bluuebunny/crossref_metadata_2025 huggingface dataset:
Repeat controlled human malaria infection of healthy UK adults with blood-stagePlasmodium falciparum: safety and parasite growth dynamics
Authors: Salkeld Jo , Themistocleous Yrene , Barrett Jordan R. , Mitton Celia H. , Rawlinson Thomas A. , Payne Ruth O. , Hou Mimi M. , Khozoee Baktash , Edwards Nick J. , Nielsen Carolyn M. , Sandoval Diana Muñoz , Bach Florian A. , Nahrendorf Wiebke , Ramon Raquel Lopez , Baker Megan , Ramos-Lopez Fernando , Folegatti Pedro M. , Quinkert Doris , Ellis Katherine J. , Poulton Ian D. , Lawrie Alison M. , Cho Jee-Sun , Nugent Fay L. , Spence Philip J. , Silk Sarah E. , Draper Simon J. , Minassian Angela M.
Published: June 2022

In endemic settings it is known that natural malaria immunity is gradually acquired following repeated exposures. Here we sought to assess whether similar acquisition of blood-stage malaria immunity would occur following repeated parasite exposure by controlled human malaria infection (CHMI). We report the findings of a repeat homologous blood-stagePlasmodium falciparum(3D7 clone) CHMI study (VAC063C;ClinicalTrials.govNCT03906474). In total, 24 healthy, unvaccinated, malaria-naïve UK adult participants underwent primary CHMI followed by drug treatment. Ten of these then underwent secondary CHMI in the same manner, and then six of these underwent a final tertiary CHMI. As with primary CHMI, malaria symptoms were common following secondary and tertiary infection, however, most resolved within a few days of treatment and there were no long term sequelae or serious adverse events related to CHMI. Despite detectable induction and boosting of anti-merozoite serum IgG antibody responses following each round of CHMI, there was no clear evidence of anti-parasitic immunity (manifest as reduced parasite growthin vivo) conferred by repeated challenge with the homologous parasite in the majority of volunteers. However, three volunteers showed some variation in parasite growth dynamicsin vivofollowing repeat CHMI that were either modest or short-lived. We also observed no major differences in clinical symptoms or laboratory markers of infection across the primary, secondary and tertiary challenges. However, there was a trend to more severe pyrexia after primary CHMI and the absence of a detectable transaminitis post-treatment following secondary and tertiary infection. We hypothesize that this could represent the initial induction of disease tolerance or clinical malaria immunity. Repeat homologous blood-stage CHMI is thus safe and provides a model with the potential to further the understanding of the acquisition of blood-stage immunity in a highly controlled setting.
A Dense sub-graph based approach for Automatic detection of Optic Disc
Authors: Jana Subrata , Banerjee Tribeni Prasad , Mitra Thakur Gour Sundar , Mitra Pabitra
Published: June 2022

Glaucoma is a situation of greater than normal intraocular pressure surrounded by the eyes. This explains the harm to the optic nerves as the limb passes in sequence to the brain. The graph base is used in this paper for automatic localization of the optic disc. This paper proposed and modified a new dense sub - graph approach to locate the affected optic disc by using DRIVE, STAIR, and Drishti -GS1 databases. This model has proved to be more accurate when compared with other standard models representing the concert’s progress. This method provides a new idea for the location of the optic disc with a system accuracy of 93%.
Theta oscillations in the human hippocampus normalize the information content of episodic memory
Authors: Santos-Pata D. , Zucca R. , Fernandez Amil A. , Principe A. , Pérez-Enríquez C. , Rocamora R. , Kwok S. C. , Verschure P.
Published: June 2022

The principles governing the formation of episodic memories from the continuous stream of sensory stimuli are not fully understood. Theoretical models of the hippocampus propose that the representational format of episodic memories comprise oscillations in the theta frequency band (2-8 Hz) that set the time boundaries in which discrete events are bound encoded in the gamma frequency range (>30 Hz). We investigated this temporal segmentation and binding process by analyzing the intracranial EEG (iEEG) of surgically implanted epileptic patients performing a virtual-navigation task. We found a positive correlation between sensory information density encountered by the subject and hippocampal theta-frequency, suggesting that the human hippocampus normalizes the information content of episodic memories relative to the density of sensory information. This interpretation is further supported by the observation that as a marker of mnemonic encoding, i.e. the amount of persistent gamma events, directly correlates with sensory information density, gamma-frequency power and the phase relation between theta and gamma oscillations remain constant. Using a theoretical model of the hippocampus, we build a model that analogously displays a similar normalization of gamma episodes per theta cycle relative to information density by accounting for the physiological signatures of theta-gamma coding through combining fast and slow inhibitory feedback. We propose that this intrinsic normalization mechanism optimizes the trade-off between the discretization and compression of continuous experience relative to the limited capacity of episodic memory.

