bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between anti-interferon-alpha autoantibodies and COVID-19 in systemic lupus erythematosus
Authors: Gupta Sarthak , Nakabo Shuichiro , Chu Jun , Hasni Sarfaraz , Kaplan Mariana J.
Published: November 2020

Objectives

Anti-type I interferon (IFN) autoantibodies have been reported in patients with systemic lupus erythematosus (SLE). Recently, an association of these autoantibodies with severe COVID-19 was reported in the general population. We assessed whether having pre-existing anti-IFNα autoantibodies was associated with COVID-19 infection in SLE patients.

Methods

Patients with SLE who developed COVID-19 between April 1st to October 1st, 2020 were studied. Biobanked pre-COVID-19 plasma from these SLE subjects and healthy controls were tested for anti-IFNα IgG autoantibodies by ELISA. The ability of plasma anti-IFNα autoantibodies to block signal transducer and activator of transcription 1 (STAT1) phosphorylation by recombinant human IFNα in vitro was assessed by flow cytometry.

Results

Ten SLE subjects with COVID-19 were identified. A 40% of these subjects had stable autoantibodies against IFNα for up to three years preceding COVID-19 diagnosis. A 50% of the subjects with these autoantibodies neutralized IFNα induced STAT1 phosphorylation.None of the other SLE samples blocked IFNα signaling.

Conclusions

We noted an increased prevalence of pre-existing anti-IFNα autoantibodies in SLE patients with COVID-19 compared to the reported prevalence in lupus patients and the general population with severe COVID-19. Autoantibodies against IFNα in SLE patients may be pathogenic and patients with them maybe at-risk of developing COVID-19.

Key Messages

What is already known about this subject?

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Anti-type I interferon (IFN) autoantibodies have been reported in patients with systemic lupus erythematosus (SLE) and have recently been associated with severe COVID-19 in the general population.

What does this study add?

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SLE subjects with COVID-19 had an increased prevalence of pre-existing anti-IFNα autoantibodies compared to the reported prevalence in lupus patients and the general population with severe COVID-19.

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Plasma from 50% of subjects with these autoantibodies were able to block in vitro activity of IFNα.

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SLE patients with pre-existing anti-IFNα autoantibodies had more severe COVID-19 manifestations.

How might this impact on clinical practice or future developments?

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Anti-IFNα autoantibodies may be pathogenic and could prove to be a helpful prognostic marker to predict which SLE patient may develop COVID-19 and inform preventive measures and management of this subset of patients.
Border Restriction as a Public Health Measure to Limit Outbreak of Coronavirus Disease 2019 (COVID-19)
Authors: Wang Chun Kwok , Chun Ka Wong , Ting Fung Ma , Ka Wai Ho , Wai Tong Louis Fan , King Pui Florence Chan , Shung Kay Samuel Chan , Chi Chun Terence Tam , Pak Leung Ho
Published: November 2020

Background

Coronavirus Disease 2019 (COVID-19) led to pandemic that affected almost all countries in the world. Many countries have implemented border restriction as a public health measure to limit local outbreak. However, there is inadequate scientific data to support such a practice, especially in the presence of an established local transmission of the disease.

Method

A novel metapopulation Susceptible-Exposed-Infectious-Recovered (SEIR) model with inspected migration was applied to investigate the effect of border restriction between Hong Kong and mainland China on the epidemiological characteristics of COVID-19 in Hong Kong. Isolation facilities occupancy was also studied.

Results

At R0 of 2·2, the cumulative COVID-19 cases in Hong Kong can be reduced by 13·99% (from 29,163 to 25,084) with complete border closure. At an in-patient mortality of 1·4%, the number of deaths can be reduced from 408 to 351 (57 lives saved). However, border closure alone was insufficient to prevent full occupancy of isolation facilities in Hong Kong; effective public health measures to reduce local R0 to below 1·6 was necessary.

Conclusion

As a public health measure to tackle COVID-19, border restriction is effective in reducing cumulative cases and mortality.

Article summary

Strengths and limitations of this study

A novel metapopulation SEIR model with inspected migration was developed to investigate the epidemiological characteristics of COVID-19 in Hong Kong, Guangdong and the rest of China (excluding Hubei) in the presence or absence of border restriction.

The presented model is also suitable for further analysis of other emerging infectious diseases.

Border restriction is an effective public health measure in reducing cumulative cases and mortality for COVID-19.

Interaction was assumed to be well-mixed within patch. The spatial effect in disease transmission within each patch is ignored, which can have a non-trivial effect on the dynamic of infectious disease.

The proposed model is deterministic in nature which ignores the randomness in migration and in the interactions among people; a stochastic model would be more realistic especially early in the disease.
A minimal model for household-based testing and tracing in epidemics
Authors: Huber Greg , Kamb Mason , Kawagoe Kyle , Li Lucy M. , McGeever Aaron , Miller Jonathan , Veytsman Boris , Zigmond Dan
Published: November 2020

In a previous work [1], we discussed virus transmission dynamics modified by a uniform clustering of contacts in the population: close contacts within households and more distant contacts between households. In this paper, we discuss testing and tracing in such a stratified population. We propose a minimal tracing strategy consisting of random testing of the entire population plus full testing of the households of those persons found positive. We provide estimates of testing frequency for this strategy to work.
Avoiding versus contracting COVID-19: On the effectiveness of social distancing at the level of the individual
Authors: Fazio Russell H. , Ruisch Benjamin C. , Moore Courtney A. , Granados Samayoa Javier A. , Boggs Shelby T. , Ladanyi Jesse T.
Published: November 2020

