bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of Social Distancing for COVID-19 Upon Diagnosis of Kawasaki Disease
Authors: Shulman Stanford , Geevarghese Bessey , Kim Kwang-Youn , Rowley Anne
Published: March 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mitigation policies have been associated with profound decreases in diagnoses of common childhood respiratory infections. A leading theory of etiology of Kawasaki disease (KD) is that it is triggered by presently unidentified ubiquitous respiratory agent. We document that mitigation policies instituted in mid-March 2020 were associated with strikingly fewer diagnoses of KD in April-December 2020 compared with the same period in the previous 8 years (P = .01), a >67% decline. This finding supports the hypothesis that KD is caused by a respiratory-transmitted agent.
Dioscorea zingiberensis ameliorates diabetic nephropathy by inhibiting NLRP3 inflammasome and curbing the expression of p66Shc in high-fat diet/streptozotocin-induced diabetic mice
Authors: Ren Chaoxing , Zhou Xiaowei , Bao Xiaowen , Zhang Jie , Tang Jun , Zhu Zhiming , Zhang Nan , Bai Yu , Xi Youli , Zhang Qi , Ma Bo
Published: March 2021

Objectives

Diabetic nephropathy (DN) is a severe diabetic complication. Dioscorea zingiberensis (DZ) possesses excellent pharmacological properties with lower toxicity. The purpose of this study was to investigate the efficacy and mechanism of DZ in DN.

Methods

DN was established by the high-fat diet combining intraperitoneal injection of streptozotocin in mice. The DZ (125 and 250 mg/kg/day) were intragastrical administered for 8 consecutive weeks. After treatment, blood, urine and kidney tissue were collected for biological detection, renal morphology, fibrosis and molecular mechanism research, respectively.

Key findings

This study has shown that DZ significantly ameliorated kidney hypertrophy, renal structural damage and abnormal function of the kidney indicators (creatinine, urinary protein and blood urea nitrogen). Further molecular mechanism data suggested that the NLRP3/Cleaved-caspase-1 signal pathway was remarkably activated in DN, and DZ treatment reversed these changes, which indicated that it effectively attenuated inflammatory response caused by hyperglycaemia. In addition, DN inhibits hyperglycaemia-induced activation of oxidative stress by suppressing the expression of p66Shc proteins.

Conclusions

DZ could efficiently suppress oxidative stress and inflammatory responses to postpone the development of DN, and its mechanism might be related to inhibition of NLRP3 and p66Shc activities. Thus, DZ could be developed into a new therapeutic agent for DN.
2MASX J00423991 + 3017515: an offset active galactic nucleus in an interacting system
Authors: Hogg J Drew , Blecha Laura , Reynolds Christopher S , Smith Krista Lynne , Winter Lisa M
Published: March 2021

We present a spectroscopic and imaging study of an abnormal active galactic nucleus (AGN), 2MASX J00423991 + 3017515. This AGN is newly identified in the hard X-rays by the Swift BAT All-Sky survey and found in an edge-on disc galaxy interacting with a nearby companion. Here, we analyse the first optical spectra obtained for this system (taken in 2011 and 2016), high-resolution imaging taken with the Hubble Space Telescope and Chandra X-ray Observatory, and 1 imaging with the Very Large Array. Two unique properties are revealed: the peaks of the broad Balmer emission lines (associated with gas orbiting very near the supermassive black hole) are blueshifted from the corresponding narrow line emission and host galaxy absorption by 1540 km s−1, and the AGN is spatially displaced from the apparent centre of its host galaxy by 3.8 kpc. We explore several scenarios to explain these features, along with other anomalies, and propose that 2MASX J00423991 + 3017515 may be an AGN with an unusually strong wind residing in a uniquely configured major merger, or that it is an AGN recoiling from either a gravitational ‘slingshot’ in a three-body interaction or from a kick due to the asymmetric emission of gravitational waves following the coalescence of two progenitor supermassive black holes.
Rapid formation of super-Earths around low-mass stars
Authors: Zawadzki Brianna , Carrera Daniel , Ford Eric B
Published: March 2021

NASA’s TESS mission is expected to discover hundreds of M dwarf planets. However, few studies focus on how planets form around low-mass stars. We aim to better characterize the formation process of M dwarf planets to fill this gap and aid in the interpretation of TESS results. We use ten sets of N-body planet formation simulations that vary in whether a gas disc is present, initial range of embryo semimajor axes, and initial solid surface density profile. Each simulation begins with 147 equal-mass embryos around a 0.2 solar mass star and runs for 100 Myr. We find that planets form rapidly, with most collisions occurring within the first 1 Myr. The presence of a gas disc reduces the final number of planets relative to a gas-free environment and causes planets to migrate inward. We find that roughly a quarter of planetary systems experience their final giant impact inside the gas disc, suggesting that some super-Earths may be able to reaccrete an extended gaseous envelope after their final giant impact, though these may be affected by additional processes such as photoevaporation. In addition, we find that the final distribution of planets does not retain a memory of the slope of the initial surface density profile, regardless of whether or not a gas disc is present. Thus, our results suggest that present-day observations are unlikely to provide sufficient information to accurately reverse-engineer the initial distribution of solids.
A self-lensing binary massive black hole interpretation of quasi-periodic eruptions
Authors: Ingram Adam , Motta Sara E , Aigrain Suzanne , Karastergiou Aris
Published: March 2021

