (Abbott). The majority of assay results were confirmed in a laboratory-developed plaque reduction neutralization test and by a SARS-CoV-2 IgG-specific line assay including measurement of generally low IgG avidities (Mikrogen recomLine Coronavirus IgG [Avidität], prototype).

Moreover, 100 stored sera collected during summer 2018 (N = 50) and winter season 2018/2019 (N = 50) were included to demonstrate test specificities. These varied from 96.0% (DiaSorin) to 100% (Epitope EDI™).

A subset of sera were retested with a lateral flow test (STANDARD Q COVID-19 IgM/IgG Duo) and a considerably lower sensitivity was noted.

Overall, the diagnostic accuracy of the six SARS-CoV-2 IgG/total antibody assays was good and varied from 92.9% (Euroimmun) to 98.4% (Abbott). Due to the different specificities, results of commercially available SARS-CoV-2 antibody tests should be interpreted with caution. A high proportion of antibody-positive patient sera demonstrated neutralizing capacity against SARS-CoV-2.
Artificial Intelligence for COVID-19 Risk Classification in Kidney Disease: Can Technology Unmask an Unseen Disease?
Authors: Monaghan Caitlin , Larkin John W. , Chaudhuri Sheetal , Han Hao , Jiao Yue , Bermudez Kristine M. , Weinhandl Eric D. , Dahne-Steuber Ines A. , Belmonte Kathleen , Neri Luca , Kotanko Peter , Kooman Jeroen P. , Hymes Jeffrey L. , Kossmann Robert J. , Usvyat Len A. , Maddux Franklin W.
Published: June 2020

Background

We developed two unique machine learning (ML) models that predict risk of: 1) a major COVID-19 outbreak in the service county of a local HD population within following week, and 2) a hemodialysis (HD) patient having an undetected SARS-CoV-2 infection that is identified after following 3 or more days.

Methods

We used county-level data from United States population (March 2020) and HD patient data from a network of clinics (February-May 2020) to develop two ML models. First was a county-level model that used data from general and HD populations (21 variables); outcome of a COVID-19 outbreak in a dialysis service area was defined as a clinic being located in one of the national counties with the highest growth in COVID-19 positive cases (number and people per million (ppm)) in general population during 22-28 Mar 2020. Second was a patient-level model that used HD patient data (82 variables) to predict an individual having an undetected SARS-CoV-2 infection that is identified in subsequent ≥3 days.

Results

Among 1682 counties with dialysis clinics, 82 (4.9%) had a COVID-19 outbreak during 22-28 Mar 2020. Area under the receiver operating characteristic curve (AUROC) for the county-level model was 0.86 in testing dataset. Top predictor of a county experiencing an outbreak was the COVID-19 positive ppm in the general population in the prior week. In a select group (n=11,664) used to build the patient-level model, 28% of patients had COVID-19; prevalence was by design 10% in the testing dataset. AUROC for the patient-level model was 0.71 in the testing dataset. Top predictor of an HD patient having a SARS-CoV-2 infection was mean pre-HD body temperature in the prior week.

Conclusions

Developed ML models appear suitable for predicting counties at risk of a COVID-19 outbreak and HD patients at risk of having an undetected SARS-CoV-2 infection.
Transmission of SARS-CoV-2 by inhalation of respiratory aerosol in the Skagit Valley Chorale superspreading event
Authors: Miller Shelly L. , Nazaroff William W , Jimenez Jose L. , Boerstra Atze , Buonanno Giorgio , Dancer Stephanie J. , Kurnitski Jarek , Marr Linsey C. , Morawska Lidia , Noakes Catherine
Published: June 2020

During the 2020 COVID-19 pandemic, an outbreak occurred following attendance of a symptomatic index case at a regular weekly rehearsal on 10 March of the Skagit Valley Chorale (SVC). After that rehearsal, 53 members of the SVC among 61 in attendance were confirmed or strongly suspected to have contracted COVID-19 and two died. Transmission by the airborne route is likely. It is vital to identify features of cases such as this so as to better understand the factors that promote superspreading events. Based on a conditional assumption that transmission during this outbreak was by inhalation of respiratory aerosol, we use the available evidence to infer the emission rate of airborne infectious quanta from the primary source. We also explore how the risk of infection would vary with several influential factors: the rates of removal of respiratory aerosol by ventilation; deposition onto surfaces; and viral decay. The results indicate an emission rate of the order of a thousand quanta per hour (mean [interquartile range] for this event = 970 [680-1190] quanta per hour) and demonstrate that the risk of infection is modulated by ventilation conditions, occupant density, and duration of shared presence with an infectious individual.