Past research has established the value of social distancing as a means of deterring the spread of COVID-19 largely by examining aggregate level data. Locales in which efforts were undertaken to encourage distancing experienced reductions in their rate of transmission. However, these aggregate results tell us little about the effectiveness of social distancing at the level of the individual, which is the question addressed by the current research. Four months after participating in a study assessing their social distancing behavior, 2,120 participants indicated whether they had contracted COVID-19. Importantly, the assessment of social distancing involved not only a self-report measure of how strictly participants had followed social distancing recommendations, but also a series of virtual behavior measures of social distancing. These simulations presented participants with graphical depictions mirroring specific real-world scenarios, asking them to position themselves in relation to others in the scene. Individuals’ social distancing behavior, particularly as assessed by the virtual behavior measure, predicted whether they contracted COVID-19 during the intervening four months. This was true when considering only participants who reported having tested positively for the virus and when considering additional participants who, although untested, believed that they had contracted the virus. The findings offer a unique form of additional evidence as to why individuals should practice social distancing. What the individual does matters, not only for the health of the collective, but also for the specific individual.
AI-Powered Effective Lens Position Prediction Improves the Accuracy of Existing Lens Formulas
Authors: Li Tingyang , Stein Joshua D. , Nallasamy Nambi
Published: November 2020

Aims

To assess whether incorporating a machine learning (ML) method for accurate prediction of postoperative anterior chamber depth (ACD) improves the refraction prediction performance of existing intraocular lens (IOL) calculation formulas.

Methods

A dataset of 4806 cataract patients were gathered at the Kellogg Eye Center, University of Michigan, and split into a training set (80% of patients, 5761 eyes) and a testing set (20% of patients, 961 eyes). A previously developed ML-based method was used to predict the postoperative ACD based on preoperative biometry. This ML-based postoperative ACD was integrated into new effective lens position (ELP) predictions using regression models to rescale the ML output for each of four existing formulas (Haigis, Hoffer Q, Holladay, and SRK/T). The performance of the formulas with ML-modified ELP was compared using a testing dataset. Performance was measured by the mean absolute error (MAE) in refraction prediction.

Results

When the ELP was replaced with a linear combination of the original ELP and the ML-predicted ELP, the MAEs ± SD (in Diopters) in the testing set were: 0.356 ± 0.329 for Haigis, 0.352 ± 0.319 for Hoffer Q, 0.371 ± 0.336 for Holladay, and 0.361 ± 0.331 for SRK/T which were significantly lower than those of the original formulas: 0.373 ± 0.328 for Haigis, 0.408 ± 0.337 for Hoffer Q, 0.384 ± 0.341 for Holladay, and 0.394 ± 0.351 for SRK/T.

Conclusion

Using a more accurately predicted postoperative ACD significantly improves the prediction accuracy of four existing IOL power formulas.
Is degree of sociality associated with reproductive senescence? A comparative analysis across birds and mammals
Authors: Vágási Csongor I. , Vincze Orsolya , Lemaître Jean-François , Pap Péter L. , Ronget Victor , Gaillard Jean-Michel
Published: November 2020

Our understanding on how widespread reproductive senescence is in the w ild and how the onset and rate of reproductive senescence vary among species in relation to life histories and lifestyles is currently limited. More specifically, whether the species-specific degree of sociality is linked to the occurrence, onset and rate of reproductive senescence remains unknown. Here, we investigate these questions using phylogenetic comparative analyses across 36 bird and 101 mammal species encompassing a wide array of life histories, lifestyles and social traits. We found that female reproductive senescence (1) is widespread and occurs with similar frequency (about two thirds) in birds and mammals; (2) occurs later in life and is slower in birds than in similar-sized mammals; (3) occurs later in life and is lower with an increasingly slower pace of life in both vertebrate classes; and (4) is only weakly associated, if any, with the degree of sociality in both classes after accounting for the effect of body size and pace of life. However, when removing the effect of species differences in pace of life, a higher degree of sociality was associated with later and weaker reproductive senescence in females, which suggests that degree of sociality is either indirectly related to reproductive senescence via the pace of life or simply a direct outcome of the pace of life.

Subject Areas

ecology, evolution
Remdesivir-based therapy improved recovery of patients with COVID-19 in the SARSTer multicentre, real-world study
Authors: Flisiak Robert , Zarębska-Michaluk Dorota , Berkan-Kawińska Aleksandra , Tudrujek-Zdunek Magdalena , Rogalska Magdalena , Piekarska Anna , Kozielewicz Dorota , Kłos Krzysztof , Rorat Marta , Bolewska Beata , Szymanek-Pasternak Anna , Mazur Włodzimierz , Lorenc Beata , Podlasin Regina , Sikorska Katarzyna , Oczko-Grzesik Barbara , Iwaszkiewicz Cezary , Szetela Bartosz , Pabjan Paweł , Pawłowska Małgorzata , Tomasiewicz Krzysztof , Polańska Joanna , Jaroszewicz Jerzy
Published: November 2020

Background

Remdesivir (RDV) is the only antiviral drug registered currently for treatment of COVID-19 after a few clinical trials with controversial results. The purpose of this study was to evaluate the effectiveness and safety of RDV in patients with COVID-19 in real world settings.