Binary supermassive black hole (SMBH) systems result from galaxy mergers, and will eventually coalesce due to gravitational wave (GW) emission if the binary separation can be reduced to ≲0.1 pc by other mechanisms. Here, we explore a gravitational self-lensing binary SMBH model for the sharp (duration ∼1 h), quasi-regular X-ray flares – dubbed quasi-periodic eruptions – recently observed from two low-mass active galactic nuclei: GSN 069 and RX J1301.9+2747. In our model, the binary is observed ∼edge-on, such that each SMBH gravitationally lenses light from the accretion disc surrounding the other SMBH twice per orbital period. The model can reproduce the flare spacings if the current eccentricity of RX J1301.9+2747 is ϵ0 ≳ 0.16, implying a merger within ∼1000 yr. However, we cannot reproduce the observed flare profiles with our current calculations. Model flares with the correct amplitude are ∼2/5 the observed duration, and model flares with the correct duration are ∼2/5 the observed amplitude. Our modelling yields three distinct behaviours of self-lensing binary systems that can be searched for in current and future X-ray and optical time-domain surveys: (i) periodic lensing flares, (ii) partial eclipses (caused by occultation of the background mini-disc by the foreground mini-disc), and (iii) partial eclipses with a very sharp in-eclipse lensing flare. Discovery of such features would constitute very strong evidence for the presence of a supermassive binary, and monitoring of the flare spacings will provide a measurement of periastron precession.
Lyman continuum leakage from low-mass galaxies with M⋆ < 108 M⊙
Authors: Izotov Y I , Worseck G , Schaerer D , Guseva N G , Chisholm J , Thuan T X , Fricke K J , Verhamme A
Published: March 2021

We present observations with the Cosmic Origins Spectrograph onboard the Hubble Space Telescope of nine low-mass star-forming galaxies at redshifts, z, in the range 0.3179–0.4524, with stellar masses $M_\star \, \lt $ 108 M⊙ and very high specific star-formation rates sSFR ∼150–630 Gyr−1, aiming to study the dependence of leaking Lyman continuum (LyC) emission on stellar mass and some other characteristics of the galaxy. We detect LyC emission in four out of nine galaxies with escape fractions, fesc(LyC), in the range of 11–35 per cent, and establish upper limits for fesc(LyC) in the remaining five galaxies. We observe a narrow Ly α emission line with two peaks in seven galaxies and likely more complex Ly α profiles in the two remaining galaxies. The velocity separation between the peaks Vsep varies in the range from ∼229 to ∼512 km s−1. Our additional data on low-mass galaxies confirm and strengthen the tight anticorrelation between fesc(LyC) and Vsep found for previous low-redshift galaxy samples with higher stellar masses. Vsep remains the best indirect indicator of LyC leakage. It is better than O32 on which fesc(LyC) depends weakly, with a large scatter. Finally, contrary to expectations, we find no increase of fesc(LyC) with decreasing galaxy stellar mass M⋆.
Detecting and analysing geomorphological structures in images of comet 67P/Churyumov–Gerasimenko using Fourier transform
Authors: Ruzicka Birko-Katarina , Schröter Matthias , Pack Andreas , Boehnhardt Hermann
Published: March 2021

We present a method for automatized detection and analysis of quasi-periodic lineament structures from images at pixel precision. The method exploits properties of the images’ frequency domain found by using the Fourier transform. We developed this method with the goal of detecting lineament structures in an image of the Hathor cliff of comet 67P/Churyumov–Gerasimenko, which are caused by layerings and furrows in the nucleus material. Using our method, we determined the orientation and wavelength range of these structures. The detected layering edges have similar orientations and spatial separations of 9–20 m, and are ubiquitous throughout the image. We suggest that the layerings are a global feature of the comet nucleus that provide information about formation and evolution of comet 67P. The furrows are non-uniformly distributed throughout the image. Their orientation is broadly parallel to the direction of the local gravity vector at the Hathor cliff, with spacings similar to those of the layering structures. The furrows are interpreted as signatures of local down-slope movement of cliff material. We demonstrate that the developed method is broadly applicable to the detection and analysis of various kinds of quasi-periodic structures like geological layering, folding and faulting, and texture analysis in general. In order to facilitate the application of our method, this paper is accompanied by a demo program written in matlab.
Health Agency and Perfectionism: The Case of Perinatal Health Inequalities
Authors: Ismaili M’hamdi Hafez , de Beaufort Inez
Published: March 2021