Practical Implications

During respiratory disease pandemics, group singing indoors should be discouraged or at a minimum carefully managed as singing can generate large amounts of airborne virus (quanta) if any of the singers is infected.

Ventilation requirements for spaces that are used for singing (e.g., buildings for religious services and rehearsal/performance) should be reconsidered in light of the potential for airborne transmission of infectious diseases.

Meetings of choirs and other kinds of singing groups during pandemics should only be in spaces that are equipped with a warning system of insufficient ventilation which may be detected with CO2 “traffic light” monitors.

Systems that combine the functions heating and ventilation (or cooling and ventilation) should be provided with a disclaimer saying “do not shut this system off when people are using the room; turning off the system will also shut down fresh air supply, which can lead to the spread of airborne infections.”
Evaluation of a Novel Therapeutic Repetitive Transcranial Magnetic Stimulation Technique Optimized for Increased Accessibility in Major Depression
Authors: Miron Jean-Philippe , Voetterl Helena , Fox Linsay , Hyde Molly , Mansouri Farrokh , Dees Sinjin , Zhou Ryan , Sheen Jack , Mir-Moghtadaei Arsalan , Blumberger Daniel M. , Daskalakis Zafiris J. , Vila-Rodriguez Fidel , Downar Jonathan
Published: June 2020

BACKGROUND

Repetitive transcranial magnetic stimulation (rTMS) is effective in major depressive disorder (MDD). However, technical complexity and operational costs might have been barriers for its wide use and implementation in some jurisdictions, thereby decreasing accessibility.

OBJECTIVE

Our main goal was to test the feasibility of a novel rTMS protocol optimized for practicality, scalability and cost-effectiveness. We hypothesized that our novel rTMS protocol would be simple to implement and well-tolerated, but less costly and allow for more treatment capacity.

METHODS

Treatment was administered in an open-room setting, allowing a single technician to attend to multiple patients. Large non-focal parabolic coils held by custom-built arms allowed simple yet efficient and accurate placement. We employed a low-frequency (LF) 1 Hz stimulation protocol (360 pulses per session), delivered on the most affordable FDA-approved devices. MDD participants received an initial accelerated rTMS course (arTMS) of 6 sessions/day over 5 days (30 total), followed by a tapering course of daily sessions (up to 25) to decrease the odds of relapse. The self-reported Beck Depression Inventory II (BDI-II) was used to measure severity of depression.

RESULTS

Forty-eight (48) patients completed the arTMS course. No serious adverse events occurred, and all patients reported manageable pain levels. Response and remission rates were 35.4% and 27.1% on the BDI-II, respectively, at the end of the tapering course.

CONCLUSION

If rTMS could be delivered for lower cost at higher volume, while preserving efficacy, safety and tolerability, it could warrant further investigation of this treatment as a first-line intervention in MDD.

TRIAL REGISTRATION

ClinicalTrials.gov Identifier: NCT04376697
Commercial Airline Protocol during Covid-19 Pandemic: An Experience of Thai Airways International
Authors: Pongpirul Krit , Kaewpoungngam Kanitha , Chotirosniramit Korn , Theprugsa Sinnop
Published: June 2020

Introduction

Coronavirus disease 2019 (COVID-19) pandemic has affected the aviation industry. Existing protocols have relied on scientifically questionable evidence and might not lead to the optimal balance between public health safety and airlines’ financial viability.

Objective

To explore the implementation feasibility of Thai Airways International protocol from the perspectives of passengers and aircrews.

Design

An online questionnaire survey of passengers and an in-depth interview with aircrews.

