bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of saliva molecular point of care for detection of SARS-CoV-2 in ambulatory care
Authors: LeGoff Jérôme , Kernéis Solen , Elie Caroline , Mercier Delarue Séverine , Gastli Nabil , Choupeaux Laure , Fourgeaud Jacques , Alby Marie-Laure , Quentin Pierre , Pavie Juliette , Brazille Patricia , Néré Marie Laure , Minier Marine , Gabassi Audrey , Leroy Chrystel , Parfait Béatrice , Tréluyer Jean-Marc , Delaugerre Constance
Published: June 2021

Background

Rapid identification of SARS-Cov-2 infected individuals is a cornerstone in strategies for the control of virus spread. The sensitivity of SARS-CoV-2 RNA detection by RT-PCR is similar in saliva and nasopharyngeal swab. Rapid molecular point-of-care tests in saliva could facilitate, broaden and speed up the diagnosis.

Objectives and methods

We conducted a prospective study in two community COVID-19 screening centers to evaluate the performances of a CE-marked RT-LAMP assay (EasyCoV™) specifically designed for the detection of SARS-CoV2 RNA from fresh saliva samples, compared to nasopharyngeal RT-PCR (reference test), to saliva RT-PCR and to nasopharyngeal antigen testing.

Results

Overall, 117 of the 1718 participants (7%) were tested positive with nasopharyngeal RT-PCR. Compared to nasopharyngeal RT-PCR, the sensitivity and specificity of the RT-LAMP assay in saliva were 34% (95%CI: 26-44) and 97% (95%CI: 96-98) respectively. The performance was similar in symptomatic and asymptomatic participants. The Ct values of nasopharyngeal RT-PCR were significantly lower in the 40 true positive subjects with saliva RT-LAMP (Ct 25.9) than in the 48 false negative subjects with saliva RT-LAMP (Ct 28.4) (p=0.028). Considering six alternate criteria for reference test, including saliva RT-PCR and nasopharyngeal antigen, the sensitivity of saliva RT-LAMP ranged between 27 and 44%.

Conclusion

In the ambulatory setting, the detection of SARS-CoV-2 from crude saliva samples with the RT-LAMP assay had a lower sensitivity than nasopharyngeal RT-PCR, saliva RT-PCR and nasopharyngeal antigen testing.

Registration number

NCT04578509

Funding Sources

French Ministry of Health and the Assistance Publique-Hôpitaux de Paris Foundation.
Predicted domination of variant Delta of SARS-CoV-2 before Tokyo Olympic games, Japan
Authors: Ito Kimihito , Piantham Chayada , Nishiura Hiroshi
Published: June 2021

Using numbers of SARS-CoV-2 variants detected in Japan, the relative instantaneous reproduction numbers of the R.1, Alpha, and Delta variants with respect to other strains circulating in Japan were estimated at 1.245, 1.437, and 1.948, respectively. The numbers can vary within 1.190–1.319 for R.1, 1.335–1.580 for Alpha, and 1.703–2.30 for Delta depending on the assumed serial interval distributions. The frequency of the Delta is expected to take over the Alpha in Japan around July 12, 2021.
Analysis of Social Combinations of Coronavirus Vaccination: Evidence from a Conjoint Analysis
Authors: Ohmura Hanako
Published: June 2021

Using a conjoint analysis based on cases in Japan, this study attempts to identify a preferable social strategic combination of “Who is vaccinated, who is not, who waits.” The analysis shows that the most desirable choice is a “wait-and-see” strategy, allowing for a risk assessment of side effects. We also find that subjects who recalled blood relatives as their familiar entities tend to prefer a “wait-and-see” strategy for themselves and their blood relatives.
Burden of Depressive and Anxiety Disorders in Nepal, 1990-2017: An Analysis of Global Burden of Disease Data
Authors: Bhatta Deepa Kumari , Budhathoki Kreeti , Paudel Kiran , Paudel Shishir , Marhatta Sujan Babu , Banskota Avinaya , Joshi Yadav Prasad
Published: June 2021

Objectives

This study aims to describe the burden of depressive and anxiety disorders in Nepal in terms of incidence, prevalence, YLDs, and DALYs by age and sex.

Design

An ecological study on disease burden.

Methods

We used the publicly available Global Burden of Disease (GBD) data from 1990 to 2017. The age and sex-specific incidence, prevalence rate, Years Lived with Disability (YLDs), and Disability Adjusted Life Years (DALYs) were examined among per 100,000 populations.

Results

Females had a higher prevalence of depressive 4094.4 (95% uncertainty interval [UI]: 3761.9-4470.3 per 100,000) and anxiety 4496.8 (95% UI: 4171.9-4837.9 per 100,000) disorders. The prevalence of major depressive disorders was comparatively higher in females (2766.7) than males (1822.9). Females also had higher YLDs for both depressive and anxiety disorders. In 2017, higher DALYs of anxiety disorder were found in the females of 45-49 years (630.1). Childhood sexual abuse was found to be the main risk factor for depressive disorder, contributing to 32.5 DALYs in both sexes. Bullying, victimization had contributed to 26.7 DALYs of anxiety.

Conclusions

The high burden of disorders in females would support in identifying major mental health challenges in Nepal and develop plans and various preventive, curative, and rehabilitative strategies.