Poor pregnancy outcomes and inequalities in these outcomes remain a major challenge, even in prosperous societies that have high-quality health care and public health policy in place. In this article, we propose that justice demands the improvement of what we call the ‘health agency’ of parents-to-be as part of a response to these poor outcomes. We take health agency to have three aspects: (i) the capacity to form health-goals one has reason to value, (ii) the control one perceives to have over achieving those health-goals and (iii) the freedom(s) one has to achieve those health-goals. We will moreover argue that this demand of justice can be best based on a perfectionist rather than neutralist method of justification. Subsequently, we will argue that perfectionist policy may be paternalistic but not wrongfully paternalistic. This leads us to conclude that perfectionism should be adopted to inform and justify public health policy that is aimed at improving health agency in general and counteracting poor pregnancy outcomes and inequalities in perinatal health outcomes in particular.
Host-interactor screens of Phytophthora infestans RXLR proteins reveal vesicle trafficking as a major effector-targeted process
Authors: Petre Benjamin , Contreras Mauricio P , Bozkurt Tolga O , Schattat Martin H , Sklenar Jan , Schornack Sebastian , Abd-El-Haliem Ahmed , Castells-Graells Roger , Lozano-Durán Rosa , Dagdas Yasin F , Menke Frank L H , Jones Alexandra M E , Vossen Jack H , Robatzek Silke , Kamoun Sophien , Win Joe
Published: March 2021

Pathogens modulate plant cell structure and function by secreting effectors into host tissues. Effectors typically function by associating with host molecules and modulating their activities. This study aimed to identify the host processes targeted by the RXLR class of host-translocated effectors of the potato blight pathogen Phytophthora infestans. To this end, we performed an in planta protein–protein interaction screen by transiently expressing P. infestans RXLR effectors in Nicotiana benthamiana leaves followed by coimmunoprecipitation and liquid chromatography-tandem mass spectrometry. This screen generated an effector–host protein interactome matrix of 59 P. infestans RXLR effectors x 586 N. benthamiana proteins. Classification of the host interactors into putative functional categories revealed over 35 biological processes possibly targeted by P. infestans. We further characterized the PexRD12/31 family of RXLR-WY effectors, which associate and colocalize with components of the vesicle trafficking machinery. One member of this family, PexRD31, increased the number of FYVE positive vesicles in N. benthamiana cells. FYVE positive vesicles also accumulated in leaf cells near P. infestans hyphae, indicating that the pathogen may enhance endosomal trafficking during infection. This interactome dataset will serve as a useful resource for functional studies of P. infestans effectors and of effector-targeted host processes.
Reasons and Defeasible Reasoning
Authors: Brunero John
Published: March 2021

According to the Reasoning View, a normative reason to φ is a premise in a pattern of sound reasoning leading to the conclusion to φ. But how should the Reasoning View account for reasons that are outweighed? One very promising proposal is to appeal to defeasible reasoning. On this proposal, when a reason is outweighed, the associated pattern of sound reasoning is defeated. Both Jonathan Way and Sam Asarnow have recently developed this idea in different ways. I argue that this appeal to defeasible reasoning faces a challenge, since reasons can be both outweighed and disabled. Way's view generates good predictions about outweighed reasons, but not about disabled reasons. Asarnow's view generates good predictions about disabled reasons, but not about outweighed reasons. We want a version of the Reasoning View that can generate good predictions about both. I present a version of the Reasoning View that can meet the challenge.
Will the demands by the covid-19 pandemic increase the intent to quit the profession of long-term care managers? A repeated cross-sectional study in Germany
Authors: Pförtner Timo-Kolja , Pfaff Holger , Hower Kira Isabel
Published: March 2021

The Corona pandemic poses major demands for long-term care, which might have impacted the intention to quit the profession among managers of long-term care facilities. We used cross-sectional data of an online survey of long-term care managers from outpatient and inpatient nursing and palliative care facilities surveyed in April 2020 (survey cycle one; n = 532) and between December 2020 and January 2021 (survey cycle two; n = 301). The results show a significant association between the perceived pandemic-specific and general demands and the intention to leave the profession. This association was significantly stronger for general demands in survey cycle two compared with survey cycle one. The results highlight the pandemic’s immediate impact on long-term care. In view of the increasing number of people in need of care and the already existing scarcity of specialized nursing staff, the results highlight the need for initiatives to ensure the provision of long-term care, also and especially in such times of crisis.
Inscriptions and Ways of Owning Books among the Sisters of Syon Abbey
Authors: King Julia
Published: March 2021

This article discusses the phenomenon of personal inscriptions in manuscripts and printed books associated with the sisters of Syon Abbey (founded 1415), the sole English Birgittine house. It argues that personal inscriptions reveal the Syon sisters’ complex ownership-like relationships with their books, and that the sisters were able to demonstrate both their individual and communal devotional identity through their interaction with each other and their books. In the first section, the article defines ‘ownership’ in its legal context and discusses it in relationship to ‘use’. The second section closely reads the Syon legislative documents to discuss the sisters’ conceptualizations of book ownership within the bounds of their order. The third section discusses the practice of inscription, using evidence from extant Syon manuscripts and early printed books. The fourth section brings these contexts together to discuss two cases of hybrid book ownership: the functional ownership developed through repeated use of the Syon processionals, and the collective individual ownership of multiple copies of printed books. The article presents a new way of understanding inscriptions and their potential for community building and individuation at Syon Abbey and contributes to our understanding of women’s reading experiences and ownership practices in England at the turn of the sixteenth century and the late-medieval period as a whole.
Medication adherence in older people with rheumatoid arthritis is lower according to electronic monitoring than according to pill count
Authors: Hartman Linda , Cutolo Maurizio , Bos Reinhard , Opris-Belinski Daniela , Kok Marc R , Griep-Wentink Hanneke (J) R M , Klaasen Ruth , Allaart Cornelia F , Bruyn George A W , Raterman Hennie G , Voshaar Marieke J H , Gomes Nuno , Pinto Rui M A , Klausch L Thomas , Lems Willem F , Boers M
Published: March 2021