Setting

Two randomly selected repatriation flights operated by Thai Airways International using Boeing 777 aircraft (TG476 from Sydney and TG492 from Auckland to Bangkok)

Participants

377 Thai passengers and 35 aircrews.

Results

The mean age of passengers was 28.14 (95%CI 26.72 to 29.55) years old; 57.03% were female. TG492 passengers were mostly students and significantly younger than that of TG476 (p<0.0001) with comparable flying experience (p=0.1192). The average body temperature was 36.52 (95%CI 36.48 to 36.55) degrees Celsius. Passengers estimated average physical distances of 1.59 (95%CI 1.48 to 1.70), 1.41 (95%CI 1.29 to 1.53), and 1.26 (95%CI 1.12 to 1.41) meters at check-in, boarding, and in-flight, respectively. Passengers were checked for body temperature during the flight 1.97 (95%CI 1.77 to 2.18) times on average which is significantly more frequent in longer than shorter flight (p<0.0001). Passengers moved around or went to the toilet during the flight 2.00 (95%CI 1.63 to 2.37) and 2.08 (95%CI 1.73 to 2.43) times which are significantly more frequent in longer than shorter flight (p=0.0186 and 0.0049, respectively). The aircrews were satisfied with the protocol and provided several practical suggestions.

Conclusion

The protocol was well received by the passengers and aircrews of the repatriation flights with some suggestions for improvement.
Worsening of kidney function is the major mechanism of heart failure in hypertension: the ALLHAT study
Authors: Khayyat-Kholghi Maedeh , Oparil Suzanne , Davis Barry R. , Tereshchenko Larisa G.
Published: June 2020

Background

We aimed to quantify the extent to which the effect of antihypertensive drugs on incident heart failure (HF) is mediated by their effect on kidney function. We hypothesized that the dynamic change in kidney function is the mechanism behind differences in the rate of incident HF in ALLHAT participants randomized to lisinopril, amlodipine, and doxazosin, in comparison to those randomized to chlorthalidone.

Methods

Causal mediation analysis of ALLHAT data (1994-2002) included participants with available baseline and 24-48 month estimated glomerular filtration rate (eGFR) (n=27,918; mean age 66±7.4; 32.4% black, 56.3% men). Change in eGFR was the mediator. Incident symptomatic HF was the primary outcome. Hospitalized/fatal HF was the secondary outcome. Linear regression (for mediator) and logistic regression (for outcome) analyses were adjusted for demographics, cardiovascular disease, and risk factors.

Results

There were 1,769 incident HF events, including 1,359 hospitalized/fatal HF events. In fully adjusted causal mediation analysis, the relative change in eGFR mediated 38% of the effect of amlodipine, 25.5% of doxazosin, and 6.3% of lisinopril on incident symptomatic HF, and 42% of the effect of amlodipine, 55.3% of doxazosin, and 12.7% of lisinopril on hospitalized/fatal HF. In lisinopril arm, eGFR changes had an opposite effect on symptomatic versus hospitalized/fatal HF outcomes. Reduction in eGFR by at least 40% explained > 50% of increased risk in hospitalized/fatal HF but 18-25% reduction of symptomatic HF risk.

Conclusion

On the risk difference scale, change in eGFR accounts for more than 50% of the mechanism by which antihypertensive medications affect HF.

Clinical Trial Registration

URL:www.clinicaltrials.govUnique identifier:NCT00000542.
The sensorimotor strategies and neuronal representations of tactile shape discrimination in mice
Authors: Rodgers Chris C , Nogueira Ramon , Pil B Christina , Greeman Esther A , Fusi Stefano , Bruno Randy M
Published: June 2020