Methods

Patients were selected from 1496 individuals included in the SARSTer national database; 122 of them received therapy with RDV and 211 were treated with lopinavir/ritonavir (LPV/r)-based therapy. The primary end-point of effectiveness was clinical improvement in the ordinal 8-point scale, which was defined as a 2-point decrease from baseline to 7, 14, 21 and 28 days of hospitalization. The secondary end-points of effectiveness included: death rate, rate of no clinical improvement within 28 days of hospitalization in the ordinal scale, rate of the need for constant oxygen therapy, duration of oxygen therapy, rate of the need for mechanical ventilation, total hospitalization time, and rate of positive RT PCR for SARS-CoV-2 after 30 days.

Findings

Significantly higher rates of clinical improvement, by 15% and 10% respectively, were observed after RDV treatment compared to LPV/r at days 21 and 28. The difference between regimens increased with worsening of oxygen saturation (SpO2) and depending on the baseline score from the ordinal scale. Statistically significant differences supporting RDV were also noted regarding the rate of no clinical improvement within 28 days of hospitalization and hospitalization duration in patients with baseline SpO2 ≤90%. In the logistic regression model only the administration of remdesivir was independently associated with at least a 2-point improvement in the ordinal scale between baseline and day 21.

Interpretation

In conclusion, data collected in this retrospective, observational, real world study supported use of remdesivir for treatment of SARS-CoV-2 infection particularly in patients with oxygen saturation ≤95%.
Glucose response to low-dose glucagon for insulin-induced mild hypoglycaemia after 12 weeks of high versus low carbohydrate diet. A pilot study
Authors: Ranjan Ajenthen G. , Schmidt Signe , Holst Jens J. , Christensen Merete B. , Nørgaard Kirsten
Published: November 2020

Objective

To compare the glucose response to low-dose glucagon after high carbohydrate diet (HCD) versus low carbohydrate diet (LCD).

Methods

Individuals with insulin pump-treated type 1 diabetes went through 12 weeks of HCD (>250 g/day) and 12 weeks of LCD (<100 g/day) in random order and separated by 12 weeks. At end of each diet, mild hypoglycaemia was induced in the fasting state by a subcutaneous insulin bolus. When plasma glucose (PG) reached 3.9 mmol/L, 100 µg glucagon was given subcutaneously.

Results

Four of six participants completed both study visits while the remaining two only completed the study visit following LCD. They were 37 (28-52) years old (median (IQR)), had BMI 25.0 (24.5-25.2) kg/m2, and HbA1c 57 (55-59) mmol/mol or 7.4 (7.2-7.5) %. Daily carbohydrate intake was 95 (86-97) g during LCD and 254 (184-259) g during HCD. Compared with HCD, LCD had a significantly lower area under the PG curve from 0-120 min (521 (394-617) vs 663 (546-746) mmol/l x min, p=0.045) and insignificant lower incremental PG peak after the glucagon bolus (1.5 (0.6-3.2) vs 3.0 (2.2-4.2) mmol/L, p=0.317).

Conclusion

In conclusion, the glucose response to low-dose glucagon was reduced after 12 weeks of LCD compared with HCD.
Cost-effectiveness of intensive care for hospitalized Covid-19 patients: experience from South Africa
Authors: Cleary SM , Wilkinson T , Tchuem CR Tamandjou , Docrat S , Solanki GC
Published: November 2020

Background

Amidst the shortages of critical care resources in the public sector resulting from the COVID-19 pandemic, the South African Government embarked on an initiative to purchase critical bed capacity from the private sector. Within an already under-funded public health sector, it is imperative that the costs and effects of potential interventions to care are assessed and weighed against the opportunity costs of their required investment.

Objective

To assess the cost-effectiveness of ICU management for admitted COVID-19 patients across the public and private health sector in South Africa.

Methods

Using a Markov modelling framework and a health system perspective, the costs and health outcomes of inpatient management of severe and critical COVID-19 patients in (1) general ward and intensive care (GW+ICU) and (2) general ward only were assessed. Disability adjusted life years (DALYs) were evaluated as health outcomes, and the cost per admission from public and private sectors was determined. The models made use of four variables: mortality rates, utilisation of inpatient days for each management approach, disability weights associated to the severity of the disease, and the unit cost per general ward day and per ICU day in public and private hospitals. The unit costs were multiplied by utilisation estimates to determine the cost per admission. DALYs were calculated as the sum of years of life lost (YLL) and years lived with disability (YLD). An incremental cost-effectiveness ratio (ICER) representing the difference in costs and health outcomes of the two management strategies - was calculated and compared to a cost-effectiveness threshold to determine the value for money of ICU management.

Results

A cost per admission of ZAR 75,127 was estimated for inpatient management of severe and critical COVID-19 patients in general wards only as opposed to ZAR 103,030 in GW+ICU. DALYs were 1.48 and 1.10 in the general ward only and GW+ICU, respectively. The ratio of difference in costs and health outcomes between the two management strategies produced an ICER equal to ZAR 73 091 per DALY averted, a value above the cost-effectiveness threshold of ZAR 38 465.