We move in continuous time and space, yet we can encode and recall discrete episodes from our past experiences. The neural mechanism behind this discretization is not fully understood. It has been previously observed that rodent locomotion modulates ongoing hippocampal theta rhythms. Thus, raising the question of whether these slow rhythms bind events together during a single oscillatory cycle relative to the movement speed or overall information density.

We quantified the effects of increasing locomotion and sensory information in modulating theta oscillations during virtual navigation with intracranial hippocampal activity from human epileptic patients.. We observed hippocampal theta waves increased with higher speed and higher sensory demands, thereby maintaining constant information per oscillatory cycle.

These results highlight the role of hippocampal theta oscillations in discretizing ongoing experience relative to the available information and explain how episodic memory integrates a fixed number of items per oscillatory theta cycle irrespective of richness of the external world.
Teasing out Missing Reactions in Genome-scale Metabolic Networks through Graph Convolutional Networks
Authors: Chen Can , Liao Chen , Liu Yang-Yu
Published: June 2022

GEnome-scale Metabolic models (GEMs) are powerful tools to predict cellular metabolism and physiological states in living organisms. However, due to our imperfect knowledge of metabolic processes, even highly curated GEMs have knowledge gaps (e.g., missing reactions). Existing gap-filling methods typically require phenotypic data as input to tease out missing reactions. We still lack a computational method for rapid and accurate gap-filling of metabolic networks before experimental data is available. Here we present a deep learning-based method — CHEbyshev Spectral HyperlInk pREdictor (CHESHIRE) — to predict missing reactions in GEMs purely from metabolic network topology. We demonstrate that CHESHIRE outperforms other topology-based methods in predicting artificially removed reactions over 926 high- and intermediate-quality GEMs. Furthermore, CHESHIRE is able to improve the phenotypic predictions of 49 draft GEMs for fermentation products and amino acids secretions. Both types of validation suggest that CHESHIRE is a powerful tool for GEM curation to reveal unknown links between reactions and observed metabolic phenotypes.
Granger causality analysis for calcium transients in neuronal networks: challenges and improvements
Authors: Chen Xiaowen , Ginoux Faustine , Mora Thierry , Walczak Aleksandra M. , Wyart Claire
Published: June 2022

One challenge in neuroscience is to understand how information flows between neuronsin vivoto trigger specific behaviors. Granger causality (GC) has been proposed as a simple and effective measure for identifying dynamical interactions. At single-cell resolution however, GC analysis is rarely used compared to directionless correlation analysis. Here, we study the applicability of GC analysis for calcium imaging data in diverse contexts. We first show that despite underlying linearity assumptions, GC analysis successfully retrieves non-linear interactions in a synthetic network simulating intracellular calcium fluctuations of spiking neurons. We highlight the potential pitfalls of applying GC analysis on realin vivocalcium signals, and offer solutions regarding the choice of GC analysis parameters. We took advantage of calcium imaging datasets from motoneurons in embryonic zebrafish to show how the improved GC can retrieve true underlying information flow. Applied to the network of brainstem neurons of larval zebrafish, our pipeline reveals strong driver neurons in the locus of the mesencephalic locomotor region (MLR), driving target neurons matching expectations from anatomical and physiological studies. Altogether, this practical toolbox can be applied onin vivopopulation calcium signals to increase the selectivity of GC to infer flow of information across neurons.
Global worming: massive invasion of North America by earthworms revealed
Authors: Mathieu Jérôme , Reynolds John Warren , Fragoso Carlos , Hadly Elizabeth
Published: June 2022