Humans and other animals can identify objects by active touch, requiring the coordination of exploratory motion and tactile sensation. The brain integrates movements with the resulting tactile signals to form a holistic representation of object identity. We developed a shape discrimination task that challenged head-fixed mice to discriminate concave from convex shapes. Behavioral decoding revealed that mice did this by comparing contacts across whiskers. In contrast, mice performing a shape detection task simply summed up contacts over whiskers. We recorded populations of neurons in the barrel cortex, which processes whisker input, to identify how it encoded the corresponding sensorimotor variables. Neurons across the cortical layers encoded touch, whisker motion, and task-related signals. Sensory representations were task-specific: during shape discrimination, neurons responded most robustly to behaviorally relevant whiskers, overriding somatotopy. We suggest a similar dynamic modulation may underlie object recognition in other brain areas and species.
Diagnostic Evidence GAuge of Single cells (DEGAS): A flexible deep-transfer learning framework for prioritizing cells in relation to disease
Authors: Johnson Travis S. , Yu Christina Y. , Huang Zhi , Xu Siwen , Wang Tongxin , Dong Chuanpeng , Shao Wei , Zaid Mohammad Abu , Huang Xiaoqing , Wang Yijie , Bartlett Christopher , Zhang Yan , Walker Brian A. , Liu Yunlong , Huang Kun , Zhang Jie
Published: June 2020

We proposeDEGAS(Diagnostic Evidence GAuge of Single cells), a novel deep transfer learning framework, to transfer disease information from patients to cells. We call such transferrable information “impressions,” which allow individual cells to be associated with disease attributes like diagnosis, prognosis, and response to therapy. Using simulated data and ten diverse single cell and patient bulk tissue transcriptomic datasets from Glioblastoma Multiforme (GBM), Alzheimer’s Disease (AD), and Multiple Myeloma (MM), we demonstrate the feasibility, flexibility, and broad applications of theDEGASframework.DEGASanalysis on newly generated myeloma single cell transcriptomics led to the identification ofPHF19highmyeloma cells associated with progression.
High-frequency oscillations in the internal globus pallidus: a pathophysiological biomarker in Parkinson's disease?
Authors: Johnson Luke A , Aman Joshua E , Yu Ying , Escobar Sanabria David , Wang Jing , Hill Meghan , Dharnipragada Rajiv , Patriat Remi , Fiecas Mark , Li Laura , Schrock Lauren E , Cooper Scott E , Johnson Matthew D , Park Michael C , Harel Noam , Vitek Jerrold L
Published: June 2020

Abnormal oscillatory neural activity in the basal ganglia is thought to play a pathophysiological role in Parkinson’s disease. Many patient studies have focused on beta frequency band (13-35 Hz) local field potential activity in the subthalamic nucleus, however increasing evidence points to alterations in neural oscillations in high frequency ranges (>100 Hz) having pathophysiological relevance. Prior studies have found that power in subthalamic high frequency oscillations (HFOs) is positively correlated with dopamine tone and increased during voluntary movements, implicating these brain rhythms in normal basal ganglia function. Contrary to this idea, in the current study we present a combination of clinical and preclinical data that support the hypothesis that HFOs in the internal globus pallidus (GPi) are a pathophysiological feature of Parkinson’s disease. Spontaneous and movement-related pallidal field potentials were recorded from deep brain stimulation (DBS) leads targeting the GPi in five externalized Parkinson’s disease patients, on and off dopaminergic medication. We identified a prominent oscillatory peak centered at 200-300 Hz in the off-medication rest recordings in all patients. High frequency power increased during movement, and the magnitude of modulation was negatively correlated with bradykinesia. Moreover, high frequency oscillations were significantly attenuated in the on-medication condition, suggesting they are a feature of the parkinsonian condition. To further confirm that GPi high frequency oscillations are characteristic of dopamine depletion, we also collected field potentials from DBS leads chronically implanted in three rhesus monkeys before and after the induction of parkinsonism with the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). High frequency oscillations and their modulation during movement were not prominent in the normal condition but emerged in the parkinsonian condition in the monkey model. These data provide the first evidence demonstrating that exaggerated, movement-modulated high frequency oscillations in the internal globus pallidus are a pathophysiological feature of Parkinson’s disease, and motivate additional investigations into the functional roles of high frequency neural oscillations across the basal ganglia-thalamocortical motor circuit and their relationship to motor control in normal and diseased states. These findings also provide rationale for further exploration of these signals for electrophysiological biomarker-based device programming and stimulation strategies in patients receiving deep brain stimulation therapy.
Predation drives specialized host plant associations in preadapted milkweed bugs (Heteroptera: Lygaeinae)
Authors: Petschenka Georg , Halitschke Rayko , Roth Anna , Stiehler Sabrina , Tenbusch Linda , Züst Tobias , Hartwig Christoph , Gámez Juan Francisco Moreno , Trusch Robert , Deckert Jürgen , Chalušová Kateřina , Vilcinskas Andreas , Exnerová Alice
Published: June 2020