Conclusions

This study indicated that purchasing additional ICU capacity from the private sector may not be a cost-effective use of limited health resources. The ‘real time’, rapid, pragmatic, and transparent nature of this analysis demonstrates a potential approach for further evidence generation for decision making relating to the COVID-19 pandemic response and South Africa’s wider priority setting agenda.
Association of COVID-19 RT-qPCR test false-negative rate with patient age, sex and time since diagnosis
Authors: Levine-Tiefenbrun Matan , Yelin Idan , Uriel Hedva , Kuint Jacob , Schreiber Licita , Herzel Esma , Katz Rachel , Ben-Tov Amir , Patalon Tal , Chodick Gabriel , Kishony Roy
Published: November 2020

Background

Routine testing for SARS-CoV-2 in the community is essential for guiding key epidemiological decisions from the quarantine of individual patients to enrolling regional and national preventive measures. Yet, the primary testing tool, the RT-qPCR based testing, is notoriously known for its low sensitivity, i.e. high risk of missed detection of carriers. Quantifying the false-negative rate (FNR) of the RT-qPCR test at the community settings and its dependence on patient demographic and disease progression is therefore key in designing and refining strategies for disease spread prevention.

Methods

Analyzing 843,917 test results of 521,696 patients, we identified false-negative (FN) and true-positive (TP) results as negative and positive results preceded by a COVID-19 diagnosis and followed by a later positive test. Regression analyses were used to determine associations of false-negative results with time of sampling after diagnosis, patient demographics and viral loads based on RT-qPCR Ct values of the next positive tests.

Findings

The overall FNR was 22.8%, which is consistent with previous studies. Yet, this rate was much lower at the first 5 days following diagnosis (10.7%) and only increased in later dates. Furthermore, the FNR was strongly associated with demographics, with odds ratio of 1.74 (95% CI: 1.58-1.90) for women over men and 1.36 (95% CI: 1.34-1.39) for 10 years younger patients. Finally, FNR was associated with viral loads (p-value 0.0005), with a difference of 1.50 (95% CI: 0.70-2.30) between the average Ct of the N gene in a positive test following a false-negative compared to a positive test following a true-positive.

Interpretation

Our results show that in the first few days following diagnosis, when results are critical for quarantine decisions, RT-qPCR testing is more reliable than previously reported. Yet the reliability of the test result is reduced in later days as well as for women and younger patients, where the viral loads are typically lower.

Funding

This research was supported by the ISRAEL SCIENCE FOUNDATION (grant No. 3633/19) within the KillCorona – Curbing Coronavirus Research Program.
Prognostic factors of chest CT findings for ICU admission and mortality in patients with COVID-19 pneumonia
Authors: Kazemi Mohammad Ali , Ghanaati Hossein , Moradi Behnaz , Chavoshi Mohammadreza , Hashemi Hassan , Hemmati Samira , Rouzrokh Pouria , Gity Masoumeh , Ahmadinejad Zahra , Abdollahi Hamed
Published: November 2020

Background

Studies have shown that CT could be valuable for prognostic issues in COVID-19

Objective

to investigate the prognostic factors of early chest CT findings in COVID-19 patients.

Materials and Methods

This retrospective study included 91 patients (34 women, and 57 men) of RT-PCR positive COVID-19 from 3 hospitals in Iran between February 25, 2020, to march 15, 2020. Patients were divided into two groups as good prognosis, discharged from the hospital and alive without symptoms (48 patients), and poor prognosis, died or needed ICU care (43 patients). The first CT images of both groups that were obtained during the first 8 days of the disease presentation were evaluated considering the pattern, distribution, and underlying disease. The total CT-score was calculated for each patient. Univariate and multivariate analysis with IBM SPSS Statistics v.26 was used to find the prognostic factors.

Results

There was a significant correlation between poor prognosis and older ages, dyspnea, presence of comorbidities, especially cardiovascular and pulmonary. Considering CT features, peripheral and diffuse distribution, anterior and paracardiac involvement, crazy paving pattern, and pleural effusion were correlated with poor prognosis. There was a correlation between total CT-score and prognosis and an 11.5 score was suggested as a cut-off with 67.4% sensitivity and 68.7% specificity in differentiation of poor prognosis patients (patients who needed ICU admission or died. Multivariate analysis revealed that a model consisting of age, male gender, underlying comorbidity, diffused lesions, total CT-score, and dyspnea would predict the prognosis better.

Conclusion

Total chest CT-score and chest CT features can be used as prognostic factors in COVID-19 patients. A multidisciplinary approach would be more accurate in predicting the prognosis.
A gain and dynamic range independent index to quantify spillover spread to aid panel design in flow cytometry
Authors: Bhowmick Debajit , van Diepen Frank , Pfauth Anita , Tissier Renaud , Ratliff Michelle
Published: November 2020