Human activities cause major ecological changes by reshuffling the spatial distribution of species. The extent to which this process affects belowground biota is a critical issue because soil organisms play a key role in ecosystem functioning and maintenance. However, the magnitude of the reshuffling of soil species remains unknown so far because of the lack of a historic baseline. Here, we begin to fill this gap with the largest spatiotemporal database of native and alien earthworms in North America. Our results reveal that the entire continent is being invaded by non-native earthworms through a variety of pathways. We show that these aliens bring novel ecological functions in most regions and thus represent a major threat to native ecosystems. Our findings demonstrate that earthworms, and most likely other soil organisms, represent a major but overlooked pool of invasive species with strong ecological impact. They need to be better integrated in control and mitigation strategies.
Viral diversity and zoonotic risk in endangered species
Authors: Nikc Kayla , Albery Gregory F. , Becker Daniel J. , Eskew Evan A. , Fagre Anna C. , Ryan Sadie J. , Carlson Colin J.
Published: June 2022

A growing body of evidence links zoonotic disease risk, including pandemic threats, to biodiversity loss and other upstream anthropogenic impacts on ecosystem health. However, there is little current research assessing viral diversity in endangered species. Here, combining IUCN Red List data on 5,876 mammal species with data on host-virus associations for a subset of 1,273 extant species, we examine the relationship between endangered species status and viral diversity, including the subset of viruses that can infect humans (zoonotic viruses). We show that fewer total viruses and fewer zoonotic viruses are known to infect more threatened species. After correcting for sampling effort, zoonotic virus diversity is mostly independent of threat status, but endangered species—despite a higher apparent research effort—have a significantly lower diversity of viruses, a property that is not explained by collinearity with host phylogeography or life history variation. Although this pattern could be generated by real biological processes, we suspect instead that endangered species may be subject to additional sampling biases not captured by the total volume of scientific literature (e.g., lower rates of invasive sampling may decrease viral discovery). Overall, our findings suggest that endangered species are no more or less likely to host viruses that pose a threat to humans, but future zoonotic threats might remain undiscovered in these species. This may be concerning, given that drivers of endangered species’ vulnerability such as habitat disturbance, wildlife trade, or climate vulnerability may increase virus prevalence in reservoirs and risk of spillover into humans.
Characterization of a KDM5 Small Molecule Inhibitor with Antiviral Activity against Hepatitis B Virus
Authors: Gilmore Sarah A. , Tam Danny , Cheung Tara L. , Snyder Chelsea , Farand Julie , Dick Ryan , Matles Mike , Feng Joy Y. , Ramirez Ricardo , Li Li , Yu Helen , Xu Yili , Barnes Dwight , Czerwieniec Gregg , Brendza Katherine M. , Appleby Todd C. , Birkus Gabriel , Willkom Madeleine , Kobayashi Tetsuya , Paoli Eric , Labelle Marc , Boesen Thomas , Tay Chin H. , Delaney William E. , Notte Gregory T. , Schmitz Uli , Feierbach Becket
Published: June 2022

Chronic hepatitis B (CHB) is a global health care challenge and a major cause of liver disease. To find new therapeutic avenues with a potential to functionally cure chronic Hepatitis B virus (HBV) infection, we performed a focused screen of epigenetic modifiers to identify replication inhibitors. From this work we identified isonicotinic acid inhibitors of the histone lysine demethylase 5 (KDM5) with potent anti-HBV activity. To enhance the cellular permeability and liver accumulation of the most potent KDM5 inhibitor identified (GS-080) an ester prodrug was developed (GS-5801) that resulted in improved bioavailability and liver exposure as well as an increased H3K4me3:H3 ratio on chromatin. GS-5801 treatment of HBV-infected primary human hepatocytes inhibited HBV replication and antigen levels. Evaluation of GS-5801 antiviral activity in a humanized mouse model of HBV infection, however, did not result in antiviral efficacy, despite achieving pharmacodynamic levels of H3K4me3:H3 predicted to be efficacious from the in vitro model. Here we discuss potential reasons for the disconnect between in vitro and in vivo efficacy, which highlight the translational difficulties of epigenetic targets for viral diseases.
Safety and uptake of fully oxidized β-carotene
Authors: Burton Graham W. , Mogg Trevor J. , Stupak Jacek , Stark Felicity C. , Twine Susan M. , Li Jianjun
Published: June 2022