Objectives

Suboptimal medication adherence is a serious problem in the treatment of chronic inflammatory diseases. To measure medication adherence, electronic monitoring is regarded as superior to pill count. GLORIA is an ongoing two-year trial on the addition of low-dose (5 mg/d) prednisolone or placebo to standard care in older people (65+ years) with RA. During the entire trial, adherence is measured with electronic caps, and with pill counts. The objective is to describe medication adherence patterns, and to compare the adherence results of the two methods.

Methods

The recorded adherence patterns of patients (blinded for treatment group) were classified according to descriptive categories. The cutoff for good adherence was set at 80% of prescribed pills taken.

Results

Trial inclusion closed in 2018 at 451 patients, but trial follow-up is ongoing; the current dataset contains adherence data of 371 patients. Mean number of recorded 90-day periods per patient was 4 (range 1–8). Based on pill count over all periods, 90% of the patients had good adherence; based on cap data, only 20%. Cap data classified 30% of patients as non-user (<20% of days an opening) and 40% as irregular user (different adherence patterns, in or between periods).

Conclusion

In our trial of older people with RA, the majority appeared to be adherent to medication according to pill count. Results from caps conflicted with those of pill counts, with patterns suggesting patients did not use the bottle for daily dispensing, despite specific advice to do so.

Trial registration

NCT02585258. ClinicalTrials.gov (https://www.clinicaltrials.gov/)
Central Vascular Access Device Complications in Pediatric Home Care Patients Managed by Family Caregivers or Nurses
Authors: Curley Michelle , Larson Josh , Pomputius William F. , Maynard Roy
Published: March 2021

There is a paucity of data regarding complications and outcomes of central vascular access devices (CVADs) in pediatric home care patients. Unlike hospital and clinic settings, home care patients commonly receive catheter care and accesses by family caregivers rather than nurses. This 2-year prospective study compared complications and outcomes of 222 CVADs managed by nurses or family caregivers. CVADs were followed for skin complications at insertion site, catheter complications, central line–associated bloodstream infection occurrences, and the outcome of dysfunctional catheters treated with alteplase. Results showed no differences in any CVAD complications, whether access and care were primarily performed by trained family caregivers or nurses.
Greenhouse gases drove the increasing trends in spring precipitation across the central USA
Authors: Zhang Wei , Villarini Gabriele
Published: March 2021

The central USA experienced major flooding during spring 2019, with both the Missouri and Mississippi Rivers at major flood stage at several locations, causing levees to breach and widespread flooding. Here, we examine the total precipitation responsible for the spring 2019 flooding across the central USA from the perspective of weather types. We focus on the weather type (referred to as ‘Midwest Water Hose’ (MWH) (Zhang and Villarini. 2019
Climate Dynamics
53
, 4217–4232. (
doi:10.1007/s00382-019-04783-4
))) that contributes the most to the total precipitation across the central USA. This weather type contributed to more than 70% of the total precipitation received across much of this region during January–May 2019, and it has been occurring increasingly frequently over the past 40 years. Furthermore, we found that climate model experiments with the historical change of greenhouse gas concentration can well reproduce the observed rising trend, while this is not the case for the natural forcing experiments. Therefore, the rising trend and the high frequency of the MWH can be mainly attributed to the rising greenhouse gases caused by human activities, rather than natural forcing.

This article is part of a discussion meeting issue ‘Intensification of short-duration rainfall extremes and implications for flash flood risks’.
Microbe Profile: Dictyostelium discoideum: model system for development, chemotaxis and biomedical research
Authors: Pears Catherine J. , Gross Julian D.
Published: March 2021

The social amoeba Dictyostelium discoideum is a versatile organism that is unusual in alternating between single-celled and multi-celled forms. It possesses highly-developed systems for cell motility and chemotaxis, phagocytosis, and developmental pattern formation. As a soil amoeba growing on microorganisms, it is exposed to many potential pathogens; it thus provides fruitful ways of investigating host-pathogen interactions and is emerging as an influential model for biomedical research.
Reanalysis of the Pfizer mRNA BNT162b2 SARS-CoV-2 vaccine data fails to find any increased efficacy following the boost: Implications for vaccination policy and our understanding of the mode of action
Authors: Saul Allan , Drummer Heidi E. , Scott Nick , Spelman Tim , Crabb Brendan S. , Hellard Margaret
Published: March 2021

Background

In clinical trials two vaccinations with mRNA vaccines have shown high efficacy in preventing COVID-19. However, in the context of a pandemic, the time to generation of protective immunity, the need for and timing of a second vaccination are matters of legitimate debate. This manuscript explores the efficacy and timing of the second dose COVID-19 vaccines, including a reanalysis of data from the Pfizer mRNA BNT162b2 mRNA SARS-CoV-2 vaccine phase 3 study.