In conventional flowcytometry one detector (primary) is dedicated for one fluorochrome. However, photons usually end up in other detectors too (fluorescence spillover). ‘Compensation’ is a process that corrects the spillover signal from all detectors except the primary detector. Post ‘compensation’, the photon counting error of spillover signals become evident as spreading of the data. The spreading induced by spillover impairs the ability to resolve stained cell population from the unstained one, potentially reducing or completely losing cell populations. For successful multi-color panel design, it is important to know the expected spillover to maximize the data resolution. The Spillover Spreading Matrix (SSM) can be used to estimate the spread, but the outcome is dependent on detector sensitivity. Simply, the same single stained sample produces different spillover spread values when detector(s) sensitivity is altered. Many researchers mistakenly use this artifact to “reduce” the spread by decreasing detector sensitivity. This can result in diminished capacity to resolve dimly expressing cell populations. Here, we introduce SQI (Spread Quantification Index), that can quantify the spillover spread independent of detector sensitivity and independent of dynamic range. This allows users to compare spillover spread between instruments having different types of detectors, which is not possible using SSM.
SATB2 induction of a neural crest mesenchyme-like program drives invasion and drug resistance in melanoma
Authors: Fazio Maurizio , van Rooijen Ellen , Dang Michelle , van de Hoek Glenn , Ablain Julien , Mito Jeffrey K. , Yang Song , Thomas Andrew , Michael John , Fabo Tania , Modhurima Rodsy , Pessina Patrizia , Kaufman Charles , Zhou Yi , White Richard M. , Zon Leonard I.
Published: November 2020

Recent genomic and scRNA-seq analyses of melanoma identified common transcriptional states correlating with invasion or drug resistance, but failed to find recurrent drivers of metastasis. To test whether transcriptional adaptation can drive melanoma progression, we made use of a zebrafishmitfa:BRAFV600E;tp53-/-model, in which malignant progression is characterized by minimal genetic evolution. We undertook an overexpression-screen of 80 epigenetic/transcriptional regulators and found neural crest-mesenchyme developmental regulator SATB2 to accelerate aggressive melanoma development. Its overexpression induces invadopodia formation and invasion in zebrafish tumors and human melanoma cell lines. SATB2 binds and activates neural crest-regulators, includingpdgfabandsnai2.The transcriptional program induced by SATB2 overlaps with known MITFlowAXLhlghand AQP1+NGFR1highdrug resistant states and functionally drives enhanced tumor propagation and resistance to Vemurafenibin vivo.Here we show that melanoma transcriptional rewiring by SATB2 to a neural crest mesenchyme-like program can drive invasion and drug resistance in endogenous tumors.
Standard Procedures for Native CZE-MS of Proteins and Protein Complexes up to 800 kDa
Authors: Jooss Kevin , McGee John P. , Melani Rafael D. , Kelleher Neil L.
Published: November 2020

Native mass spectrometry (nMS) is a rapidly growing method for the characterization of large proteins and protein complexes, preserving “native” non-covalent inter- and intramolecular interactions. Direct infusion of purified analytes into a mass spectrometer represents the standard approach for conducting nMS experiments. Alternatively, CZE can be performed under native conditions, providing high separation performance while consuming trace amounts of sample material. Here, we provide standard operating procedures for acquiring high quality data using CZE in native mode coupled online to various Orbitrap mass spectrometers via a commercial sheathless interface, covering a wide range of analytes from 30 – 800 kDa. Using a standard protein mix, the influence of various CZE method parameters were evaluated, such as BGE/conductive liquid composition and separation voltage. Additionally, a universal approach for the optimization of fragmentation settings in the context of protein subunit and metalloenzyme characterization is discussed in detail for model analytes. A short section is dedicated to troubleshooting of the nCZE-MS setup. This study is aimed to help normalize nCZE-MS practices to enhance the CE community and provide a resource for production of reproducible and high-quality data.
Engineered Red Blood Cells Carrying PCSK9 Inhibitors Persistently Lower LDL and Prevent Obesity
Authors: Deshycka Rhogerry , Sudaryo Valentino , Huang Nai-Jia , Xie Yushu , Smeding Liyan Y. , Choi Moon Kyung , Ploegh Hidde L. , Lodish Harvey F. , Pishesha Novalia
Published: November 2020

Low plasma levels of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) are associated with decreased low-density lipoprotein (LDL) cholesterol and a reduced risk of cardiovascular disease. PCSK9 binds to the epidermal growth factor-like repeat A (EGFA) domain of LDL receptors (LDLR), very low-density lipoprotein receptors (VLDLR), apolipoprotein E receptor 2 (ApoER2), and lipoprotein receptor–related protein 1 (LRP1) and accelerates their degradation, thus acting as a key regulator of lipid metabolism. Antibody and RNAi - based PCSK9 inhibitor treatments lower cholesterol and prevent cardiovascular incidents in patients, but their high cost hampers market penetration. We sought to develop a safe, long-term and one-time solution to treat hyperlipidemia. We created a cDNA encoding a chimeric protein in which the extracellular N-terminus of glycophorin A was fused to the LDLR EGFA domain and introduced this gene into mouse bone marrow hematopoietic stem and progenitor cells (HSPCs). Following transplantation into irradiated mice, the animals produced red blood cells (RBCs) with the EGFA domain (EGFA-GPA RBCs) displayed on their surface. These animals showed significantly reduced plasma PCSK9 (66.5% decrease) and reduced LDL levels (40% decrease) for as long as 12 months post-transplantation. Furthermore, the EGFA-GPA mice remained lean for life and maintained normal body weight under high-fat diet. Hematopoietic stem cell gene therapy can generate red blood cells expressing an EGFA - glycophorin A chimeric protein as a practical and long-term strategy for treating chronic hyperlipidemia and obesity.
Music for cells? A systematic review of studies investigating the effects of audible sound played through speaker-based systems to cell cultures
Authors: Kwak Dongho , Combriat Thomas , Wang Chencheng , Scholz Hanne , Danielsen Anne , Jensenius Alexander Refsum
Published: November 2020