Spontaneous oxidation of β-carotene yields a polymer-rich product (OxBC) also containing small amounts of many apocarotenoids. OxBC extends β-carotene’s benefits beyond vitamin A, finding utility in supporting health in livestock, pets, and humans. Although naturally occurring OxBC is consumed in foods and feeds, a direct demonstration here of safety of synthetic OxBC supports its increasing usage. A toxicological study in rats showed a maximum tolerated single oral dose, an LD50, and a NOAEL of 5,000, 30,079 and 1875 mg/kg body weight, respectively. The repeat-dose 90-day oral toxicity study showed no adverse physiological or pathological effects. A first study of OxBC uptake by mice over 2-5 days into a select set of tissues showed OxBC already was naturally present. The highest levels were in liver, lung, and hamstring. Despite dosing, no net increases occurred in liver, kidney, lung, and muscle. Net increases occurred in urine, intestinal content, plasma, feces, spleen, and cecum, consistent with processing of OxBC and preferential elimination of polymer. Compared to the 4:1 polymer: apocarotenoid ratio of OxBC, polymer was enriched in liver and spleen and depleted in lung, kidney, hamstring, and abdominal muscle. The apparent control of OxBC in major tissues further supports its safety.
Centrin-deficient Leishmania mexicana confers protection against Old World visceral leishmaniasis
Authors: Karmakar Subir , Volpedo Greta , Zhang Wen-Wei , Lypaczewski Patrick , Ismail Nevien , Oliveira Fabiano , Oristian James , Meneses Claudio , Gannavaram Sreenivas , Kamhawi Shaden , Hamano Shinjiro , Valenzuela Jesus G. , Matlashewski Greg , Satoskar Abhay R , Dey Ranadhir , Nakhasi Hira L.
Published: June 2022

Leishmaniasis is one of the top neglected tropical diseases with significant morbidity and mortality in low and middle-income countries (LMIC). However, this disease is also spreading in the developed world. Currently, there is a lack of effective strategies to control this disease. Vaccination can be an effective measure to control leishmaniasis and has the potential to achieve disease elimination. Recently, we have generated centrin gene-deleted new world L. mexicana (LmexCen-/-) parasites using CRISPR/Cas9 and showed that they protect mice against a homologous L. mexicana infection that causes cutaneous disease. In this study, we tested whether LmexCen-/- parasites can also protect against visceral leishmaniasis caused by L. donovani in a hamster model. We show that immunization with LmexCen-/- parasites is safe and does not cause lesions. Furthermore, such immunization conferred protection against visceral leishmaniasis caused by a needle-initiated L. donovani challenge, as indicated by a significant reduction in the parasite burdens in the spleen and liver and lack of mortality. Similar control of parasite burden was also observed against a sand fly mediated L. donovani challenge. Importantly, immunization with LmexCen-/- down-regulated the Th2 response as indicated by a significant reduction in the anti-inflammatory cytokines such as IL-10 and IL-4 and increased pro-inflammatory cytokine IFN-γ resulting in higher IFN-γ/IL-10 and IFN-γ/IL4 ratios compared to non-immunized animals. This contrasts with our studies with L. major centrin deletion mutants that showed a dominant Th1 response compared to L. major wild-type infection suggesting the divergent mechanisms of protection in the two mutant parasites. LmexCen-/- immunization resulted in long-lasting protection against L. donovani infection. Further, since the efficacy of LmCen-/- has not been determined against Leishmania strains prevalent in the Americas, LmexCen-/- may be a viable alternative. Taken together, our study demonstrates that immunization with LmexCen-/- parasites is safe and efficacious against old world visceral leishmaniasis.
Prioritizing transcription factor perturbations from single-cell transcriptomics
Authors: Singh Rohit , Li Joshua Shing Shun , Tattikota Sudhir Gopal , Liu Yifang , Xu Jun , Hu Yanhui , Perrimon Norbert , Berger Bonnie
Published: June 2022

The explosive growth of regulatory hypotheses from single-cell datasets demands accurate prioritization of hypotheses forin vivovalidation. However, current computational methods emphasize overall accuracy in regulatory network reconstruction rather than prioritizing a limited set of causal transcription factors (TFs) that can be feasibly tested. We developed Haystack, a hybrid computational-biological algorithm that combines active learning and the concept of optimal transport theory to nominate and validate high-confidence causal hypotheses. Our novel approach efficiently identifies and prioritizes transient but causally-active TFs in cell lineages. We applied Haystack to single-cell observations, guiding efficient and cost-effectivein vivovalidations that reveal causal mechanisms of cell differentiation inDrosophilagut and blood lineages. Notably, all the TFs shortlisted for the final, imaging-based assays were validated as drivers of differentiation. Haystack’s hypothesis-prioritization approach will be crucial for validating concrete discoveries from the increasingly vast collection of low-confidence hypotheses from single-cell transcriptomics.
No Ramp Needed: Spandrels, Statistics, and a Slippery Slope
Authors: Sejour Richard , Leatherwood Janet , Yurovsky Alisa , Futcher Bruce
Published: June 2022