Methods and findings

A non-weighted three-segment, two knot linear regression was fitted to the published cumulative infection incidence from the Pfizer BNT162b2 vaccine Phase III trial using the lspine routine in R. The optimal knot days were estimated through sensitivity analysis and the confidence limits for efficacy estimates were determined by Monte Carlo Simulations. This analysis showed the vaccine was effective from day 11 post first vaccination. The estimated efficacy over the period 11 to 28 days post first vaccination was 0.94 and there was no detectable increase in efficacy following the second vaccination. The efficacy post first vaccination substantially preceded the development of detectable serum neutralizing antibody.

Conclusions

Strongly protective immunity develops rapidly following a single vaccination and at least in the short period covered by the timetable of the Phase III trial, there was no additional benefit from a second vaccination. This increases options for use of this vaccine, e.g., for ring fence vaccination, for use in travelers and for mass vaccination rollout. It highlights the need for further research into duration of immunity following a single vaccination and for understanding mechanisms of protection.
Multi-objective Risk-based Resource Allocation for Urban Pandemic Preparedness: The COVID-19 Case in Bogotá, Colombia
Authors: Prieto Jeisson , Gomez Jonatan
Published: March 2021

Determining how best to allocate resources to be used during a pandemic is a strategic decision that directly affects the success of pandemic response operations. However, government agencies have finite resources, so they can’t monitor everything all of the time: they have to decide how best to allocate their scarce resources (i.e., budget for antivirals and preventive vaccinations, Intensive Care Unit (ICU), ventilators, non-intensive Care Unit (non-ICU), doctors) across a broad range of risk exposures (i.e., geographic spread, routes of transmission, overall poverty, medical preconditions). This paper establishes a comprehensive risk-based emergency management framework that could be used by decision-makers to determine how best to manage medical resources, as well as suggest patient allocation among hospitals and alternative healthcare facilities. A set of risk indexes are proposed by modeling the randomness and uncertainty of allocating resources in a pandemic. The city understudy is modeled as a Euclidean complex network, where depending on the neighborhood influence of allocating a resource in a demand point (i.e., informing citizens, limit social contact, allocate a new hospital) different network configurations are proposed. Finally, a multi-objective risk-based resource allocation (MoRRA) framework is proposed to optimize the allocation of resources in pandemics. The applicability of the framework is shown by the identification of high-risk areas where to prioritize the resource allocation during the current COVID-19 pandemic in Bogotá, Colombia.
Retrospective large-scale evaluation of an AI system as an independent reader for double reading in breast cancer screening
Authors: Sharma Nisha , Ng Annie Y. , James Jonathan J. , Khara Galvin , Ambrozay Eva , Austin Christopher C. , Forrai Gabor , Fox Georgia , Glocker Ben , Heindl Andreas , Karpati Edit , Rijken Tobias M. , Venkataraman Vignesh , Yearsley Joseph E. , Kecskemethy Peter D.
Published: March 2021

Importance

Screening mammography with two human readers increases cancer detection and lowers recall rates, but workforce shortages make double reading unsustainable in many countries. Artificial intelligence (AI) as an independent reader in double reading may support screening performance while improving cost-effectiveness. The clinical validation of AI requires large-scale, multi-vendor studies on unenriched cohorts.

Objective

To evaluate the performance of the Mia® AI system on data that the AI system would process in real-world deployments.

Design

A retrospective study simulating the impact of AI on an unenriched screening sample.

Setting

Seven European breast screening sites representing four centers: three from the UK and one in Hungary (HU), between 2009 and 2019.

Participants

The sample included 275,900 cases (177,882 participants) from seven screening sites, involving two countries and four hardware vendors from 2009 to 2019.

Intervention

Simulation of double reading using AI as an independent reader in breast cancer screening on historical data.

Main Outcomes and Measures

Performance was determined for standalone AI compared to the historical single reader and for simulated double reading with AI compared to historical double reading, assessing non-inferiority and superiority on relevant screening metrics using a non-inferiority margin of 10% relative difference and a one-sided alpha of 2.5% for both tests.

Results

Standalone AI detected 29.8% of missed interval cancers. When compared with historical double reading, double reading with AI showed non-inferiority for sensitivity and superiority for recall rate, specificity and positive predictive value. AI as an independent reader reduced the workload for the second human reader but increased the arbitration rate from 3.3% to 12.3%. Applying the AI system could have reduced the human reading time required by up to 44.8% and reduced the recall rate by a relative 7.7% (from 5.2% to 4.8%).

Conclusions and Relevance

Using the AI system as an independent reader maintains or improves the double reading standard of care, while substantially reducing the workload. Thus, it has the potential to provide operational and economic benefits.