Strength and limitations of this study

This is one of the few studies that have provided the burden of depressive and anxiety disorders in developing nations such as Nepal.

The data used in this study were based on the GBD studies which utilize exhaustive information sources and comprehensive investigations.

Estimation of the burden of diseases was restricted to standard epidemiological measures and other financial and social burdens were not considered.

Due to use of secondary data and information which were only available publicly this may not representative of the whole nation.
Designing and implementing state-level fertility preservation health insurance benefit mandates
Authors: Flores Ricardo E. , Yoeun Sara W. , Mesina Omar , Kaiser Bonnie N. , McMenamin Sara B. , Su H. Irene
Published: June 2021

Objective

To describe the design and implementation of state-level fertility preservation (FP) health insurance benefit mandates and regulation and to provide stakeholders with guidance on best practices, gaps, and implementation needs.

Design

Legal mapping and implementation framework-guided analysis

Setting

U.S. states with state-level fertility preservation health insurance benefit mandates

Patient(s)

Individuals at risk of iatrogenic infertility

Intervention(s)

State laws mandating health insurance benefit coverage for fertility preservation services.

Main Outcome Measure(s)

Design features of FP mandated benefit legislation; implementation process

Result(s)

Between June, 2017 and March, 2021, 11 states passed FP benefit mandate laws. On average, states took 223 days to implement their mandates from the start of the laws’ enactment dates to their corresponding effective dates, and a majority issued regulatory guidance after the law was in effect. Significant variation was observed in which FP services were specified for inclusion or exclusion in the laws and/or regulator guidance. Federal policies impacted state level implementation, with the ACA and HIPAA guiding design of fertility preservation benefits. In addition, a majority of states referenced medical society clinical practice guidelines in the design of FP mandated benefits.

Conclusions

Our policy scan documented significant variation in the design and implementation of health insurance benefit mandates for FP services. Future considerations for policy development include specificity and flexibility of benefit design, reference to external clinical practice guidelines to drive benefit coverage, inclusion of Medicaid populations in required coverage, and consideration of interaction with relevant state and federal policies. In addition, key considerations for implementation include the sufficient length of time for the implementation period, regulator guidance issued prior to the law going into effect, and explicit allocation of resources for the implementation process.
VAERS data reveals no increased risk of neuroautoimmune adverse events from COVID-19 vaccines
Authors: Csefalvay Chris von
Published: June 2021

Neuroautoimmune disorders, such as multiple sclerosis and Guillain-Barre syndrome, have been documented in relation to various vaccines in the past. This paper uses passive reporting information from the CDC/FDA’s VAERS system to analyse whether neuroautoimmune presentations are reported at a relatively higher or lower rate, vis-a-vis other adverse effects, for COVID-19 vaccines than for other vaccines. Through computing the reporting odds ratios for a range of symptoms and comparator vaccines, a clear indication in favour of the safety of COVID-19 vaccines emerges, with reports of neuroautoimmune adverse events in relation to other adverse events being over 70% less likely for COVID-19 than for comparator vaccines (ROR : 0.292, p < 0.0001). In comparison with other vaccines given as part of routine care in adulthood, COVID-19 vaccines have the lowest reporting odds ratio of neuroautoimmune adverse effects (median ROR: 0.246).
Estimating decay curves of neutralising antibodies to SARS-CoV-2 infection
Authors: Poehler Megan , Gibson Liam , Lustig Audrey , Moreland Nicole Jane , McGregor Reuben , James Alex
Published: June 2021

Estimating the longevity of an individual's immune response to the Sars-Cov-2 virus is vital for future planning, particularly of vaccine requirements. Neutralising antibodies (Nabs) are increasingly being recognised as a correlate of protection and whilst there are many studies which follow the response of a cohort of people, each study alone is not enough to predict the long term response. Studies use different assays to measure Nabs making them hard to combine. We present a modelling method which can combine multiple datasets and can be updated as more detailed data becomes available. Combining data from six published datasets we predict that after a short period of rapid decay the half-life of the NAb response is approximately one year giving optimism that the response will be long-lived.
Multimodal deep learning enhances diagnostic precision in left ventricular hypertrophy
Authors: Soto Jessica Torres , Hughes J. Weston , Sanchez Pablo Amador , Perez Marco , Ouyang David , Ashley Euan
Published: June 2021

Determining the etiology of left ventricular hypertrophy (LVH) can be challenging due to the similarity in clinical presentation and cardiac morphological features of diverse causes of disease. In particular, distinguishing individuals with hypertrophic cardiomyopathy (HCM) from the much larger set of individuals with manifest or occult hypertension (HTN) is of major importance for family screening and the prevention of sudden death. We hypothesized that deep learning based joint interpretation of 12 lead electrocardiograms and echocardiogram videos could augment physician interpretation. We chose not to train on proximate data labels such as physician over-reads of ECGs or echocardiograms but instead took advantage of electronic health record derived clinical blood pressure measurements and diagnostic consensus (often including molecular testing) among physicians in an HCM center of excellence. Using over 18,000 combined instances of electrocardiograms and echocardiograms from 2,728 patients, we developed LVH-Fusion. On held-out test data, LVH-Fusion achieved an F1-score of 0.71 in predicting HCM, and 0.96 in predicting HTN. In head-to-head comparison with human readers LVH-Fusion had higher sensitivity and specificity rates than its human counterparts. Finally, we use explainability techniques to investigate local and global features that positively and negatively impact LVH-Fusion prediction estimates providing confirmation from unsupervised analysis the diagnostic power of lateral T wave inversion on the ECG and proximal septal hypertrophy on the echocardiogram for HCM. In conclusion, these results show that deep learning can provide effective physician augmentation in the face of a common diagnostic dilemma with far reaching implications for the prevention of sudden cardiac death.
Single-Cell Classification Using Graph Convolutional Networks
Authors: Wang Tianyu , Bai Jun , Nabavi Sheida
Published: June 2021