Previously, Tuller et al. found that the first 30 to 50 codons of the genes of yeast and other eukaryotes are slightly enriched for rare codons, so are presumably translated somewhat slowly. They argued, based on informatics, that this initial slow translation “ramp” was adaptive; and increased efficiency of translation by queuing ribosomes to prevent collisions. Today, the translational speeds of different codons are known, and indeed rare codons are translated slowly. We re-examined the slow translation ramp. We confirm the finding that 5’ regions are enriched for rare codons. However, we also find that the 5’ ends of yeast genes are poorly conserved in evolution, suggesting that they are unstable and turn over relatively rapidly. When a new 5’ end formsde novo, it is likely to include codons that would otherwise be rare. Because evolution has had a relatively short time to select against these codons, 5’ ends are typically slightly enriched for rare, slow codons. Opposite to the expectation of Tuller et al., we show by direct experiment that genes with slowly translated codons at the 5’ end are expressed relatively poorly, and substituting faster codons improves expression. Further informatic studies suggest that for natural genes, slow 5’ ends are correlated with poor gene expression, opposite to the expectation of Tuller et al. Thus we conclude that slow 5’ translation is a “spandrel”; it is a non-adaptive consequence of something else, in this case the turnover of 5’ ends in evolution, and it does not improve translation.

Highlight

The 5’ ends of yeast genes are unstable over evolutionary time, enriching for rare codons, slowing translation; slow initial translation does not enhance expression.
Increasing Muscle Hypertrophy with a Natural Product Designed to Inhibit SIRT1
Authors: Pathak Suraj , Wallace Marita , Athalye Sonia , Schenk Simon , Langer Henning T. , Baar Keith
Published: June 2022

Muscle mass and strength are predictors of longevity. We have previously identified a series of molecular brakes that slow muscle growth in response to stress. One potential stress that we hypothesized would limit muscle growth is caloric stress through the activation of SIRT1. We therefore identified natural product inhibitors of SIRT1 and tested their effects on load-induced increases in muscle fiber cross-sectional area (fCSA) using an incomplete factorial design. Supplying varying amounts of three natural products for the full two-week period of overload resulted in increases in fCSA that varied from −2 to 113%. Using these data, we produced a model that predicted the optimal combination and concentration of each natural product and validated this model in a separate cohort of animals. Following two weeks of overload, fCSA in the optimal group increased 62%, whereas in the placebo fCSA increased only 3%. The greater increase in fCSA was not the result of an increase in ribosomal mass. In fact, the optimal group showed significantly less of the 5⍰ external transcribed spacer, a marker of 47S ribosomal RNA synthesis, and a trend for decreased total RNA. In spite of the lower ribosome mass, the increase in protein synthesis was similar, suggesting that the natural product cocktail may be increasing ribosomal efficiency rather than capacity. These data suggest that inhibition of SIRT1, together with exercise, may be useful in increasing muscle fCSA.
The disconnect2 mutation disrupts the tjp1b gene that is required for electrical synapse formation
Authors: Michel Jennifer Carlisle , Lasseigne Abagael M. , Marsh Audrey J. , Miller Adam C.
Published: June 2022

To investigate electrical synapse formation in vivo we used forward genetics to disrupt genes affecting Mauthner cell electrical synapses in larval zebrafish. We identify the disconnect2 (dis2) mutation for its failure to localize neural gap junction channels at electrical synapses. We mapped this mutation to chromosome 25 and identified a splice-altering mutation in the tjp1b gene. We demonstrated that the dis2 mutation disrupts tjp1b function using complementation analysis with CRISPR generated mutants. We conclude that the dis2 mutation disrupts the tjp1b gene that is required for electrical synapse formation.