Trial Registration

Registered on ISRCTN, study ID: ISRCTN18056078
Rapid stress hardening in the Antarctic midge improves male fertility by increasing courtship success and preventing the decline of accessory gland proteins following cold exposure
Authors: Ajayi Oluwaseun M. , Gantz J. D. , Finch Geoffrey , Lee Richard E. , Denlinger David L. , Benoit Joshua B.
Published: March 2021

Rapid hardening is a process that quickly improves an animal’s performance following exposure to a potentially damaging stress. Features of reproduction can be improved by rapid hardening, but little is known about how rapid hardening may contribute to physiological responses in the cold environment of Antarctica. In this study of the Antarctic midge,Belgica antarctica(Diptera, Chironomidae), we examine how rapid hardening in response to dehydration (RDH) or cold (RCH) improves male pre- and post-copulatory function related to fertility when the insects are subsequently subjected to a damaging cold exposure. Neither RDH nor RCH improved survival in response to lethal cold stress, but male activity following sublethal cold exposure was enhanced. Both RCH and RDH improved mating success of males compared to those subjected directly to a sublethal bout of cold. Egg viability decreased following direct exposure to sublethal cold, but improved following RCH and RDH. Sublethal cold exposure reduced expression of four accessory gland proteins, while expression remained high in males exposed to RCH. Though rapid hardening may be cryptic in males, this study shows that it can be revealed by pre- and post-copulatory interactions with females.
Visual stimulation with blue wavelength light drives V1 effectively eliminating stray light contamination during two-photon calcium imaging
Authors: Kuznetsova Tatiana , Antos Kamil , Malinina Evgenya , Papaioannou Stylianos , Medini Paolo
Published: March 2021

BACKGROUND

Brain visual circuits are often studiedin vivoby imaging Ca2+indicators with green-shifted emission spectra. Polychromatic white visual stimuli have a spectrum that partially overlaps indicators’ emission spectra, resulting in significant contamination of calcium signals.

NEW METHOD

To overcome light contamination problems we choose blue visual stimuli, having a spectral composition not overlapping with Ca2+indicator’s emission spectrum. To compare visual responsiveness to blue and white stimuli we used electrophysiology (visual evoked potentials–VEPs) and 3D acousto-optic two-photon(2P) population Ca2+imaging in mouse primary visual cortex (V1).

RESULTS

VEPs in response to blue and white stimuli had comparable peak amplitudes and latencies. Ca2+imaging revealed that the populations of neurons responding to blue and white stimuli were largely overlapping, that their responses had similar amplitudes, and that functional response properties such as orientation and direction selectivities were also comparable.

COMPARISON WITH EXISTING METHODS

Masking or shielding the microscope are often used to minimize the contamination of Ca2+signal by white light, but they are time consuming, bulky and thus can limit experimental design, particularly in the more and more frequently used awake set-up. Blue stimuli not interfering with imaging allow to omit shielding without affecting V1 physiological responsiveness.

CONCLUSIONS

Our results show that the selected blue light stimuli evoke physiological responses comparable to those evoked by white stimuli in mouse V1. This will make complex designs of imaging experiments in behavioral set-ups easier, and facilitate the combination of Ca2+imaging with electrophysiology and optogenetics.

Highlights

White and blue light trigger VEPs with similar amplitudes and latencies in mouse V1

Blue-and white-responding neurons are two largely overlapping neuronal populations

Blue and white evoke Ca2+responses similar in magnitude and latency

Blue and white evoke Ca2+responses similar in orientation/direction selectivity

Blue stimuli could be an alternative to white ones in behavior and opto-physiological tests

Abstract Figure
Effect of SARS-CoV-2 proteins on vascular permeability
Authors: Rauti Rossana , Shahoha Meishar , Leichtmann-Bardoogo Yael , Nasser Rami , Tamir Rina , Miller Victoria , Babich Tal , Shaked Kfir , Ehrlich Avner , Ioannidis Konstantinos , Nahmias Yaakov , Sharan Roded , Ashery Uri , Maoz Ben M.
Published: March 2021

SARS-CoV-2 infection leads to severe disease associated with cytokine storm, vascular dysfunction, coagulation, and progressive lung damage. It affects several vital organs, seemingly through a pathological effect on endothelial cells. The SARS-CoV-2 genome encodes 29 proteins, whose contribution to the disease manifestations, and especially endothelial complications, is unknown. We cloned and expressed 26 of these proteins in human cells and characterized the endothelial response to overexpression of each, individually. Whereas most proteins induced significant changes in endothelial permeability, nsp2, nsp5_c145a (catalytic dead mutant of nsp5) and nsp7 also reduced CD31, and increased von Willebrand factor expression and IL-6, suggesting endothelial dysfunction. Using propagation-based analysis of a protein–protein interaction (PPI) network, we predicted the endothelial proteins affected by the viral proteins that potentially mediate these effects. We further applied our PPI model to identify the role of each SARS-CoV-2 protein in other tissues affected by COVID-19. Overall, this work identifies the SARS-CoV-2 proteins that might be most detrimental in terms of endothelial dysfunction, thereby shedding light on vascular aspects of COVID-19.
GPRuler: metabolic Gene-Protein-Reaction rules automatic reconstruction
Authors: Di Filippo Marzia , Damiani Chiara , Pescini Dario
Published: March 2021

Background

Metabolic network models are increasingly being used in health care and industry. As a consequence, many tools have been released to automate their reconstruction processde novo. In order to enable gene deletion simulations and integration of gene expression data, these networks must include gene-protein-reaction (GPR) rules, which describe with a Boolean logic relationships between the gene products (e.g., enzyme isoforms or subunits) associated with the catalysis of a given reaction. Nevertheless, the reconstruction of GPRs still remains a largely manual and time consuming process. Aiming at fully automating the reconstruction process of GPRs for any organism, we propose the open-source python-based frameworkGPRuler.