Host plant specialization across herbivorous insects varies dramatically, but the underlying evolutionary mechanisms are little-known. The milkweed bugs (Heteroptera: Lygaeinae) are ancestrally associated with plants of the Apocynaceae from which they commonly sequester cardiac glycosides for defense, facilitated by resistant Na+/K+-ATPases and adaptations for transport, storage and discharge of toxins. Here, we show that three Lygaeinae species independently colonized four novel non-apocynaceous hosts, convergently producing cardiac glycosides. A fourth species shifted to a new source of toxins by tolerating and sequestering alkaloids from meadow saffron (Colchicum autumnale, Colchicaceae). Across three species tested, feeding on seeds containing toxins did not improve growth, but sequestration mediated protection against predatory lacewing larvae and birds. We conclude that physiological preadaptations and convergent phytochemistry facilitated novel specialized host associations. Therefore, selection by predators on sequestration of defenses, rather than the exploitation of novel dietary resources, can lead to obligatory specialized host associations in generalist insects.
Cdc42 GTPase Activating Proteins (GAPs) Maintain Generational Inheritance of Cell Polarity and Cell Shape in Fission Yeast
Authors: Pino Marbelys Rodriguez , Nuñez Illyce , Chen Chuan , Das Maitreyi E. , Wiley David J. , D’Urso Gennaro , Buchwald Peter , Vavylonis Dimitrios , Verde Fulvia
Published: June 2020

The highly conserved small GTPase Cdc42 regulates polarized cell growth and morphogenesis from yeast to humans. We previously reported that Cdc42 activation exhibits oscillatory dynamics inSchizosaccharomyces pombecells. Mathematical modeling suggests that this dynamic behavior enables a variety of symmetric and asymmetric Cdc42 distributions to coexist in cell populations. For individual wild type cells, however, growth follows a stereotypical pattern where Cdc42 distribution is initially asymmetrical in young daughter cells and becomes more symmetrical as cell volume increases, enabling bipolar growth activation. To explore whether different states of Cdc42 activation are possible in a biological context, we examinedS. pombe rga4Δ mutant cells, lacking the Cdc42 GTPase activating protein (GAP) Rga4. We found that monopolarrga4Δ mother cells divide asymmetrically leading to the emergence of both symmetric and asymmetric Cdc42 distributions inrga4Δ daughter cells. Using genetic screening approaches to identify mutants that alter therga4Δ phenotype, we tested the predictions of different computational models that reproduce the unequal fate of daughter cells. We found experimentally that the unequal distribution of active Cdc42 GTPase in daughter cells is consistent with an unequal inheritance of another Cdc42 GAP, Rga6, in the two daughter cells. Our findings highlight the crucial role of Cdc42 GAP protein localization in determining the morphological fate of cell progeny and ensuring consistent Cdc42 activation and growth patterns across generations.
Oral drug repositioning candidates and synergistic remdesivir combinations for the prophylaxis and treatment of COVID-19
Authors: Bakowski Malina A. , Beutler Nathan , Chen Emily , Nguyen Tu-Trinh H. , Kirkpatrick Melanie G. , Parren Mara , Yang Linlin , Ricketts James , Gupta Anil K. , Hull Mitchell V. , Schultz Peter G. , Burton Dennis R. , Chatterjee Arnab K. , McNamara Case W. , Rogers Thomas F.
Published: June 2020