There have been several studies investigating whether musical sound can be used as cell stimuli in recent years. We systematically searched publications to get an overview of studies that have used audible sound played through speaker-based systems to induce mechanical perturbation in cell cultures. A total of 12 studies were identified. We focused on the experimental setups, the sound materials used as stimuli, and the outcomes. The stimuli were categorized into simple and complex sounds. The effects were reported as enhanced cell migration, proliferation, colony formation, and differentiation ability. However, there are significant differences in methodologies and cell type-specific outcomes, which made it difficult to find a systematic pattern in the results. We suggest that future experiments should consider using: 1) a more controlled acoustic environment), 2) standardized sound and noise measurement methods, and 3) a more comprehensive range of controlled sound stimuli.
Short-Beaked Echidna (Tachyglossus aculeatus) Home Range at Fowlers Gap Arid Zone Research Station, NSW
Authors: Badgery Georgia J. , Lawes Jasmin C. , Leggett Keith E.A.
Published: November 2020

Echidnas(Tachyglossus aculeatus)are found Australian-wide and appear to be remarkably well-adapted to arid zones, yet, nearly all echidna research has been conducted in temperate, tropical and alpine zones. This study investigated the home range and movement of echidnas in western New South Wales. Radio telemetry tracking was used to locate the echidnas daily during the study period (March-May 2019 and August 2019); the home range was 1.47± 1.21 km2. This is over twice the reported home range of temperate environments (>0.65 km2) suggesting that echidnas exhibit larger home ranges in arid zones. This study provides insight into the movement and home range of echidnas in arid zones, revealing that desert echidnas have large home ranges, dependent on the availability of resources.
Experimental evolution of adaptive divergence under varying degrees of gene flow
Authors: Tusso Sergio , Nieuwenhuis Bart P.S. , Weissensteiner Bernadette , Immler Simone , Wolf Jochen B.W.
Published: November 2020

Adaptive divergence is the key evolutionary process generating biodiversity by means of natural selection. Yet, the conditions under which it can arise in the presence of gene flow remain contentious. To address this question, we subjected 132 sexually reproducing fission yeast populations sourced from two independent genetic backgrounds to disruptive ecological selection and manipulated the level of migration between environments. Contrary to theoretical expectations, adaptive divergence was most pronounced when migration was either absent (‘allopatry’) or maximal (‘sympatry’), but was much reduced at intermediate rates (‘parapatry’, ‘local mating’). This effect was apparent across central life history components (survival, asexual growth, and mating), but differed in magnitude between ancestral genetic backgrounds. The evolution of some fitness components was constrained by pervasive negative correlations (trade-off between asexual growth and mating), while others changed direction under the influence of migration (e.g. survival and mating). In allopatry, adaptive divergence was mainly conferred by standing genetic variation and resulted in ecological specialization. In sympatry, divergence was mainly mediated by novel mutations enriched in a subset of genes and was characterized by the repeated emergence of two strategies: an ecological generalist and an asexual growth specialist. Multiple loci showed consistent evidence for antagonistic pleiotropy across migration treatments and provide a conceptual link between adaptation and divergence. This evolve-and-resequence experiment demonstrates that rapid ecological differentiation can arise even under high rates of gene flow. It further highlights that adaptive trajectories are governed by complex interactions of gene flow, ancestral variation and genetic correlations.
Chronic BDNF simultaneously inhibits and unmasks superficial dorsal horn neuronal activity
Authors: Alles Sascha R.A. , Odem Max A. , Lu Van B. , Cassidy Ryan M. , Smith Peter A.
Published: November 2020

Brain-derived neurotrophic factor (BDNF) is critically involved in the pathophysiology of chronic pain. However, the mechanisms of BDNF action on specific neuronal populations in the spinal superficial dorsal horn (SDH) requires further study. We used chronic BDNF treatment (200 ng/ml, 5-6 days) of defined-medium, serum-free spinal organotypic cultures to study intracellular calcium ([Ca2+]i) fluctuations. A detailed quantitative analysis of these fluctuations using the Frequency-independent biological signal identification (FIBSI) program revealed that BDNF simultaneously depressed activity in some SDH neurons while it unmasked a particular subpopulation of ‘silent’ neurons causing them to become spontaneously active. Blockade of gap junctions disinhibited a subpopulation of SDH neurons and reduced BDNF-induced synchrony in BDNF-treated cultures. BDNF reduced neuronal excitability by measuring spontaneous excitatory postsynaptic currents. This was similar to the depressive effect of BDNF on the [Ca2+]ifluctuations. This study reveals novel regulatory mechanisms of SDH neuronal excitability in response to BDNF.
Investigating age- and sex-specific effects of socialization on voluntary ethanol administration using a novel vapor paradigm
Authors: Walker Christopher D. , Sexton Hannah G. , Risher Mary-Louise
Published: November 2020

Introduction

Adolescence is characterized as a transitional developmental period between childhood and adulthood that is associated with increased freedom and novel experiences that are frequently peer-influenced. Due to newfound independence, there is a higher prevalence of alcohol consumption, which is heightened by the rewarding effects of alcohol. However, the contributions of social interaction and sexual dimorphism to alcohol intake are not fully understood. Here we explore the use a novel self-administration ethanol (EtOH) vapor system to investigate the sexual dimorphic nature of socially facilitated ethanol exposure.