Results

By mining text and data from 9 different biological databases,GPRulercan reconstruct GPRs starting either from just the name of the target organism or from an existing metabolic model. The performance of the developed tool is evaluated at small-scale level for a manually curated metabolic model, and at genome-scale level for three metabolic models related toHomo sapiensandSaccharomyces cerevisiaeorganisms. By exploiting these models as benchmarks, the proposed tool shown its ability to reproduce the original GPR rules with a high level of accuracy. In all the tested scenarios, after a manual investigation of the mismatches between the rules proposed byGPRulerand the original ones, the proposed approach revealed to be in many cases more accurate than the original models.

Conclusions

By complementing existing tools for metabolic network reconstruction with the possibility to reconstruct GPRs quickly and with a few resources,GPRulerpaves the way to the study of context-specific metabolic networks, representing the active portion of the complete network in given conditions, for organisms of industrial or biomedical interest that have not been characterized metabolically yet.
HNF4α isoforms regulate the circadian balance between carbohydrate and lipid metabolism in the liver
Authors: Deans Jonathan R. , Deol Poonamjot , Titova Nina , Radi Sarah H. , Vuong Linh M. , Evans Jane R. , Pan Songqin , Fahrmann Johannes , Yang Jun , Hammock Bruce D. , Fiehn Oliver , Fekry Baharan , Eckel-Mahan Kristin , Sladek Frances M.
Published: March 2021

Hepatocyte Nuclear Factor 4α (HNF4α), a master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2). P1-HNF4α is the major isoform in the adult liver while P2-HNF4α is thought to be expressed only in fetal liver and liver cancer. Here, we show that P2- HNF4α is expressed at ZT9 and ZT21 in the normal adult liver and orchestrates a distinct transcriptome and metabolome via unique chromatin and protein-protein interactions. We demonstrate that while P1-HNF4α drives gluconeogenesis, P2-HNF4α drives ketogenesis and is required for elevated levels of ketone bodies in females. Exon swap mice expressing only P2- HNF4α exhibit subtle differences in circadian gene regulation and disruption of the clock increases expression of P2-HNF4α. Taken together, we propose that the highly conserved two-promoter structure of theHnfagene is an evolutionarily conserved mechanism to maintain the balance between gluconeogenesis and ketogenesis in the liver in a circadian fashion.
Brain Dynamics of Spatial Reference Frame Proclivity in Active Navigation
Authors: Yang Che-Sheng , Liu Jia , Singh Avinash Kumar , Huang Kuan-Chih , Lin Chin-Teng
Published: March 2021

Recent research into navigation strategy of different spatial reference frame proclivities (RFPs) has revealed that the parietal cortex plays an important role in processing allocentric information to provide a translation function between egocentric and allocentric spatial reference frames. However, most studies merely focused on a passive experimental environment, which is not truly representative of our daily spatial learning/navigation tasks. This study investigated the factor associated with brain dynamics that causes people to switch their preferred spatial strategy in different environments in virtual reality (VR) based active navigation task to bridge the gap. High-resolution electroencephalography (EEG) signals were recorded to monitor spectral perturbations on transitions between egocentric and allocentric frames during a path integration task. Our brain dynamics results showed navigation involved areas including the parietal cortex with modulation in the alpha band, the occipital cortex with beta and low gamma band perturbations, and the frontal cortex with theta perturbation. Differences were found between two different turning-angle paths in the alpha band in parietal cluster event-related spectral perturbations (ERSPs). In small turning-angle paths, allocentric participants showed stronger alpha desynchronization than egocentric participants; in large turning-angle paths, participants for two reference frames had a smaller difference in the alpha frequency band. Behavior results of homing errors also corresponded to brain dynamic results, indicating that a larger angle path caused the allocentric to have a higher tendency to become egocentric navigators in the active navigation environment.
Infusion of CCR5 Gene-Edited T Cells Allows Immune Reconstitution, HIV Reservoir Decay, and Long-Term Virological Control
Authors: Zeidan Joumana , Sharma Ashish A. , Lee Gary , Raad Angie , Fromentin Remi , Fourati Slim , Ghneim Khader , Sanchez Gabriela P. , Benne Clarisse , Canderan Glenda , Procopio Francesco A. , Balderas Robert , Monette Georges , Lalezari Jacob P. , Heffernan Jane M. , Sabbagh Laurent , Chomont Nicolas , Ando Dale , Deeks Steven G. , Sekaly Rafick-Pierre
Published: March 2021