Background

Analyzing single-cell RNA sequencing (scRNAseq) data plays an important role in understanding the intrinsic and extrinsic cellular processes in biological and biomedical research. One significant effort in this area is the identification of cell types. With the availability of a huge amount of single cell sequencing data and discovering more and more cell types, classifying cells into known cell types has become a priority nowadays. Several methods have been introduced to classify cells utilizing gene expression data. However, incorporating biological gene interaction networks has been proved valuable in cell classification procedures.

Results

In this study, we propose a multimodal end-to-end deep learning model, named sigGCN, for cell classification that combines a graph convolutional network (GCN) and a neural network to exploit gene interaction networks. We used standard classification metrics to evaluate the performance of the proposed method on the within-dataset classification and the cross-dataset classification. We compared the performance of the proposed method with those of the existing cell classification tools and traditional machine learning classification methods.

Conclusions

Results indicate that the proposed method outperforms other commonly used methods in terms of classification accuracy and F1 scores. This study shows that the integration of prior knowledge about gene interactions with gene expressions using GCN methodologies can extract effective features improving the performance of cell classification.
Measuring the repertoire of age-related behavioral changes in Drosophila melanogaster
Authors: Overman Katherine E. , Choi Daniel M. , Leung Kawai , Shaevitz Joshua W. , Berman Gordon J.
Published: June 2021

Aging affects almost all aspects of an organism – its morphology, its physiology, its behavior. Isolating which biological mechanisms are regulating these changes, however, has proven difficult, potentially due to our inability to characterize the full repertoire of an animal’s behavior across the lifespan. Using data from fruit flies (D. melanogaster) we measure the full repertoire of behaviors as a function of age. We observe a sexually dimorphic pattern of changes in the behavioral repertoire during aging. Although the stereotypy of the behaviors and the complexity of the repertoire overall remains relatively unchanged, we find evidence that the observed alterations in behavior can be explained by changing the fly’s overall energy budget, suggesting potential connections between metabolism, aging, and behavior.
Changes to household income in a Kenyan informal settlement during COVID-19
Authors: Tompsett Anna , Baum Aaron , Bukachi Vera , Kipkemboi Pascal , K’oyoo Allan Ouko , Varela Ana Varela , Mulligan Joseph
Published: June 2021

More than a billion people live in densely-populated informal settlements worldwide. Crowded living conditions and limited resources may render these populations vulnerable to the health and economic effects of the COVID-19 pandemic. Representative and longitudinal survey data are needed to accurately measure impacts in these populations, but such data are scarce. Using satellite data and spatial sampling to ensure representativeness, we use longitudinal survey data on 1,033 households comprising 3,681 individuals collected pre- and post-pandemic to measure the economic effects of the COVID-19 pandemic households in six areas of the informal settlement of Kibera, Nairobi. The economic impacts are sizable and long-lasting. Household incomes declined at the start of the pandemic by 59% (95% CI: 50% to 69%) and remained 21% (95% CI: 13% to 28%) below the baseline level after six months. Respondents primarily attributed these declines in income to fewer labor market opportunities or lower demand for services, rather than the direct health impacts of the pandemic. The findings raise serious concerns about the welfare consequences of the COVID-19 pandemic for residents of informal settlements.

Summary box

Residents of informal settlements may be highly vulnerable to the economic impacts of the COVID-19 pandemic, but the longitudinal and representative survey data needed to measure impacts in these populations are scarce.

We use an innovative spatial sampling strategy to collect representative survey data from residents in six areas of the informal settlement of Kibera, Nairobi.

Relative to a pre-pandemic baseline, household incomes declined by 59% on average during the first three months of the pandemic. Six months later, incomes were still 21% below baseline.

Households attributed declines in income primarily to fewer labour market opportunities or lower demand for services (43% of respondents) rather than the direct health impacts of the pandemic (1%).