The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. A high-throughput, high-content imaging assay of human HeLa cells expressing the SARS-CoV-2 receptor ACE2 was used to screen ReFRAME, a best-in-class drug repurposing library. From nearly 12,000 compounds, we identified 66 compounds capable of selectively inhibiting SARS-CoV-2 replication in human cells. Twenty-four of these drugs show additive activity in combination with the RNA-dependent RNA polymerase inhibitor remdesivir and may afford increased in vivo efficacy. We also identified synergistic interaction of the nucleoside analog riboprine and a folate antagonist 10-deazaaminopterin with remdesivir. Overall, seven clinically approved drugs (halofantrine, amiodarone, nelfinavir, simeprevir, manidipine, ozanimod, osimertinib) and 19 compounds in other stages of development may have the potential to be repurposed as SARS-CoV-2 oral therapeutics based on their potency, pharmacokinetic and human safety profiles.
The nucleus serves as the pacemaker for the cell cycle
Authors: Afanzar O. , Buss G. K , Stearns T. , Ferrell J. E.
Published: June 2020

Mitosis is a dramatic cellular process that affects all parts of the cell. InXenopusembryos and extracts it is driven by the activation of a bistable trigger circuit, whose various components are localized in the nucleus, centrosome, and cytoplasm. In principle, whichever cellular location has the fastest intrinsic rhythm should act as a pacemaker for the process. Here we followed tubulin polymerization and depolymerization inXenopusegg extracts supplemented with demembranated sperm, and thereby identified locations where mitosis first occurred. We found that mitosis was commonly first initiated at sperm-derived nuclei and their accompanying centrosomes, and then spread outward in circular trigger waves. The cell cycle was ∼20% more rapid at the nucleus/centrosome-associated trigger wave sources than in the regions of the extract that appeared not to be entrained by trigger waves. Nuclei produced from phage DNA, which did not possess centrosomes, also acted as trigger wave sources, but purified centrosomes in the absence of nuclei did not. We conclude that the nucleus accelerates mitotic entry and propose that it acts as a pacemaker for cell cycle.

One Sentence Summary

Studies in cyclingXenopusegg extracts show that mitosis first occurs in the nucleus and then spreads outward through the cytoplasm in circular trigger waves.
Identification of potential biomarkers or therapeutic targets of mesenchymal stem cells in multiple myeloma by bioinformatics analysis
Authors: Li Zhi-Ran , Cai Wen-Ke , Yang Qin , Shen Ming-Li , Zhang Hua-Zhu , Huang Qian , Zhao Gui-Xin , Chen Ke-Yan , He Gong-Hao
Published: June 2020

Objectives

Mesenchymal stem cells (MSCs) play important roles in multiple myeloma (MM) pathogenesis. Previous studies have discovered a group of MM-associated potential biomarkers in MSCs derived from bone marrow (BM-MSCs). However, no study of the bioinformatics analysis was conducted to explore the key genes and pathways of MSCs derived from adipose (AD-MSCs) in MM. The aim of this study was to screen potential biomarkers or therapeutic targets of AD-MSCs and BM-MSCs in MM.

Methods

The gene expression profiles of AD-MSCs (GSE133346) and BM-MSCs (GSE36474) were downloaded from Gene Expression Omnibus (GEO) database. Gene Oncology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and protein-protein interaction (PPI) network of differentially expressed genes (DEGs) were performed.

Results

A total of 456 common downregulated DEGs in two datasets were identified and the remaining DEGs in GSE133346 were further identified as specific DEGs of AD-MSCs. Furthermore, a PPI network of common downregulated DEGs was constructed and seven hub genes were identified. Importantly, cell cycle was the most significantly enrichment pathway both in AD-MSCs and BM-MSCs from MM patients.

Conclusion

We identified key genes and pathways closely related with MM progression, which may act as potential biomarkers or therapeutic targets of MM.
Immobilization, Direct Electrochemistry and Electrocatalysis of Hemoglobin on Peptide-Carbon Nanotube Modified Electrode
Authors: Sheikholeslam Mohammadali , Nanda Piyush , Pritzker Mark , Chen P.
Published: June 2020