Antiretroviral therapy (ART) fails to fully restore immune function and is not curative. A single infusion of CCR5 gene-edited autologous CD4+T cells (SB-728-T) led to sustained increases in CD4+T cell counts, improved T cell homeostasis, and reduced the estimated size of the HIV reservoir. These outcomes were associated with the expansion and long-term persistence of a novel CCR5 gene-edited CD4+T memory stem cell (CD45RAintROintTSCM) subset that can replenish the pool of more differentiated memory cells. We showed that novel CD45RAintROintTSCMcells are transcriptionally distinct from the previously described CD45RA+TSCMand are minimally differentiated cells uncommitted to a specific Th-lineage. Subsequently, we showed in an independent trial that infusion of the SB-728-T cell product resulted in partial control of viral replication upon cessation of ART which was correlated with the frequencies of CCR5 gene-edited TSCMand their TEMprogeny. Interestingly, one participant that remained off ART to this date demonstrated long-term maintenance of CCR5 gene-edited cells and increased frequency of polyfunctional HIV-specific CD4+and CD8+T cells, contributing to low levels of viral load 5 years post-infusion. Consequently, the generation of HIV protected memory CD4+T cells by CCR5 disruption can contribute toward novel interventions aimed at achieving a sustained ART-free viral remission of HIV disease.
Development of a chemiluminescence immunoassay to accurately detect African swine fever virus antibodies in serum
Authors: Yang Yong , Lv Changjie , Fan Junqing , Zhao Ya , Jiang Lili , Sun Xiaomei , Zhang Qiang , Jin Meilin
Published: March 2021

The outbreak of African swine fever (ASF) has caused significant economic losses to animal husbandry worldwide. Currently, there is no effective vaccine or treatment available to control the disease, and therefore, efficient disease control is dependent on early detection and diagnosis of ASF virus (ASFV). In this study, a chemiluminescent immunoassay (CLIA) was developed using the ASFV protein p54 as a serum diagnostic antigen and an anti-p54 monoclonal antibody. After optimizing the working parameters of the CLIA, the sensitivity of the established CLIA was 1:128, ASFV-specific serum antibody was identified, and there was no cross-reaction with other swine virus antibodies. After testing 49 clinical serum samples, the consistency rate between the CLIA and the World Organization for Animal Health (OIE) recommended commercial kit was 100%. Thus, this CLIA had a high degree of specificity, sensitivity, and reliability, and could be used as a rapid detection method for epidemiological investigations of ASFV infection.
The Mechanism of Neurite Outgrowth Induction by Novel Synthetic Retinobenzoic Acids
Authors: Zhang Yang , Yoshimi Yoji , Funatsu Osamu , Hayashi Ryuto , Komagawa Shinsuke , Saito Shinichi , Nagahara Yukitoshi , Ikekita Masahiko
Published: March 2021

Retinoids are a family of vitamin A-derived molecules and include the biologically active metabolite, retinoic acid (RA). RA acts as a specific modulator of neuronal differentiation and proliferation. However, teratogenicity and a large excess of RA have been found in animal studies. Thus, development of effective and stable retinoids is desirable. In this study, we showed that treatment with novel synthetic retinobenzoic acids promotes neurite outgrowth in a selected subpopulation of the human neuroblastoma cell line SK-N-SH. Furthermore, we found that, although acting via a different mechanism, retinobenzoic acids have the same neurite outgrowth-inducing effect as RA. Retinoids, including RA, bind to nuclear retinoic acid receptors (RARs). Therefore, we examined the expression of RARs in retinobenzoic acid-treated cells. Similar to already known retinoids, novel synthetic retinobenzoic acids promote the upregulation of RARβ and have no effect on RARα or γ. These results suggest that retinobenzoic acids act via RARβ during neurite outgrowth. Moreover, stimulation with RA or retinobenzoic acids significantly increased the phosphorylation levels of both ERK1/2 and mTOR. ERK1/2 and mTOR inhibition blocked the retinobenzoic acid-induced increase in neurite outgrowth, suggesting that retinobenzoic acids promoted neurite outgrowth by activating the ERK1/2 and mTOR signaling pathways. Notably, the RA-induced increase in neurite outgrowth was blocked by the ERK1/2 inhibitor U0126, but not by the mTOR inhibitor rapamycin. In addition, ERK1/2 inhibition blocked the upregulation of RARβ promoted by RA and retinobenzoic acids. In contrast, mTOR inhibition had no effect on upregulation of RARβ. Our results show that novel synthetic retinobenzoic acids induce neurite outgrowth by a different mechanism than RA. These findings suggest that activation of both ERK1/2, which results in downstream regulation of RARβ, and mTOR, are responsible for the novel synthetic retinobenzoic acid-induced neurite outgrowth in human neuroblastoma cells.
Placental uptake and metabolism of 25(OH)Vitamin D determines its activity within the fetoplacental unit
Authors: Ashley Brogan , Simner Claire , Manousopoulou Antigoni , Jenkinson Carl , Hey Felicity , Frost Jennifer M , Rezwan Faisal I , White Cory H , Lofthouse Emma , Hyde Emily , Cooke Laura , Barton Sheila , Mahon Pamela , Curtis Elizabeth M , Moon Rebecca J , Crozier Sarah R , Inskip Hazel M , Godfrey Keith M , Holloway John W , Cooper Cyrus , Jones Kerry S , Lewis Rohan M , Hewison Martin , Garbis Spiros D , Branco Miguel R , Harvey Nicholas C , Cleal Jane K
Published: March 2021

Pregnancy 25-hydroxyvitamin D (25(OH)D) concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D3 by endocytosis, placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy.