bluuebunny/crossref_metadata_2025 huggingface dataset:
Ivermectin as a potential treatment for mild to moderate COVID-19 – A double blind randomized placebo-controlled trial
Authors: Ravikirti  , Roy Ranjini , Pattadar Chandrima , Raj Rishav , Agarwal Neeraj , Biswas Bijit , Majhi Pramod Kumar , Rai Deependra Kumar , Shyama  , Kumar Anjani , Sarfaraz Asim
Published: January 2021

Objective

Ivermectin has been suggested as a treatment for COVID-19.This randomised control trial was conducted to test the efficacy of Ivermectin in the treatment of mild and moderate COVID-19.

Design

Parallel, double blind, randomised, placebo controlled trial Setting: A tertiary care dedicated COVID-19 hospital in Bihar, India

Participants

Adult patients (> 18 years) admitted with mild to moderate COVID 19 disease (saturation > 90% on room air, respiratory rate < 30 and no features of shock) with no contraindications to ivermectin and willing to participate in the study

Intervention

Patients in the intervention arm were given ivermectin 12 mg on day 1 and day 2 of admission. Patients in the placebo arm were given identical looking placebo tablets. Rest of the treatment was continued as per the existing protocol and the clinical judgment of the treating teams.

Outcome Measures

The primary outcome measure was a negative RT-PCR test for SARS-CoV-2 on day 6 of admission. The secondary outcome measures were symptom status on day 6, discharge status on day 10, admission to ICU, need for invasive mechanical ventilation and in-hospital mortality.

Results

A total of 115 patients were enrolled for the study of which 112 were included in the final analysis. Of them, 55 were randomised to the intervention arm while 57 were randomised to the placebo arm. There was no significant difference in the baseline characteristics of the two arms. There was no significant difference in the primary outcome, i.e. negative RT-PCR status on day 6 between the two groups. Similarly, there was no significant difference between the two groups in most of the secondary outcome measures, viz. symptom status on day 6, discharge status on day 10, admission to ICU, and need for invasive mechanical ventilation. However, while there was no in-hospital mortality in the intervention arm, there were 4 deaths in the placebo arm. As a result, all patients in the intervention arm (n=56) were successfully discharged as compared to 93.1% (n=54/58) in the placebo arm (RR 1.1, 95% CI 1.0 to 1.2, p=0.019).

Conclusion

There was no difference in the primary outcome i.e. negative RT-PCR status on day 6 of admission with the use of ivermectin. However, a significantly higher proportion of patients were discharged alive from the hospital when they received ivermectin.

Strengths and Limitations of the Study

This study was randomised and double blind, thereby minimizing the chance of bias.

All outcome measures except symptom status on day 6 were objective and placebo control was used for comparison.

Only single repeat RT-PCR was done. So median time to viral clearance in the two groups could not be calculated.

Severe cases were not included in the study.
Microglia deficiency accelerates prion disease but does not enhance prion accumulation in the brain
Authors: Bradford Barry M. , McGuire Lynne I. , Hume David A. , Pridans Clare , Mabbott Neil A.
Published: January 2021

Prion diseases are transmissible, neurodegenerative disorders associated with misfolding of the prion protein. Previous studies show that reduction of microglia accelerates CNS prion disease and increases the accumulation of prions in the brain, suggesting that microglia provide neuroprotection by phagocytosing and destroying prions. InCsf1rΔFIREmice, the deletion of an enhancer withinCsf1rspecifically blocks microglia development, however, their brains develop normally and show none of the deficits reported in other microglia-deficient models.Csf1rΔFIREmice were used as a refined model in which to study the impact of microglia-deficiency on CNS prion disease. AlthoughCsf1rΔFIREmice succumbed to CNS prion disease much earlier than wild-type mice, the accumulation of prions in their brains was reduced. Instead, astrocytes displayed earlier, non-polarized reactive activation with enhanced synaptic pruning and unfolded protein responses. Our data suggest that rather than simply phagocytosing and destroying prions, the microglia instead provide host-protection during CNS prion disease and restrict the harmful activities of reactive astrocytes.

Main points

CNS prion disease is accelerated in mice completely lacking microglia. The rate of prion accumulation in the brain was unaltered in absence of microglia. Microglia provide host-protection during CNS prion disease independent of prion clearance.
Chromosome fusion affects genetic diversity and evolutionary turnover of functional loci, but consistently depends on chromosome size
Authors: Cicconardi Francesco , Lewis James J , Martin Simon H , Reed Robert D. , Danko Charles G , Montgomery Stephen H
Published: January 2021

Major changes in chromosome number and structure are linked to a series of evolutionary phenomena, including intrinsic barriers to gene flow or suppression of recombination due to chromosomal rearrangements. However, chromosome rearrangements can also affect the fundamental dynamics of molecular evolution within populations by changing relationships between linked loci and altering rates of recombination. Here, we build chromosome-level assemblyEueides isabellaand, together with the chromosome-level assembly ofDryas iulia, examine the evolutionary consequences of multiple chromosome fusions inHeliconiusbutterflies. These assemblies pinpoint fusion points on 10 of the 21 autosomal chromosomes and reveal striking differences in the characteristics of fused and unfused chromosomes. The ten smallest autosomes inD. iuliaandE. isabella, which have each fused to a longer chromosome inHeliconius, have higher repeat and GC content, and longer introns than predicted by their chromosome length. Following fusion, these characteristics change to become more in line with chromosome length. The fusions also led to reduced diversity, which likely reflects increased background selection and selection against introgression between diverging populations, following a reduction in per-base recombination rate. We further show that chromosome size and fusion impact turnover rates of functional loci at a macroevolutionary scale. Together these results provide further evidence that chromosome fusion inHeliconiuslikely had dramatic effects on population level processes shaping rates of neutral and adaptive divergence. These effects may have impacted patterns of diversification inHeliconius, a classic example of an adaptive radiation.
Periodicity in the embryo: emergence of order in space, diffusion of order in time
Authors: Alicea Bradly , Parent Jesse , Singh Ujjwal
Published: January 2021

Does embryonic development exhibit characteristic temporal features? This is apparent in evolution, where evolutionary change has been shown to occur in bursts of activity. Using two animal models (Nematode,Caenorhabditis elegansand Zebrafish,Danio rerio) and simulated data, we demonstrate that temporal heterogeneity exists in embryogenesis at the cellular level, and may have functional consequences. Cell proliferation and division from cell tracking data is subject to analysis to characterize specific features in each model species. Simulated data is then used to understand what role this variation might play in producing phenotypic variation in the adult phenotype. This goes beyond a molecular characterization of developmental regulation to provide a quantitative result at the phenotypic scale of complexity.
Myeloperoxidase-induced fibrinogen unfolding and clotting
Authors: Barinov Nikolay A. , Pavlova Elizaveta R. , Tolstova Anna P. , Dubrovin Evgeniy V. , Klinov Dmitry V.
Published: January 2021

Fibrinogen is a major protein of blood coagulation system and is a promising component of biomaterials and protein matrixes. Conformational changes of fibrinogen underlie the important mechanism of thrombin mediated fibrinogen clotting but also may induce the loss of its biological activity and (amyloid) aggregation. Understanding and controlling of fibrinogen unfolding is important for the development of fibrinogen based materials with tunable properties. We have discovered that myeloperoxidase induces denaturation of fibrinogen molecules followed by fibrinogen clotting, which is not thrombin-dependent. This is the first example of ATP-independent, non-targeted protein-induced protein denaturation. The morphological structure of unfolded fibrinogen molecules and “non-conventional” fibrinogen clots has been characterized using high-resolution atomic force microscopy and scanning electron microscopy techniques. Circular dichroism (CD) spectroscopy has shown no significant changes of the secondary structure of the fibrinogen clots. The absorbance spectrophotometry has demonstrated that the kinetics of myeloperoxidase induced fibrinogen clotting strongly decays with growth of ionic strength indicating a major role of the Debye screening effect in regulating of this process. The obtained results provide with the novel concepts of protein unfolding and open new insights into fibrinogen clotting. Moreover, they give new possibilities in biotechnological and biomedical applications, e.g., for regulation of fibrinogen clotting and platelet adhesion and for the development of fibrinogen-based matrices.

The organization of a protein molecule is characterized by different hierarchical levels such as primary, secondary, tertiary and quaternary structure. Protein unfolding or denaturation, i.e. its transformation to a lower order structure (and loss of a higher order structure), is a biologically and biotechnologically relevant process. Protein unfolding is a prerequisite for an alternative folding pathway including amyloid aggregation1,2. Unfolded proteins may be used in development of protein films and coatings with special properties such as enhanced mechanical stability3–5, resistance to protein adsorption or platelet adhesion6,7and other advantages8. Unfolding of a protein molecule may lead to the loss of its biological function9that has important consequences in biosensor10,11and pharmaceutical applications12.
Dysregulation of the basal ganglia indirect pathway prior to cell loss in the Q175 mouse model of Huntington’s disease
Authors: Callahan Joshua W. , Wokosin David L. , Bevan Mark D.
Published: January 2021

The psychomotor symptoms of Huntington’s disease (HD) are linked to degeneration of the basal ganglia indirect pathway. To determine how this pathway is perturbed prior to cell loss, optogenetic- and reporter-guided electrophysiological interrogation approaches were applied to early symptomatic 6-month-old Q175 HD mice. Although cortical activity was unaffected, indirect pathway striatal projection neurons were hypoactivein vivo, consistent with reduced cortical input strength and dendritic excitability. Downstream parvalbumin-expressing prototypic external globus pallidus (GPe) neurons were hyperactivein vivoand exhibited elevated autonomous firingex vivo. Optogenetic inhibition of prototypic GPe neurons ameliorated the abnormal hypoactivity of postsynaptic subthalamic nucleus (STN) and putative arkypallidal neuronsin vivo. In contrast to STN neurons, autonomous arkypallidal activity was unimpairedex vivo. Together with previous studies, these findings demonstrate that basal ganglia indirect pathway neurons are highly dysregulated in Q175 mice through changes in presynaptic activity and/or intrinsic properties 6-12 months before cell loss.
Comparison between slow, anisotropic LE4PD fluctuations and the Principal Component Analysis modes of Ubiquitin
Authors: Beyerle E. R. , Guenza M. G.
Published: January 2021