The direct electrochemistry of hemoglobin (Hb) immobilized on a glassy carbon electrode (GCE) by mixing with a hybrid dispersion of self-assembling peptide EFK8 and single-walled carbon nanotubes (SWNT) was investigated and shown to have effective properties as a biosensor for hydrogen peroxide (H2O2). Preliminary experiments involving cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) showed that the presence of SWNTs in the modifying peptide layer on GCE significantly enhanced the electrochemical response of the electrode for the ferricyanide/ferrocyanide redox couple. Also, when more layers of the peptide-SWNT dispersion were applied to the surface, the electrochemical response of the GCE was further increased. This behavior was then exploited to fabricate a biosensor for H2O2by mixing hemoglobin with the hybrid peptide-SWNT dispersion and casting this mixture on a glassy carbon electrode. AFM imaging, CV and EIS analysis revealed successful immobilization of Hb on the electrode and the ability of the electrode to enable direct electron transfer from Hb to the electrode surface. In particular, CVs obtained in 0.1M PBS (pH 7.0) showed that the immobilized Hb retained its bio-catalytic activity for Fe ions, indicating that it had not denatured and the hybrid layer remained biocompatible with Hb. Furthermore, this electrode was found to accurately measure the H2O2concentration over the range from 20 to 9.6×102μM in 0.1M PBS (pH 7.0) under mediatorless conditions using both CV and amperometry techniques. In this way, the EFK8-SWNT hybrid layer shows promise as a biocompatible layer for simple non-covalent enzyme immobilization and the basis of a mediatorless biosensor.
Impact of transposable elements on methylation and gene expression across natural accessions ofBrachypodium distachyon
Authors: Wyler Michele , Stritt Christoph , Walser Jean-Claude , Baroux Célia , Roulin Anne C.
Published: June 2020

Transposable elements (TEs) constitute a large fraction of plant genomes and are mostly present in a transcriptionally silent state through repressive epigenetic modifications such as DNA methylation. TE silencing is believed to influence the regulation of adjacent genes, possibly as DNA methylation spreads away from the TE. Whether this is a general principle or a context-dependent phenomenon is still under debate, pressing for studying the relationship between TEs, DNA methylation and nearby gene expression in additional plant species. Here we used the grassBrachypodium distachyonas a model and produced DNA methylation and transcriptome profiles for eleven natural accessions. In contrast to what is observed inArabidopsis thaliana, we found that TEs have a limited impact on methylation spreading and that only few TE families are associated to a low expression of their adjacent genes. Interestingly, we found that a subset of TE insertion polymorphisms is associated with differential gene expression across accessions. Thus, although not having a global impact on gene expression, distinct TE insertions may contribute to specific gene expression patterns inB. distachyon.

Significance statement

Transposable elements (TEs) are a major component of plant genomes and a source of genetic and epigenetic innovations underlying adaptation to changing environmental conditions. Yet molecular evidence linking TE silencing and nearby gene expression are lacking for many plant species. We show that in the model grass Brachypodium DNA methylation spreads over very short distances around TEs, with an influence on gene expression for a small subset of TE families.
Wheat blast caused byMagnaporthe oryzaepv.Triticumis efficiently controlled by the plant defence inducer isotianil
Authors: Portz Katharina , Casanova Florencia , Jordine Angelina , Bohnert Stefan , Mehl Andreas , Portz Daniela , Schaffrath Ulrich
Published: June 2020

Wheat blast caused byMagnaporthe oryzaepv.Triticum(MoT) is an upcoming threat to wheat cultivation worldwide. The disease crossing over to wheat first gained attention in South America, with increasing interest coming from its more recent appearance in the big wheat growing areas of Asia. The increasing economic relevance of the disease and the lack of genetic resistance in current wheat breading material, besides fungicide resistance already present in fungal pathogen populations, highlighted the need to evaluate the potential of isotianil as an alternative plant protection measure. Isotianil is already registered in Asia for the protection of rice againstM. oryzaebut because the agronomic practices and disease development of blast differ between rice and wheat, the efficacy of isotianil against wheat blast was hard to predict. Testing isotianil in the currently available formulations, applied either as seed treatment or soil drench, resulted in a significant reduction of disease severity. The efficacy was comparably high, on different wheat cultivars and using several fungal isolates with different degrees of virulence. Microscopic analyses revealed that isotianil treatment can prevent invasive growth of the pathogen. No phytotoxicity from isotianil treatment was observed on wheat plants up to the stage of heading. Importantly, isotianil not only protects wheat plants at the seedling stage but also on spikes thereby preventing losses due to this most severe disease syndrome. In summary, the results showed the high potential of isotianil to protect against wheat blast.