Methods

Adolescent and adult male and female Sprague-Dawley rats underwent a novel voluntary intermittent EtOH vapor paradigm. Nosepoke initiated self-administration vapor chambers administered 20mg/L of vaporized EtOH or air into the chamber following each nosepoke. Beginning on postnatal day 30 (PND30), during the onset of adolescence, or 70 (PND70), at the onset of adulthood, animals were placed in vapor chambers for 4hr every other day for 40 sessions. All animals underwent 10 sessions with their cagemate (social access) followed by 10 sessions in isolation (isolated access), a 10-day forced abstinence period, 10 sessions isolated access, and 10 sessions social access.

Results

These data reveal that despite low EtOH consumption across all groups, adolescent (PND30) and adult (PND70) female rats voluntarily self-administered more EtOH vapor per body weight than age-matched males, while male rats increased EtOH preference over sessions regardless of age. In addition, all rats regardless of sex or age voluntarily self-administered more EtOH vapor per body weight during the social access session than during the subsequent isolated access sessions.

Conclusion

These data demonstrate that under these experimental parameters, male and female rats regardless of age do not self-administer high quantities of EtOH vapor using this paradigm. Further work is required to determine whether the nose-poke EtOH vapor self-administration apparatus can be modified to promote high voluntary EtOH consumption that can be socially facilitated. These data demonstrate that with further investigation, the self-administration EtOH vapor system could be an effective alternative to other methods of voluntary EtOH administration to further our understanding of socially facilitated drinking.
The zinc finger protein CLAMP promotes long-range chromatin interactions that mediate dosage compensation of theDrosophilamale X-chromosome
Authors: Jordan William , Larschan Erica
Published: November 2020

Drosophiladosage compensation is an important model system for defining how active chromatin domains are formed. The Male-specific lethal dosage compensation complex (MSLc) increases transcript levels of genes along the length of the single male X-chromosome to equalize with that on the two female X-chromosomes. The strongest binding sites for MSLc cluster together in three-dimensional space independent of MSLc because clustering occurs in both sexes. CLAMP, a non-sex specific, ubiquitous zinc finger protein, binds synergistically with MSLc to enrich the occupancy of both factors on the male X-chromosome. Here, we demonstrate that CLAMP promotes the observed clustering of MSLc bindings sites. Genome-wide, CLAMP promotes interactions between active chromatin regions. Moreover, the X-enriched CLAMP protein more strongly promotes longer-range interactions on the X-chromosome than autosomes. Genome-wide, CLAMP promotes interactions between active chromatin regions together with other insulator proteins. Overall, we define how long-range interactions which are modulated by a locally enriched ubiquitous transcription factor promote hyper-activation of the X-chromosome to mediate dosage compensation.
Bacterially produced small molecules stimulate diatom growth
Authors: Sittmann John , Bae Munhyung , Mevers Emily , Li Muzi , Quinn Andrew , Sriram Ganesh , Clardy Jon , Liu Zhongchi
Published: November 2020

Diatoms are photosynthetic microalgae that fix a significant fraction of the world’s carbon. Because of their photosynthetic efficiency and high-lipid content, diatoms are priority candidates for biofuel production. Here, we report that sporulatingBacillus thuringiensiswhen in co-culture with a marine diatomPhaeodactylum tricornutumsignificantly increases the diatom cell count. Bioassay-guided purification led to the identification of two diketopiperazines (DKPs) that both stimulateP. tricornutumgrowth and increase its lipid content. RNA-seq analysis revealed upregulation of a small set ofP. tricornutumgenes involved in iron starvation response and nutrient recycling when DKP was added to the diatom culture. This work demonstrates that two DKPs produced by a bacterium could positively impactP. tricornutumgrowth and lipid content, offering new approaches to enhanceP. tricornutum-based biofuel production. As increasing numbers of DKPs are isolated from marine microbes, the work gives potential clues to bacterially produced growth factors for marine microalgae.

One sentence summary

Two diketopiperazines (DKPs) produced by sporulating bacteriumBacillus thuringiensisstimulate diatomP. tricornutumgrowth and increase diatom lipid content.
Shared genetic architecture underlying root metaxylem phenotypes under drought stress in cereals
Authors: Klein Stephanie P. , Reeger Jenna E. , Kaeppler Shawn M. , Brown Kathleen M. , Lynch Jonathan P.
Published: November 2020

Root metaxylem are phenotypically diverse structures whose function is related to their anatomy, particularly under drought stress. Much research has dissected the genetic machinery underlying metaxylem phenotypes in dicots, but monocots are relatively unexplored. In maize (Zea mays), a robust pipeline integrated a GWAS of root metaxylem phenes under well-watered and water stress conditions with a gene co-expression network to identify candidate genes most likely to impact metaxylem phenotypes. We identified several promising candidate genes in 14 gene co-expression modules inferred to be functionally relevant to xylem development. We also identified five gene candidates that co-localized in multiple root metaxylem phenes in both well-watered and water stress conditions. Using a rice GWAS conducted in parallel, we detected overlapping genetic architecture influencing root metaxylem phenotypes by identifying eight pairs of syntenic candidate genes significantly associated with metaxylem phenes. There is evidence that the genes of these syntenic pairs may be involved in biosynthetic processes related to the cell wall, hormone signaling, oxidative stress responses, and drought responses. Our study demonstrates a powerful new strategy for identifying promising gene candidates and suggests several gene candidates that may enhance our understanding of vascular development and responses to drought in cereals.

One sentence summary

Cross-species genome-wide association studies and a gene coexpression network identified genes associated with root metaxylem phenotypes in maize under water stress and non-stress and rice.
Mosquitoes of the Maculipennis complex in Northern Italy
Authors: Calzolari Mattia , Desiato Rosanna , Albieri Alessandro , Bellavia Veronica , Bertola Michela , Bonilauri Paolo , Callegari Emanuele , Canziani Sabrina , Lelli Davide , Mosca Andrea , Mulatti Paolo , Peletto Simone , Ravagnan Silvia , Roberto Paolo , Torri Deborah , Pombi Marco , Di Luca Marco , Montarsi Fabrizio
Published: November 2020

The correct identification of mosquito vectors is often hampered by the presence of morphologically indiscernible sibling species. The Maculipennis complex is one of these groups which include both malaria vectors of primary importance and species of low/negligible epidemiological relevance, of which distribution data in Italy are outdated. Our study was aimed at providing an updated distribution of Maculipennis complex in Northern Italy through the sampling and morphological/molecular identification of specimens from five regions. The most abundant species wasAnopheles messeae s.l.(2032), followed byAnopheles maculipennis s.s.(418),Anopheles atroparvus(28) andAnopheles melanoon(13). The distribution of species was characterized by Ecological Niche Models (ENMs), fed by recorded points of presence. ENMs provided clues on the ecological preferences of the detected species, withAn. messeae s.l.linked to stable breeding sites andAn. maculipennis s.s.more associated to ephemeral breeding sites. We demonstrate that historicalAnophelesmalaria vectors are still widespread in Northern Italy.
Coevolutionary phage training leads to greater bacterial suppression and delays the evolution of phage resistance
Authors: Borin Joshua M. , Avrani Sarit , Barrick Jeffrey E. , Petrie Katherine L. , Meyer Justin R.
Published: November 2020

The evolution of antibiotic resistant bacteria threatens to become the leading cause of worldwide mortality. This crisis has renewed interest in the practice of phage therapy. Yet, bacteria’s capacity to evolve resistance is likely to debilitate this therapy as well. To combat the evolution of phage resistance and improve treatment outcomes, many have suggested leveraging phages’ ability to counter resistance by evolving phages on target hosts before using them in therapy (phage training). We found that during in vitro experiments, a phage trained for 28 days suppressed bacteria ∼1000-fold for 3-8 times longer than its untrained ancestor. This extension was due to a delay in the evolution of resistance. Several factors contributed to this prolonged suppression. Mutations that confer resistance to trained phages are ∼100× less common and, while the target bacterium can evolve complete resistance to the untrained phage in a single step, multiple mutations are required to evolve complete resistance to trained phages. Mutations that confer resistance to trained phages are more costly than mutations for untrained phage resistance. And when resistance does evolve, trained phages are better able to suppress these forms of resistance. One way the trained phage improved was through recombination with a gene in a defunct prophage in the host genome, which doubled phage fitness. This direct transfer of information encoded by the host but originating from a relict phage provides a previously unconsidered mode of training phage. Overall, we provide a case study for successful phage training and uncover mechanisms underlying its efficacy.

Significance Statement

The evolution of antibiotic resistant bacteria threatens to claim over 10 million lives annually by 2050. This crisis has renewed interest in phage therapy, the use of bacterial viruses to treat infections. A major barrier to successful phage therapy is that bacteria readily evolve phage resistance. One idea proposed to combat resistance is “training” phages by using their natural capacity to evolve to counter resistance. Here, we show that training phages by coevolving them with their host for one month enhanced their capacity for suppressing bacterial growth and delayed the emergence of resistance. Enhanced suppression was caused by several mechanisms, suggesting that the coevolutionary training protocol produces a robust therapeutic that employs complementary modes of action.
Measuring mutagenicity in ecotoxicology: A case study of Cd exposure inChironomus riparius
Authors: Doria Halina Binde , Waldvogel Ann-Marie , Pfenninger Markus
Published: November 2020

Existing mutagenicity tests for metazoans lack the direct observation of enhanced germline mutation rates after exposure to anthropogenic substances, therefore being inefficient. Cadmium (Cd) is a metal described as a mutagen in mammalian cells and listed as a group 1 carcinogenic and mutagenic substance. But Cd mutagenesis mechanism is not yet clear. Therefore, in the present study, we propose a method coupling short-term mutation accumulation (MA) lines with subsequent whole genome sequencing (WGS) and a dedicated data analysis pipeline to investigate if chronic Cd exposure onChironomus ripariuscan alter the rate at whichde novopoint mutations appear. Results show that Cd exposure did not affect the basal germline mutation rate nor the mutational spectrum inC. riparius, thereby arguing that exposed organisms might experience a range of other toxic effects before any mutagenic effect may occur. We show that it is possible to establish a practical and easily implemented pipeline to rapidly detect germ cell mutagens in a metazoan test organism. Furthermore, our data implicate that it is questionable to transfer mutagenicity assessments based onin vitromethods to complex metazoans.

Main find of the work

Cd chronic exposure under environmental realistic concentrations did not exert mutagenicity; It is questionable to transferin vitromutagenicity assessments to complex metazoans.