Proteins’ biological function and folding mechanisms are often guided by large-scale, slow motions, which involve crossing high energy barriers. In a simulation trajectory, these slow fluctuations are commonly identified using a principal component analysis (PCA). Despite the popularity of this method, a complete analysis of its predictions based on the physics of protein motion has been so far limited. This study formally connects the PCA to a Langevin model of protein dynamics and analyzes the contributions of energy barriers and hydrodynamic interactions to the slow PCA modes of motion. To do so, we introduce an anisotropic extension of the Langevin Equation for Protein Dynamics, called the LE4PD-XYZ, which formally connects to the PCA ‘essential dynamics’. The LE4PD-XYZ is an accurate coarse-grained diffusive method to model protein motion, which describes anisotropic fluctuations in the protein’s alpha-carbons. The LE4PD accounts for hydrodynamic effects and mode-dependent free-energy barriers. This study compares large-scale anisotropic fluctuations identified by the LE4PD-XYZ to the mode-dependent PCA’s predictions, starting from a microsecond-long alpha-carbon molecular dynamics atomistic trajectory of the protein ubiquitin. We observe that the inclusion of free-energy barriers and hydrodynamic interactions has important effects on the identification and timescales of ubiquitin’s slow modes.
Disrupted PDZ-domain binding motif of the dopamine transporter uniquely alters nanoscale distribution, dopamine homeostasis and reward motivation
Authors: Sørensen Gunnar , Rickhag Mattias , Leo Damiana , Lycas Matthew D. , Ridderstrøm Pernille Herrstedt , Weikop Pia , Herborg Freja , Woldbye David , Wörtwein Gitta , Gainetdinov Raul R. , Fink-Jensen Anders , Gether Ulrik
Published: January 2021

The dopamine transporter (DAT) is part of a presynaptic multi-protein network involving interactions with scaffold proteins via its C-terminal PDZ-domain binding sequence. In a mouse model expressing DAT with mutated PDZ binding sequence (DAT-AAA), we previously demonstrated the importance of this binding sequence for striatal expression of DAT. Here we show by application of direct Stochastic Reconstruction Microscopy (dSTORM) not only that the striatal level of transporter is reduced in DAT-AAA mice, but also that the nanoscale distribution of the transporter is altered with a higher propensity of DAT-AAA to localize to irregular nanodomains in dopaminergic terminals. In parallel, we observe mesostriatal dopamine (DA) adaptations and changes in DA-related behaviors different from those seen in other genetic DAT mouse models. DA levels in striatum are reduced to ∼45% of wild type (WT), accompanied by elevated DA turnover. Nonetheless, Fast-Scan Cyclic Voltammetry recordings on striatal slices reveal a larger amplitude and prolonged clearance rate of evoked DA release in DAT-AAA mice compared to WT mice. Autoradiography and radioligand binding show reduced DA D2 receptor levels while immunohistochemistry and autoradiography show unchanged DA D1 receptor levels. In behavioral experiments, we observe enhanced self-administration of liquid food under both a fixed-ratio (FR1) and progressive-ratio (PR) schedule of reinforcement, but a reduction compared to WT when using cocaine as reinforcer. Summarized, our data demonstrate how disruption of PDZ-domain interactions causes changes in DAT expression and its nanoscopic distribution that in turn alter DA clearance dynamics.
Contraction-expansion dynamics of reef species in response to sea-level changes
Authors: Hoareau TB , Pretorius PC
Published: January 2021

The contraction-expansion model (CEM) describes the dynamics of species that survived in refugia during the last glacial maximum (LGM) and expanded their range when environmental conditions slowly improved from the Late Glacial through to the Holocene. The CEM has been proposed to describe the dynamics of reef species in response to sea-level fluctuations from a range of disciplines, but genetic inferences rather suggest stable population sizes since the last glacial period. Here, we address this paradox by providing a new model of modern reef development, by assessing the effect of LGM bottlenecks using genetic simulations, and by using a survey of the literature on reef species to compile both estimates of times to expansion and applied rates of molecular evolution. Using previously published radiocarbon dates of core data, we propose a synthetic model for the dynamics of modern coral reefs in the Indo-Pacific region. This model describes both an initiation at 9.9 ka and subsequent development that confirms a strong influence of sea-level fluctuations on reef dynamics. Simulations based on mtDNA datasets showed that pre-LGM genetic signatures of expansion are lost. Recent literature shows that, although genetic expansions of tropical marine species are frequent (>95%), the onset of these expansions is old (median ~110 ka), which indicates that most populations have remained stable since before the LGM. These pre-LGM expansions are explained by the low mutation rates (1.66% changes/site/Myr) known to be inadequate to calibrate time at population level. Specific calibrations should help solve the paradox and generalise the CEM for reef species.
Nuclear Morphometry is a superior Prognostic Predictor in comparison to Histological grading in Renal cell Carcinoma: A Retrospective Clinico-pathological study
Authors: Agrawal Shruti , Jain Nikunj
Published: January 2021

Background

Renal cell carcinoma (RCC) comprises of a spectrum of clinico-pathologically distinct entities thereby making it difficult to accurately predict the clinical outcome. Though many predictive factors have been described in literature, tumor stage and nuclear grade have been established to consistently correlate with the tumor behaviour. However, tumors in the same stage have shown to behave differently. Similarly subjectivity and lack of reproducibility in nuclear grade mandates use of more objective parameters such as digital nuclear morphometry which could provide consistent and more reliable results in predicting prognosis. The study was conducted with the main objective of comparing the histological grade and the nuclear morphometric variables in RCC for predicting the clinical outcome.

Material and methods

A total of 219 cases of renal tumors in adults were retrieved retrospectively from the archives of pathology department in Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow and their clinical, gross and microscopic features were noted. Nuclear grading was done in 181 cases of clear cell and papillary RCC of which computer-assisted morphometry for various nuclear parameters was done in 100 cases where a follow-up data of at least 3 years was available. Nuclear grade and morphometric parameters were correlated statistically with the clinical outcome of the patients.

Results

Histological nuclear grade did not show statistically significant correlation with progression free survival (PFS). Higher values of mean nuclear area, mean nuclear circumference, mean nuclear major diameter and mean nuclear minor diameter were significant predictors of PFS with a strong inverse correlation.

Conclusion

Nuclear morphometry is a more reliable predictor of clinical outcome in patients of RCC when compared to histological grade and should be included in predictive model with other clinical and pathological parameters to accurately determine tumor behaviour.
Quantifying non-communicable diseases’ burden in Egypt using State-Space model
Authors: El-Saadani Somaya , Saleh Mohamed , Ibrahim Sarah A.
Published: January 2021

The study aimed to model and quantify the health burden induced by four non-communicable diseases in Egypt, the first to be conducted in the context of a less developing county. The study used the State-Space model and adopted two Bayesian methods: Particle Filter and Particle Independent Metropolis-Hastings to model and estimate the NCDs’ health burden trajectories. We drew on time-series data of the International Health Metric Evaluation, CAPMAS’s Annual Bulletin of Health Services Statistics, the World Bank, and WHO data. Both Bayesian methods showed that the burden trajectories are on the rise. Most of the findings agreed with our assumptions and are in line with the literature. Previous year burden strongly predicts the burden of the current year. High prevalence of the risk factors, disease prevalence, and the disease’s severity level all increase illness burden. Years of life lost due to death has high loadings in most of the diseases. Contrary to the study assumption, results found a negative relationship between disease burden and health services utilization which can be attributed to the lack of full health insurance coverage and the pattern of health care seeking behavior in Egypt. Our study highlights that Particle Independent Metropolis-Hastings is sufficient in estimating the parameters of the study model, in the case of time-constant parameters. The study recommends using state Space models with Bayesian estimation approaches with time-series data in public health and epidemiology research.
Increased Risk of Autopsy-Proven Pneumonia with Sex, Season and Neurodegenerative Disease
Authors: Beach Thomas G. , Russell Aryck , Sue Lucia I. , Intorcia Anthony J. , Glass Michael J. , Walker Jessica E. , Arce Richard , Nelson Courtney M. , Hidalgo Tony , Chiarolanza Glenn , Mariner Monica , Scroggins Alex , Pullen Joel , Souders Leslie , Sivananthan Kimberly , Carter Niana , Saxon-LaBelle Megan , Hoffman Brittany , Garcia Angelica , Callan Michael , Fornwalt Brandon E. , Carew Jeremiah , Filon Jessica , Cutler Brett , Papa Jaclyn , Curry Jasmine R. , Oliver Javon , Shprecher David , Atri Alireza , Belden Christine , Shill Holly A. , Driver-Dunckley Erika , Mehta Shyamal H. , Adler Charles H. , Haarer Chadwick F. , Ruhlen Thomas , Torres Maria , Nguyen Steve , Schmitt Dasan , Fietz Mary , Lue Lih-Fen , Walker Douglas G. , Mizgerd Joseph P. , Serrano Geidy E.
Published: January 2021

There has been a markedly renewed interest in factors associated with pneumonia, a leading cause of death worldwide, due to its frequent concurrence with pandemics of influenza and Covid-19 disease. Reported predisposing factors to both bacterial pneumonia and pandemic viral lower respiratory infections are wintertime occurrence, older age, obesity, pre-existing cardiopulmonary conditions and diabetes. Also implicated are age-related neurodegenerative diseases that cause parkinsonism and dementia. We investigated the prevalence of autopsy-proven pneumonia in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), a longitudinal clinicopathological study, between the years 2006 and 2019 and before the beginning of the Covid-19 pandemic. Of 691 subjects dying at advanced ages (mean 83.4), pneumonia was diagnosed postmortem in 343 (49.6%). There were 185 subjects without dementia or parkinsonism while clinicopathological diagnoses for the other subjects included 319 with Alzheimer’s disease dementia, 127 with idiopathic Parkinson’s disease, 72 with dementia with Lewy bodies, 49 with progressive supranuclear palsy and 78 with vascular dementia. Subjects with one or more of these neurodegenerative diseases all had higher pneumonia rates, ranging between 50 and 61%, as compared to those without dementia or parkinsonism (40%). In multivariable logistic regression models, male sex and a non-summer death both had independent contributions (ORs of 1.67 and 1.53) towards the presence of pneumonia at autopsy while the absence of parkinsonism or dementia was a significant negative predictor of pneumonia (OR 0.54). Male sex, dementia and parkinsonism may also be risk factors for Covid-19 pneumonia. The apolipoprotein E4 allele, as well as obesity, chronic obstructive pulmonary disease, diabetes, hypertension, congestive heart failure, cardiomegaly and cigarette smoking history, were not significantly associated with pneumonia, in contradistinction to what has been reported for Covid-19 disease.
Competing Health Risks Associated with the COVID-19 Pandemic and Early Response: A Scoping Review
Authors: Baral Stefan , Rao Amrita , Twahirwa Rwema Jean Olivier , Lyons Carrie , Cevik Muge , Kågesten Anna E. , Diouf Daouda , Sohn Annette H. , Phaswana-Mafuya Nancy , Kamarulzaman Adeeba , Millett Gregorio , Marcus Julia L. , Mishra Sharmistha
Published: January 2021

Background

COVID-19 has rapidly emerged as a global public health threat with infections recorded in nearly every country. Responses to COVID-19 have varied in intensity and breadth, but generally have included domestic and international travel limitations, closure of non-essential businesses, and repurposing of health services. While these interventions have focused on testing, treatment, and mitigation of COVID-19, there have been reports of interruptions to diagnostic, prevention, and treatment services for other public health threats.

Objectives

We conducted a scoping review to characterize the early impact of COVID-19 on HIV, tuberculosis, malaria, sexual and reproductive health, and malnutrition.

Methods

A scoping literature review was completed using searches of PubMed and preprint servers (medRxiv/bioRxiv) from January 1st to October 31st, 2020, using Medical Subject Headings (MeSH) terms related to SARS-CoV-2 or COVID-19 and HIV, tuberculosis, malaria, sexual and reproductive health, and malnutrition. Empiric studies reporting original data collection or mathematical models were included, and available data synthesized by region. Studies were excluded if they were not written in English.

Results

A total of 1604 published papers and 205 preprints met inclusion criteria, including 8.2% (132/1604) of published studies and 10.2% (21/205) of preprints: 7.3% (68/931) on HIV, 7.1% (24/339) on tuberculosis, 11.6% (26/224) on malaria, 7.8% (13/166) on sexual and reproductive health, and 9.8% (13/132) on malnutrition. Thematic results were similar across competing health risks, with substantial indirect effects of the COVID-19 pandemic and response on diagnostic, prevention, and treatment services for HIV, tuberculosis, malaria, sexual and reproductive health, and malnutrition.

Discussion

COVID-19 emerged in the context of existing public health threats that result in millions of deaths every year. Thus, effectively responding to COVID-19 while minimizing the negative impacts of COVID-19 necessitates innovation and integration of existing programs that are often siloed across health systems. Inequities have been a consistent driver of existing health threats; COVID-19 has worsened disparities, reinforcing the need for programs that address structural risks. The data reviewed here suggest that effective strengthening of health systems should include investment and planning focused on ensuring the continuity of care for both rapidly emergent and existing public health threats.
Corynebacterium glutamicumregulation beyond transcription: Organizing principles and reconstruction of an extended regulatory network incorporating regulations mediated by small RNA and protein-protein interactions
Authors: Escorcia-Rodríguez Juan M. , Tauch Andreas , Freyre-González Julio A.
Published: January 2021

Corynebacterium glutamicumis a Gram-positive bacterium found in soil where the condition changes demand plasticity of the regulatory machinery. The study of such machinery at the global scale has been challenged by the lack of data integration. Here, we report three regulatory network models forC. glutamicum:strong(3040 interactions) constructed solely with regulations previously supported by directed experiments;all evidence(4665 interactions) containing thestrongnetwork, regulations previously supported by non-directed experiments, and protein-protein interactions with a direct effect on gene transcription; andsRNA(5222 interactions) containing theall evidencenetwork and sRNA-mediated regulations. Compared to the previous version (2018), thestrongandall evidencenetworks increased by 75 and 1225 interactions, respectively. We analyzed the system-level components of the three networks to identify how they differ and compared their structures against those for the networks of more than 40 species. The inclusion of the sRNAs regulations changed the proportions of the system-level components and increased the number of modules but decreased their size. TheC. glutamicumregulatory structure contrasted with other bacterial regulatory networks. Finally, we used thestrongnetworks of three model organisms to provide insights and future directions of theC. glutamicumregulatory network characterization.
Commercial vaccines do not confer protection against two genetic strains ofPiscirickettsia salmonis, LF-89-like and EM-90-like, in Atlantic salmon
Authors: Figueroa Carolina , Torrealba Débora , Morales-Lange Byron , Mercado Luis , Dixon Brian , Conejeros Pablo , Silva Gabriela , Soto Carlos , Gallardo José A.
Published: January 2021

In Atlantic salmon, vaccines have failed to control and prevent Piscirickettsiosis, for reasons that remain elusive. In this study, we report the efficacy of a commercial vaccine developed with thePiscirickettsia salmonisisolate AL100005 against other two isolates which are considered highly and ubiquitously prevalent in Chile: LF-89-like and EM-90-like. Two cohabitation trials were performed to mimic real-life conditions and vaccine performance: 1) post smolt fish were challenged with a single infection of LF-89-like, 2) adults were coinfected with EM-90-like and a low coinfection of sea lice. In the first trial, the vaccine delayed smolt mortalities by two days; however, unvaccinated and vaccinated fish did not show significant differences in survival (unvaccinated: 60.3%, vaccinated: 56.7%; p = 0.28). In the second trial, mortality started three days later for vaccinated fish than unvaccinated fish. However, unvaccinated and vaccinated fish did not show significant differences in survival (unvaccinated: 64.6%, vaccinated: 60.2%, p= 0.58). Thus, we found no evidence that the evaluated vaccines confer effective protection against of LF-89-like or EM-90-like with estimated relative survival proportions (RPSs) of −9% and −12%, respectively. More studies are necessary to evaluate whether pathogen heterogeneity is a key determinant of the vaccine efficacy againstP. salmonis.
ConVarT: a search engine for matching human genetic variants with variants from non-human species
Authors: Pir Mustafa S. , Bilgin Halil I. , Sayici Ahmet , Coşkun Fatih , Torun Furkan M. , Zhao Pei , Kang Yahong , Cevik Sebiha , Kaplan Oktay I.
Published: January 2021

The availability of genetic variants, together with phenotypic annotations from model organisms, facilitates comparing these variants with equivalent variants in humans. However, existing databases and search tools do not make it easy to scan for equivalent variants, namely “matching variants” (MatchVars) between humans and other organisms. Therefore, we developed an integrated search engine called ConVarT (http://www.convart.org/) for matching variants between humans, mice, andC. elegans. ConVarT incorporates annotations (including phenotypic and pathogenic) into variants, and these previously unexploited phenotypic MatchVars from mice andC. eleganscan give clues about the functional consequence of human genetic variants. Our analysis shows that many phenotypic variants in different genes from mice andC. elegans, so far, have no counterparts in humans, and thus, can be useful resources when evaluating a relationship between a new human mutation and a disease.
An edge-centric model for harmonizing multi-relational network datasets
Authors: Faskowitz Joshua , Tanner Jacob C. , Mišić Bratislav , Betzel Richard F.
Published: January 2021

Functional and structural connections vary across conditions, measurements, and time. However, how to resolve multi-relational measures of connectivity remains an open challenge. Here, we propose an extension of structural covariance and morphometric similarity methods to integrate multiple estimates of connectivity into a single edge-centric network representation. We highlight the utility of this method through two applications: an analysis of multi-task functional connectivity data and multi-measure structural networks. In these analyses, we use data-driven clustering techniques to identify collections of edges that covary across tasks and measures, revealing overlapping mesoscale architecture. We also link these features to node-level properties such as modularity and canonical descriptors of brain systems. We further demonstrate that, in the case of multi-task functional networks, edge-level features are consistent across individuals yet exhibit subject-specificity. We conclude by highlighting other instances where the edge-centric model may be useful.
Neural correlates of orbital telorism
Authors: Pawlak Mikolaj A. , Knol Maria J. , Vernooij Meike W. , Ikram M. Arfan , Adams Hieab H.H. , Evans T. E.
Published: January 2021

Orbital telorism, the interocular distance, is a clinically informative and in extremes is considered a minor physical anomaly. While its extremes, hypo- and hypertelorism, have been linked to disorders often related to cognitive ability, little is known about the neural correlates of normal variation of telorism within the general population. We derived measures of orbital telorism from cranial magnetic resonance imaging (MRI) by calculating the distance between the eyeball center of gravity in two population-based datasets (N=5,653, N=29,824, Mean age 64.66, 63.75 years). This measure was found to be related grey matter tissue density within numerous regions of the brain, including, but surprisingly not limited to, the frontal regions, in both positive and negative directions. Additionally, telorism was related to several cognitive functions, such as Perdue Pegboard test (Beta, P-value, (CI95%) −0.02, 1.63×10-7(−0.03;-0.01)) and fluid intelligence (0.02, 4.75×10-06(0.01:0.02)), with some relationships driven by individuals with a smaller orbital telorism. This is reflective of the higher prevalence of hypo-telorism in developmental disorders, specifically those that accompany lower cognitive lower functioning. This study suggests, despite previous links only made in clinical extremes, that orbital telorism holds some relation to structural brain development and cognitive function in the general population. This relationship is likely driven by shared developmental periods.
The renal inflammatory network of nephronophthisis
Authors: Quatredeniers Marceau , Bienaimé Frank , Ferri Giulia , Isnard Pierre , Porée Esther , Billot Katy , Birgy Eléonore , Ceccarelli Salomé , Silbermann Flora , Braeg Simone , Nguyen-Khoa Thao , Salomon Rémi , Gubler Marie-Claire , Wolfgang Kuehn E. , Saunier Sophie , Viau Amandine
Published: January 2021

STRUCTURED ABSTRACT

BACKGROUND

The majority of genetic kidney disease leading to kidney failure is caused by mutations in ciliary genes. How cilia malfunction leads to progressive kidney damage is poorly understood, but recent evidence links ciliopathy genes to CCL2 dependent macrophage recruitment in autosomal dominant polycystic kidney disease (ADPKD), the most studied renal ciliopathy. Whether or not renal inflammation is involved in other renal ciliopathies is unclear.

METHODS

We combined mice models with kidney biopsies and renal epithelial cells sampled from human urine to characterize the renal inflammatory network of nephronophthisis (NPH), the most frequent renal ciliopathy in children.

RESULTS

In human, mutations in cilia genes involved in NPH enhance urine excretion of the chemokine CCL2, causing abnormal macrophage recruitment in kidney tissues from NPH patients. Differing from ADPKD, inactivatingCcl2specifically in mouse tubular cells does not rescue the NPH phenotype, suggesting that other inflammatory mediators are involved. Using transcriptional data from 2 NPH models, we identify a set of pro-inflammatory cytokines upregulated in this disease, independently of CCL2. The majority of detectable transcripts from this set are specifically upregulated in kidney cells from NPH patients. In line with the function of these cytokines, NPH kidneys show disproportionate neutrophils and T cells infiltrates compared to healthy subject or hypertensive and diabetic chronic kidney disease patients.

CONCLUSIONS

This study reveals that inflammation is a central aspect in human NPH and delineates a specific set of inflammatory mediators that regulates immune cell recruitment in human NPH.

SIGNIFICANCE STATEMENT

Mutations in genes encoding primary cilia proteins are the leading cause of genetic kidney failure. In autosomal dominant polycystic kidney disease (ADPKD), deregulated cilia signaling leads to kidney infiltration by macrophages through the chemokine CCL2. Little is known about renal inflammation in nephronophthisis (NPH), the most frequent pediatric renal ciliopathy. Using NPH mice models, tissues and cells from NPH patients, we unveil renal inflammation as preeminent feature of NPH. Remarkably, the renal inflammatory evoked by ciliary gene mutations in NPH does not overlap with ADPKD: it is CCL2 independent, involves a prominent recruitment of neutrophils and T cells and a specific cytokine signature. This unforeseen findings strengthen the link between primary cilia and renal inflammation.
Social Reactivation of Fear Engrams Enhances Memory Recall
Authors: Finkelstein Abby Basya , Leblanc Héloïse , Cole Rebecca H. , Gallerani Troy , Vieira Anahita , Zaki Yosif , Ramirez Steve
Published: January 2021

For group-living species such as humans and rodents, conspecific interactions pervasively shape emotion (1–3), attention (4), and cognitive ability (5–8). Higher-order cognitive processes such as memory within a social brain are thus interlaced with social influences. Traditional laboratory rodent cages offer a limited but nonetheless rich multi-modal landscape of communication, including auditory calls (9–12), chemical signaling (13, 14), and tactile stimulation (15, 16). The absence of such social encounters in singly housed animals results in cognitive impairments and depression-like phenotypes (17), likely obscuring how the social brain has evolved to function. It is thus important to understand the relationship between social context and how individuals process memories. As social interaction recruits hippocampal (18) and amygdalar (19) circuitry that also serves as hubs for non-social memory traces(20–24), we hypothesized that pre-existing ensembles in these regions can be modulated by social experiences and lead to changes in memory expression. Here we show that stressful social experiences enhance the recall of previously acquired fear memories in male but not female mice. Activity-dependent tagging of cells in the dentate gyrus (DG) during fear learning revealed that these ensembles were endogenously reactivated during the social experiences in males. These reactivated cells were shown to be functional components of engrams, as optogenetic stimulation of the cells active during the social experience in previously fear conditioned animals was sufficient to drive fear-related behaviors. Our findings suggest that social encounters can reactivate pre-existing DG engrams and thereby strengthen discrete memories.

Significance Statement

Social environments can bolster and protect cognitive abilities. However, the relationship between social stimuli and individually learned memories remains enigmatic. Our work reveals that exposure to a stressed, naïve non-familiar conspecific or to the ambient olfactory-auditory cues of a recently stressed familiar conspecific induces reactivation of the cellular ensembles associated with a fear memory in the hippocampus. Artificially activating the hippocampal ensemble active during the social experience induces fearful behaviors only in animals that have previously acquired a negative memory, suggesting a fear-driving function of the reactivated ensembles and demonstrating the interaction between individual history and social experience. The neural resurgence of fear-driving ensembles during social experiences leads to a context-specific enhancement of fear recall. Our findings provide evidence that unlike directly physical stressors, ambient social stimuli can reactivate and amplify an individual’s memories.
Macrophage depletion impairs neonatal tendon regeneration
Authors: Howell Kristen L. , Kaji Deepak A. , Montero Angela , Yeoh Kenji , Nasser Philip , Huang Alice H.
Published: January 2021

Tendons are dense connective tissues that transmit muscle forces to the skeleton. After adult injury, healing potential is generally poor and dominated by scar formation. Although the immune response is a key feature of healing, the specific immune cells and signals that drive tendon healing have not been fully defined. In particular, the immune regulators underlying tendon regeneration are almost completely undetermined due to a paucity of tendon regeneration models. Using a mouse model of neonatal tendon regeneration, we screened for immune-related markers and identified upregulation of several genes associated with inflammation, macrophage chemotaxis, and TGFβ signaling after injury. Depletion of macrophages using AP20187 treatment of MaFIA mice resulted in impaired functional healing, reduced cell proliferation, reduced ScxGFP+ neo-tendon formation, and altered tendon gene expression. Collectively, these results show that inflammation is a key component of neonatal tendon regeneration and demonstrate a requirement for macrophages in effective functional healing.
Oxidative stress alters transcript localization of disease-causing genes in the retinal pigment epithelium
Authors: Kaczynski Tadeusz J. , Au Elizabeth D. , Farkas Michael H.
Published: January 2021

Nuclear retention is a mechanism whereby RNA transcripts are held in the nucleus to maintain a proper nuclear-to-cytoplasmic balance or as a stockpile for use in responding to stimuli. Many mechanisms are employed to determine whether transcripts are retained or exported to the cytoplasm, though the extent to which tissue- or cell-type, stressors, or disease pathogenesis affect this process remains unclear. As the most biochemically active tissue in the body, the retina must mitigate endogenous and exogenous stressors to maintain cell health and tissue function. Oxidative stress, believed to contribute to the pathogenesis, or progression, of age-related macular degeneration (AMD) and inherited retinal dystrophies (IRDs), is produced both internally from biochemical processes, as well as externally from environmental insult. To evaluate the effect of oxidative stress on transcript localization in the retinal pigment epithelium (RPE), we performed poly-A RNA sequencing on nuclear and cytoplasmic fractions from induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells exposed to hydrogen peroxide, as well as untreated controls. Under normal conditions, the number of mRNA transcripts retained in the nucleus exceeded that found in studies of other tissues. Further, the nuclear-to-cytoplasmic ratio of transcripts is altered following oxidative stress, as is the retention of genes associated with AMD, IRDs, and those important for RPE physiology. These results provide a retention catalog of all expressed mRNA in iPSC-RPE under normal conditions and after exposure to hydrogen peroxide, offering insight into one of the potential roles oxidative stress plays in the progression of visual disorders.
Substantial intraspecific variation in energy budgets: biology or artefact?
Authors: Potter Tomos , Reznick David N , Coulson Tim
Published: January 2021

Dynamic energy budget (DEB) models provide a mechanistic description of life-histories in terms of fluxes of energy through biological processes. In these models, life-histories are a function of environmental conditions and of fundamental traits of the organism relating to the acquisition, allocation, and use of energy.

These traits are described by the parameters of the DEB model, which have been estimated for over 2500 species. Recent work has aimed to compare species on the basis of differences in DEB parameters.

We show that caution is required in such analyses, because (i) parameter estimates vary considerably as an artefact of the types of data used to fit the models, and (ii) there is substantial intraspecific variation in parameter values, reflecting biological differences among populations.

We show that similar patterns of growth and reproduction can be reproduced with very different parameter sets. Our results imply that direct comparison of DEB parameters across populations or species may be invalid. However, valid comparisons are possible if differences in the types of data used to fit the models are taken into account.

We estimated DEB parameters for 16 populations of Trinidadian guppy, identifying differences in resource allocation and metabolic rate consistent with evolved life-history differences among these populations.

Variation in parameter values was substantial: if intraspecific variation in DEB parameters is greater than currently measured levels of interspecific variation, the detection of broad-scale patterns in energy budgets across species will be challenging.
A co-culture microplate for real-time measurement of microbial interactions
Authors: Jo Charles , Bernstein David B. , Vaisman Natalie , Frydman Horacio M. , Segrè Daniel
Published: January 2021

The dynamic structures of microbial communities emerge from the complex network of interactions between their constituent microbial organisms. Quantitative measurements of these microbial interactions are important for understanding and engineering microbial community structure. Here, we present the development and application of the BioMe plate, a redesigned microplate device in which pairs of wells are separated by porous membranes. BioMe facilitates the measurement of dynamic microbial interactions and integrates easily with standard laboratory equipment. We first applied BioMe to recapitulate recently characterized, natural symbiotic interactions between bacteria isolated from theD. melanogastergut microbiome. Specifically, the BioMe plate allowed us to observe the benefit provided by twoLactobacillistrains to anAcetobacterstrain. We next explored the use of BioMe to gain quantitative insight into the engineered obligate syntrophic interaction between a pair ofE. coliamino acid auxotrophs. We integrated experimental observations with a mechanistic computational model to quantify key parameters associated with this syntrophic interaction, including metabolite secretion and diffusion rates. This model also allowed us to explain the slow growth observed for auxotrophs growing in adjacent wells, by demonstrating that under the relevant range of parameters, local exchange between auxotrophs is essential for efficient growth. The BioMe plate provides a scalable and flexible approach for the study of dynamic microbial interactions.
Oncofly: A CURE for Cancer
Authors: Reed Floyd A. , de Couet H. Gert
Published: January 2021

Course-based Undergraduate Research Experiences (CURE’s) are emerging as a means to engage large numbers of undergraduate students in meaningful inquiry-based research activities. We describe here a simple laboratory exercise as part of an undergraduate genetics course that illustrates the contributions of oncogenes and tumor suppressors to the formation of neoplasms in an invertebrate model system. In addition, students were challenged to investigate whether flies reared on a diet containing a variety of additives display a higher number of invasive tumors in the larval abdomen.

The goal of the exercise was to (i) familiarize students with the multigenic origin of the cancer phenotype, to (ii) introduce some of the fundamental molecular cancer hallmarks, and to (iii) highlight the significance of invertebrate model systems in biomedical research. Furthermore, (iv) students learn to execute a molecular test for transgenic produce and (v) apply statistical tools to test a simple hypothesis.

We evaluated student learning and changes in opinions and attitudes relating to environmental versus genetic causes of cancer and several common misconceptions using a questionnaire before and after completing the exercise.

Overall, significant improvements in the rate of factually correct responses and reductions in uncertainty were demonstrated. Although resistance to change was apparent in regard to identifying some risk factors, there was clear learning and understanding of the core concepts of carcinogenesis and the utility of basic research with model organisms.