The declines in income we document raise concerns about the welfare of residents of informal settlements during the COVID-19 pandemic.
Study on the mucosal and serological immune response to the Novel Coronavirus (SARS-CoV-2) vaccines
Authors: Chan Renee WY , Liu Shaojun , Cheung Jonathan Y , Tsun Joseph GS , Chan Kate C , Chan Kathy YY , Fung Genevieve PG , Li Albert M , Lam Hugh Simon
Published: June 2021

Vaccines that elicit mucosal immune responses against SARS-CoV-2 could potentially be of exceptional importance in providing first line defense at the site of viral entry. The serological antibody response induced by SARS-CoV-2 vaccines have already been well characterized. In order to understand the mucosal immune response profiles of SARS-CoV-2 vaccines, we examined both the mucosal and systemic responses of subjects vaccinated by two different vaccination platforms: mRNA (Comirnaty) and inactivated virus (CoronaVac). Serial nasal epithelial lining fluid (NELF) and peripheral blood samples were collected in ten subjects who had received CoronaVac and thirty-two subjects who had received Comirnaty. We quantified IgA and IgG specific to SARS-CoV-2 S1 protein by ELISA in NELF and plasma samples. The neutralization effect of these two sample types were evaluated by surrogate ACE-SARS-CoV-2 Spike protein ELISA. Only Comirnaty induced nasal SARS-CoV-2 S1 protein-specific (S1-specific) IgA and IgG responses, which were evident as early as on 14±2 days after the first dose. The NELF samples of 72% of subjects became IgA+IgG+, while in 62.5% of subjects the samples were neutralizing by 7±2 days after the second dose. In 45% of the subjects their NELF remained neutralizing 50 days after the booster of Comirnaty. In plasma, 91% and 100% Comirnaty subjects possessed S1-specific IgA+IgG+ on 14±2 days after the first dose and 7±2 days after booster, respectively. The plasma collected on 7±2 days after booster was 100% neutralizing. The induction of S1-specific antibody by CoronaVac was IgG dominant, and 70% of the subjects possessed S1-specific IgG by 7±2 days after booster and were all neutralizing. This study reveals that Comirnaty is able to induce S1-specific IgA and IgG response with neutralizing activity in the nasal mucosa in addition to a consistent systemic response. The clinical implications and the biological mechanism of an additional nasal immune response induced by vaccines such as Comirnaty warrant further investigation.

One Sentence Summary

mRNA vaccine (CoronaVac) elicits mucosal IgA and IgG in the nasal epithelial lining fluid together with ELISA-detected anti-wild-type spike neutralizing antibodies as early as day 14 post vaccination.
Grey and white matter volume changes after preterm birth: A meta-analytic approach
Authors: Schmitz-Koep Benita , Haller Bernhard , Coupé Pierrick , Menegaux Aurore , Gaser Christian , Zimmer Claus , Wolke Dieter , Bartmann Peter , Sorg Christian , Hedderich Dennis M.
Published: June 2021

Objective

Lower brain grey matter volumes (GMV) and white matter volumes (WMV) have been reported at single time points in preterm-born individuals. While large MRI studies in the normative population have led to a better understanding of brain growth trajectories across the lifespan, such results remain elusive for preterm-born individuals since large, aggregated datasets of preterm-born individuals do not exist. To close this gap, we investigated GMV and WMV in preterm-born individuals as reported in the literature and contrasted it against individual volumetric data and trajectories from the general population.

Study design

Systematic database search of PubMed and Web of Science in March 2021 and extraction of outcome measures by two independent reviewers. Individual data on full-term controls was extracted from freely available databases. Mean GMV, WMV, total intracranial volume (TIV), and mean age at scan were the main outcome measures.

Results

Of 532 identified records, nine studies were included with 538 preterm-born subjects between 1.1 and 28.5 years of age. Reference data was generated from 880 full-term controls between 1 and 30 years of age. GMV was consistently lower in preterm-born individuals from infancy to early adulthood with no evidence for catch-up growth. While GMV changes followed a similar trajectory as full-term controls, WMV was particularly low in adolescence after preterm birth.

Conclusions

Results demonstrate altered brain volumes after premature birth across the first half of lifespan with particularly low white matter volumes in adolescence. Future studies should address this issue in large aggregated datasets of preterm-born individuals.
Stopping vs Resting state during motor imagery paradigm
Authors: Orset Bastien , Lee Kyuhwa , Chavarriaga Ricardo , Millán José del. R
Published: June 2021

Current non-invasive Brain Machine interfaces commonly rely on the decoding of sustained motor imagery activity (MI). This approach enables a user to control brain-actuated devices by triggering predetermined motor actions. One major drawback of such strategy is that users are not trained to stop their actions. Indeed, the termination process involved in BMI is poorly understood with most of the studies assuming that the end of an MI action is similar to the resting state. Here we hypothesize that the process of stopping MI (MI termination) and resting state are two different processes that should be decoded independently due to the exhibition of different neural pattens. We compared the detection of both states transitions of an imagined movement, i.e. rest-to-movement (onset) and movement-to-rest (offset). Our results shows that both decoders show significant differences in term of performances and latency (N=17 Subjects) with the offset decoder able to detect faster and better MI termination. While studying this difference, we found that the offset decoder is primarily based on the use of features in Beta band which appears earlier. Based on this finding, we also proposed a Random Forrest based decoder which enable to distinguish three classes (MI, MI termination and REST).
Synthetic Natural Product Inspired Peptides
Authors: Hostetler Matthew A. , Smith Chloe , Nelson Samantha , Budimir Zachary , Modi Ramya , Woolsey Ian , Frerk Autumn , Baker Braden , Gantt Jessica , Parkinson Elizabeth I.
Published: June 2021

Natural products (NPs) are a bountiful source of bioactive molecules. Unfortunately, discovery of novel bioactive NPs is challenging due to cryptic biosynthetic gene clusters (BGCs), low titers, and arduous purifications. Herein, we describe SNaPP (Synthetic Natural Product Inspired Peptides), a method for identifying NP-inspired bioactive molecules. SNaPP expedites bioactive molecule discovery by combining bioinformatics predictions of non-ribosomal peptide synthetases (NRPS) with chemical synthesis of the predicted NPs (pNPs). SNaPP utilizes a recently discovered cyclase, the penicillin binding protein (PBP)-like cyclase, as the lynchpin for the development of a library of cyclic peptide pNPs. Analysis of 500 BGCs allowed for identification of 131 novel pNPs. 51 diverse pNPs were synthesized using solid phase peptide synthesis and in-solution cyclization. Antibacterial testing revealed 14 pNPs with antibiotic activity, including activity against multidrug-resistant Gram-negative bacteria. Overall, SNaPP demonstrates the power of combining bioinformatics predictions with chemical synthesis to accelerate the discovery of bioactive molecules.
DOPAL initiates αSynuclein-mediated impaired proteostasis in neuronal projections leading to enhanced vulnerability in Parkinson’s disease
Authors: Masato A. , Plotegher N. , Thor A. , Adams S. , Sandre M. , Cogo S. , De Lazzari F. , Fontana C. M. , Martinez P. A. , Strong R. , Bellucci A. , Bisaglia M. , Greggio E. , Valle L. Dalla , Boassa D. , Bubacco L.
Published: June 2021

Dopamine dyshomeostasis has been acknowledged to be among the determinants of nigrostriatal neuron degeneration in Parkinson’s disease (PD). Several studies in experimental models and postmortem PD patients underlined increasing levels of the aldehydic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is highly reactive towards proteins. DOPAL has been shown to covalently modify the presynaptic protein αSynuclein (αSyn), whose misfolding and aggregation represent a major trait of PD pathology, triggering αSyn oligomerization in dopaminergic neurons. Here, we demonstrated that DOPAL elicits αSyn neuronal accumulation and hampers αSyn clearance at synapses and the soma. By combining cellular and in vivo models, we provided evidence that DOPAL-induced αSyn buildup lessens neuronal resilience, compromises synaptic integrity, and overwhelms protein quality control pathways, specifically at neuronal projections. The resulting progressive decline of neuronal homeostasis leads to dopaminergic neuron loss and motor impairment, corroborating the αSyn-DOPAL interplay as an early event in PD neurodegeneration.
Structure of mycobacterial cytochrome bcc in complex with Q203 and TB47, two anti-TB drug candidates
Authors: Zhou Shan , Wang Weiwei , Zhou Xiaoting , Zhang Yuying , Lai Yuezheng , Tang Yanting , Xu Jinxu , Yang Xiaolin , Guddat Luke W. , Wang Quan , Gao Yan , Rao Zihe , Gong Hongri
Published: June 2021

Pathogenic mycobacteria pose a sustained threat to global human health. Recently, cytochrome bcc complexes have gained interest as targets for antibiotic drug development. However, there is currently no structural information for the cytochrome bcc complex from these pathogenic mycobacteria. Here, we report the structures of M. tuberculosis cytochrome bcc alone (2.68 Å resolution) and in complex with clinical drug candidates Q203 (2.67 Å resolution) and TB47 (2.93 Å resolution) determined by single-particle cryo-electron microscopy. M. tuberculosis cytochrome bcc forms a dimeric assembly with endogenous menaquinone/menaquinol bound at the quinone/quinol binding pockets. Q203 and TB47 are bound to the quinol-binding site. Hydrogen bonds are formed between the inhibitor and the side chains of QcrBThr313 and QcrBGlu314, residues that are conserved across pathogenic mycobacteria. These high-resolution structures provide a basis for the design of new mycobacterial cytochrome bcc inhibitors that could be developed into broad spectrum drugs to treat mycobacterial infections.
Nitrates increase abscisic acid levels to regulate haustoria formation in the parasitic plant Phtheirospermum japonicum
Authors: Kokla Anna , Leso Martina , Zhang Xiang , Simura Jan , Cui Songkui , Ljung Karin , Yoshida Satoko , Melnyk Charles W.
Published: June 2021

Parasitic plants are globally prevalent pathogens that withdraw nutrients from their host plants using an organ known as the haustorium. Some, the obligate parasites are entirely dependent on their hosts for survival, whereas others, the facultative parasites, are independent of their hosts and infect depending on environmental conditions and the presence of the host. How parasitic plants regulate their haustoria in response to their environment is largely unknown. Using the facultative root parasite Phtheirospermum japonicum, we found that external nutrient levels modified haustorial numbers. This effect was independent of phosphate and potassium but nitrates were sufficient and necessary to block haustoria formation. Elevated nitrate levels prevented the activation of hundreds of genes associated with haustoria formation, downregulated genes associated with xylem development and increased levels of abscisic acid (ABA). Enhancing ABA levels independently of nitrates blocked haustoria formation whereas reducing ABA biosynthesis allowed haustoria to form in the presence of nitrates suggesting that nitrates mediated haustorial regulation in part via ABA production. Nitrates also inhibited haustoria formation and reduced infectivity of the obligate root parasite Striga hermonthica, suggesting a more widely conserved mechanism by which parasitic plants adapt their extent of parasitism according to nitrogen availability in the external environment.
Repression of Hypoxia-Inducible Factor-1 Contributes to Increased Mitochondrial Reactive Oxygen Species Production in Diabetes
Authors: Zheng Xiaowei , Narayanan Sampath , Xu Cheng , Angelstig Sofie Eliasson , Grünler Jacob , Zhao Allan , Toro Alessandro Di , Bernardi Luciano , Mazzone Massimiliano , Carmeliet Peter , Sole Marianna Del , Solaini Giancarlo , Forsberg Elisabete A , Zhang Ao , Brismar Kerstin , Schiffer Tomas A. , Ekberg Neda Rajamand , Botusan Ileana Ruxandra , Palm Fredrik , Catrina Sergiu-Bogdan
Published: June 2021

Background

Excessive production of mitochondrial reactive oxygen species (ROS) is a central mechanism for the development of diabetes complications. Recently, hypoxia has been identified to play an additional pathogenic role in diabetes. In this study, we hypothesized that ROS overproduction was secondary to the impaired responses to hypoxia due to the inhibition of hypoxia-inducible factor-1 (HIF-1) by hyperglycemia.

Methods

The dynamic of ROS levels was analysed in the blood of healthy subjects and individuals with type 1 diabetes after exposure to hypoxia (ClinicalTrials.gov registration no. NCT02629406). The relation between HIF-1, glucose levels, ROS production and its functional consequences were analyzed in renal mIMCD-3 cells and in kidneys of mouse models of diabetes.

Results

Exposure to hypoxia increased circulating ROS in subjects with diabetes, but not in subjects without diabetes. High glucose concentrations repressed HIF-1 both in hypoxic cells and in kidneys of animals with diabetes, through a HIF prolyl-hydroxylase (PHD) - dependent mechanism. The impaired HIF-1 signaling contributed to excess production of mitochondrial ROS through increased mitochondrial respiration that was mediated by Pyruvate dehydrogenase kinase 1 (PDK1) and was followed by functional consequences. The restoration of HIF-1 function attenuated ROS overproduction despite persistent hyperglycemia, and conferred protection against apoptosis and renal injury in diabetes.

Conclusions

We conclude that the repression of HIF-1 plays a central role in mitochondrial ROS overproduction in diabetes and is a potential therapeutic target for diabetic complications. These findings are highly significant and timely since the first PHD inhibitor that can activate HIF-1 has been newly approved for clinical use.
Conservation of endangered galaxiid fishes in the Falkland Islands requires urgent action on invasive brown trout
Authors: Minett J. F. , Fowler D.M. , Jones J.A.H. , Brickle P. , Crossin G.T. , Consuegra S. , de Leaniz C. Garcia
Published: June 2021

Non-native salmonids are protected in the Southern hemisphere where they sustain aquaculture and valuable sport fisheries, but also impact on native galaxiid fishes, which poses a conservation conundrum. Legal protection and human-assisted secondary releases may have helped salmonids to spread, but this has seldom been tested. We reconstructed the introduction of brown trout (Salmo trutta) to the Falkland Islands using historical records and modelled its dispersal. Our results indicate that establishment success was ∼88%, and that dispersal was facilitated by proximity to introduction sites and density of stream-road crossings, suggesting it was human assisted. Brown trout has already invaded 54% of Falkland rivers, which are 2.9-4.5 times less likely to contain native galaxiids than uninvaded streams. Without strong containment we predict brown trout will invade nearly all suitable freshwater habitats in the Falklands within the next ∼70 years, which might put native freshwater fishes at a high risk of extinction.
The locus of recognition memory signals in human cortex depends on the complexity of the memory representations
Authors: Sanders D. Merika W. , Cowell Rosemary A.
Published: June 2021

According to a “Swiss Army Knife” model of the brain, cognitive functions such as episodic memory and face perception map onto distinct neural substrates. In contrast, representational accounts propose that each brain region is best explained not by which specialized function it performs, but by the type of information it represents with its neural firing. In a functional MRI study, we asked whether the neural signals supporting recognition memory fall mandatorily within the medial temporal lobes (MTL), traditionally thought the seat of declarative memory, or whether these signals shift within cortex according to the content of the memory. Participants studied objects and scenes that were unique conjunctions of pre-defined visual features. Next, we tested recognition memory in a task that required mnemonic discrimination of both simple features and complex conjunctions. Feature memory signals were strongest in posterior visual regions, declining with anterior progression towards the MTL, while conjunction memory signals followed the opposite pattern. Moreover, feature memory signals correlated with feature memory discrimination performance most strongly in posterior visual regions, whereas conjunction memory signals correlated with conjunction memory discrimination most strongly in anterior sites. Thus, recognition memory signals shifted with changes in memory content, in line with representational accounts.
Disentangling top-down drivers of mortality underlying diel population dynamics ofProchlorococcusin the North Pacific Subtropical Gyre
Authors: Beckett Stephen J. , Demory David , Coenen Ashley R. , Casey John R. , Dugenne Mathilde , Follett Christopher L. , Connell Paige , Carlson Michael C.G. , Hu Sarah K. , Wilson Samuel T. , Muratore Daniel , Rodriguez-Gonzalez Rogelio A. , Peng Shengyun , Becker Kevin W. , Mende Daniel R. , Armbrust E. Virginia , Caron David A. , Lindell Debbie , White Angelicque E. , Ribalet François , Weitz Joshua S.
Published: June 2021

Photosynthesis fuels primary production at the base of marine food webs. Yet, in many surface ocean ecosystems, diel-driven primary production is tightly coupled to daily loss. This tight coupling raises the question: which top-down drivers predominate in maintaining persistently stable picocyanobacterial populations over longer time scales? Motivated by high-frequency surface water measurements taken in the North Pacific Subtropical Gyre (NPSG), we developed multitrophic models to investigate bottom-up and top-down mechanisms underlying the balanced control ofProchlorococcuspopulations. We find that incorporating photosynthetic growth with viral- and predator-induced mortality is sufficient to recapitulate daily oscillations ofProchlorococcusabundances with baseline community abundances. In doing so, we infer that grazers function as the primary top-down factor despite high standing viral particle densities while identifying the potential for light-dependent viral traits and non-canonical loss factors to shape the structure and function of marine microbial communities.
Rapid homeostatic modulation of transsynaptic nanocolumn rings
Authors: Muttathukunnel Paola , Frei Patrick , Perry Sarah , Dickman Dion , Müller Martin
Published: June 2021

Robust neural information transfer relies on a delicate molecular nano-architecture of chemical synapses. Neurotransmitter release is controlled by a specific arrangement of proteins within presynaptic active zones. How the specific presynaptic molecular architecture relates to postsynaptic organization, and how synaptic nano-architecture is transsynaptically regulated to achieve stable synaptic transmission remains enigmatic. Using time-gated stimulated emission depletion (gSTED) microscopy at the Drosophila neuromuscular junction, we here find that presynaptic nano-rings formed by the active-zone scaffold Bruchpilot (Brp) precisely align with postsynaptic glutamate receptor (GluR) rings. Individual rings harbor ~5 transsynaptically-aligned Brp-GluR ‘nanocolumns’. Intriguingly, acute GluR impairment rapidly triggers the formation of new transsynaptic nanocolumns on the minute time scale during homeostatic plasticity. We reveal distinct phases of structural transsynaptic homeostatic plasticity, with postsynaptic reorganization preceding presynaptic modulation. Finally, the auxiliary GluR subunit Neto-β promotes structural and functional homeostatic plasticity. Thus, transsynaptic nanocolumns arrange in stereotypic rings that are rapidly modulated during homeostatic plasticity to stabilize synaptic efficacy.

One Sentence Summary

Rapid changes of transsynaptic nanocolumn rings during homeostatic plasticity.
Zinc2+ ion inhibits SARS-CoV-2 main protease and viral replication in vitro
Authors: Panchariya Love , Khan Wajahat Ali , Kuila Shobhan , Sonkar Kirtishila , Sahoo Sibasis , Ghoshal Archita , Kumar Ankit , Verma Dileep Kumar , Hasan Abdul , Das Shubhashis , Thakur Jitendra K , Halder Rajkumar , Sunil Sujatha , Arockiasamy Arulandu
Published: June 2021

Zinc deficiency is linked to poor prognosis in COVID-19 patients while clinical trials with Zinc demonstrate better clinical outcome. The molecular target and mechanistic details of anti-coronaviral activity of Zinc remain obscure. We show that ionic Zinc not only inhibits SARS-CoV-2 main protease (Mpro) with nanomolar affinity, but also viral replication. We present the first crystal structure of Mpro-Zn2+ complex at 1.9 Å and provide the structural basis of viral replication inhibition. We show that Zn2+ coordinates with the catalytic dyad at the enzyme active site along with two previously unknown water molecules in a tetrahedral geometry to form a stable inhibited Mpro-Zn2+ complex. Further, natural ionophore quercetin increases the anti-viral potency of Zn2+. As the catalytic dyad is highly conserved across SARS-CoV, MERS-CoV and all variants of SARS-CoV-2, Zn2+ mediated inhibition of Mpro may have wider implications.
Emergent properties of coupled bistable switches
Authors: Hari Kishore , Harlapur Pradyumna , Gopalan Aditi , Ullanat Varun , Duddu Atchuta Srinivas , Jolly Mohit Kumar
Published: June 2021

Understanding the dynamical hallmarks of network motifs is one of the fundamental aspects of systems biology. Positive feedback loops constituting one or two nodes – self-activation, toggle switch, and double activation loops – are commonly observed motifs in regulatory networks underlying cell-fate decision systems. Their individual dynamics are well-studied; they are capable of exhibiting bistability. However, studies across various biological systems suggest that such positive feedback loops are interconnected with one another, and design principles of coupled bistable motifs remain unclear. We wanted to ask what happens to bistability or multistability traits and the phenotypic space (collection of phenotypes exhibited by a system) due to the couplings. In this study, we explore a set of such interactions using discrete and continuous simulation methods. Our results suggest that couplings that do not connect the bistable switches in a way that contradicts the connections within individual bistable switches lead to a steady state space that is strictly a subset of the set of possible combinations of steady states of bistable switches. Furthermore, adding direct and indirect self-activations to these coupled networks can increase the frequency of multistability. Thus, our observations reveal specific dynamical traits exhibited by various coupled bistable motifs.
Nucleus accumbens D1-receptors regulate and focus transitions to reward-seeking action
Authors: Grima LL , Panayi MC , Haermson O , Syed E , Manohar SG , Husain M , Walton ME
Published: June 2021

While it is well established that dopamine transmission is integral in mediating the influence of reward expectations on reward-seeking actions, the precise causal role of dopamine transmission in moment-to-moment cue-driven behavioural control remains contentious. This is a particular issue in situations where it is necessary to refrain from responding to achieve a beneficial outcome. To examine this, we manipulated dopamine transmission pharmacologically as rats performed a Go/No-Go task that required them to either make or withhold action to gain either a small or large reward. Stimulation of D1Rs, both globally and locally in the nucleus accumbens core (NAcC) region consistently disrupted No-Go performance, potentiating inappropriate responses that clustered strongly just after cue presentation. D1R blockade did not, however, improve rats’ ability to withhold responses, but instead primarily disrupted performance on Go trials. While global D1R blockade caused a general reduction of invigoration of reward seeking actions, intra-NAcC administration of the D1R antagonist by contrast increased the likelihood that Go trial performance was in an “unfocused” state. Such a state was characterised, both on and off drug, by a reduction in the precision and speed of responding even though the appropriate action sequence was often executed. These findings suggests that the balance of activity at NAcC D1Rs plays a key role in enabling the rapid activation of a focused, reward-seeking state to enable animals to efficiently and accurately achieve their goal.
Musculoskeletal modelling of sprawling and parasagittal forelimbs provides insight into synapsid postural transition
Authors: Brocklehurst Robert J. , Fahn-Lai Philip , Regnault Sophie , Pierce Stephanie E.
Published: June 2021

The sprawling–parasagittal postural shift was a major transition during synapsid evolution and is considered key to mammalian ecological diversity. Despite a good fossil record, debate remains over when the shift to parasagittal posture occurred, primarily due to limited comparative biomechanical data on extant species. Here, we built forelimb musculoskeletal models of three extant taxa that bracket the sprawling–parasagittal transition: a tegu lizard, an echidna, and an opossum. We measured shoulder joint range of motion (ROM) about all three degrees of rotational freedom and characterized shoulder muscle moment arms (MMAs) across the entire pose space. Our results show that both the opossum and the tegu had high shoulder joint ROM, and both were substantially higher than the echidna. However, the opossum occupied a distinct region of pose space characterized by high humeral retraction angles. There are clear interspecific differences in MMAs related to posture, with the sprawling tegu and echidna emphasizing humeral depression, and the parasagittal opossum emphasizing humeral elevation. There are also notable differences between our sprawling taxa, with the echidna possessing much greater moment arms for humeral pronation than the tegu. We demonstrate clear functional variation between locomotor grades and use these data to hypothesize major shifts in forelimb function and posture along the mammalian stem.
Evolutionary History Impacts Phyllosphere Community Assembly on Forage Grasses
Authors: Bechtold Emily K. , Nüsslein Klaus
Published: June 2021

Benefits leaf bacterial communities provide to plant hosts are reduced by external stress. Understanding how plant hosts impact phyllosphere community assembly, how microbes influence plant traits, and how this interaction changes under stress will advance our insight into the evolutionary relationship between plants and their microbial communities. We investigated phyllosphere community assembly change over time, between host species, and under drought stress on three native temperate grasses and three non-native tropical grasses. By growing them together, effects of host geography and differences in environmental variables were eliminated allowing us to test evolutionary history on community assembly. We found evidence of phylosymbiosis which increased significantly under drought stress, indicating phyllosphere communities and their response to stress relate to grass species phylogeny. We also show native temperate grasses displayed stronger cophylogenetic relationships between grass hosts and their microbial communities and had increased selection by host species over time compared to non-native tropical hosts. Interestingly, the functional marker genenifH, though differentially present on all host species was not susceptible to drought. The evidence of shared evolutionary history, presence of functionally important bacteria, and responses to drought suggest that microbial communities are important plant traits that coevolve alongside their plant hosts.
Fire and forest loss in the Dominican Republic during the 21st Century
Authors: Martínez-Batlle José-Ramón
Published: June 2021

Forest loss is an environmental issue that threatens ecosystems in the Dominican Republic (the DR). Although shifting agriculture by slash-and-burn methods is thought to be the main driver of forest loss in the DR, empirical evidence of this relationship is still lacking. Since remotely sensed data on fire occurrence is a suitable proxy for estimating the spread of shifting agriculture, here I explore the association between forest loss and fire during the first 18 years of the 21st Century using zonal statistics and spatial autoregressive models on different spatio-temporal layouts. First, I found that both forest loss and fire were spatially autocorrelated and statistically associated with each other at a country scale over the study period, particularly in the western and central part of the DR. However, no statistical association between forest loss and fire was found in the eastern portion, a region that hosts a large international tourism hub. Second, deforestation and fire showed a joint cyclical variation pattern of approximately four years up to 2013, and from 2014 onwards deforestation alone followed a worrying upward trend, while at the same time fire activity declined significantly. Third, I found no significant differences in forest loss patterns between the deforested area of small (<1 ha) and large (>1 ha) clearings of forest. I propose these findings hold potential to inform land management policies that help reduce forest loss, particularly in protected areas, mountain areas, and the vicinity of tourism hubs.