Description

Neural networks are circuits of neurons wired together during development that provide an animal with specialized behavioral outputs. Dedicated adhesions called neuronal synapses create sites of communication between neurons and can be categorized as either electrical or chemical. This work identifies a new mutation in tjp1b that is shown to be required for electrical synapse formation.
Electrical synapse formation is differentially regulated by distinct isoforms of a postsynaptic scaffold
Authors: Michel Jennifer Carlisle , Grivette Margaret M. B. , Harshfield Amber T. , Huynh Lisa , Komons Ava P. , Loomis Bradley , McKinnis Kaitlan , Miller Brennen T. , Nguyen Ethan Q. , Huang Tiffany W. , Lauf Sophia , Michel Elias S. , Michel Mia E. , Marsh Audrey J. , Kaye Lila E. , Lasseigne Abagael M. , Lukowicz-Bedford Rachel M. , Farnsworth Dylan R. , Martin E. Anne , Miller Adam C.
Published: June 2022

Electrical synapses are neuronal gap junction (GJ) channels associated with a macromolecular complex called the electrical synapse density (ESD), which regulates development and dynamically modifies electrical transmission. However, the proteomic makeup and molecular mechanisms utilized by the ESD that direct electrical synapse formation are not well understood. Using the Mauthner cell of zebrafish as a model, we previously found that the intracellular scaffolding protein ZO1b is a member of the ESD, localizing postsynaptically, where it is required for GJ channel localization, electrical communication, neural network function, and behavior. Here, we show that the complexity of the ESD is further diversified by the genomic structure of the ZO1b gene locus. The ZO1b gene is alternatively initiated at three transcriptional start sites resulting in isoforms with unique N-termini that we call ZO1b-Alpha, -Beta, and - Gamma. We demonstrate that ZO1b-Beta and ZO1b-Gamma are broadly expressed throughout the nervous system and localize to electrical synapses. By contrast, ZO1b-Alpha is expressed mainly non-neuronally and is not found at synapses. We generate mutants in all individual isoforms, as well as double mutant combinationsin cison individual chromosomes, and find that ZO1b-Beta is necessary and sufficient for robust GJ channel localization. ZO1b-Gamma, despite its localization to the synapse, plays an auxiliary role in channel localization. This study expands the notion of molecular complexity at the ESD, revealing that an individual genomic locus can contribute distinct isoforms to the macromolecular complex at electrical synapses. Further, independent scaffold isoforms have differential contributions to developmental assembly of the interneuronal GJ channels. We propose that ESD molecular complexity arises both from the diversity of unique genes and from distinct isoforms encoded by single genes. Overall, ESD proteomic diversity is expected to have critical impacts on the development, structure, function, and plasticity of electrical transmission.
A Note on the Effects of Digital Primary Health Care on Utilization: Concepts, Evidence, and Descriptive Analysis of Non-Experimental Register Data from Sweden
Authors: Ekman Björn , Thulesius Hans , Wilkens Jens , Arvidsson Eva
Published: June 2022

Digital technologies for health care may lower costs while enhancing access to services. However, concerns have been raised that digital care may lead to over-use of services and not be as effective as in-person visits. Previous studies have found varying effects across different contexts, study designs, and outcome measures. This study contributes to the emerging evidence on the effects of digital care on primary care utilization by developing a conceptual model for primary care use and then comparing the effects of digital primary care with in-person visits and telephone contacts. Register data from Sweden over a two-year period (2017-2018) in a sample of patients diagnosed with an infection are used to describe the effects. Findings show that the majority of patients require a single consultation across either model of care. A relatively small share of patients makes multiple consultations per episode of care both across and within models of care. Compared with in-person visits and telephone contacts, digital care is associated with fewer consultations per episode of care and involve lower rates of laboratory tests and antibiotic prescriptions. Digital care is provided by a physician to a larger extent compared with the other models of care in the current sample. Further analysis will be conducted to establish any causal effects of digital primary contacts on identified outcomes.
Retrospective analysis of SARS-CoV-2 omicron invasion over delta in French regions in 2021-22: a status-based multi-variant model
Authors: Haschka Thomas , Vergu Elisabeta , Roche Benjamin , Poletto Chiara , Opatowski Lulla
Published: June 2022

Background

SARS-CoV-2 is a rapidly spreading disease affecting human life and the economy on a global scale. The disease has caused so far more then 5.5 million deaths. The omicron outbreak that emerged in Botswana in the south of Africa spread around the globe at further increased rates, and caused unprecedented SARS-CoV-2 infection incidences in several countries. At the start of December 2021 the first omicron cases were reported in France.

Methods

In this paper we investigate the contagiousness of this novel variant relatively to the delta variant that was also in circulation in France at that time. Using a dynamic multi-variant model accounting for cross-immunity through a status-based approach, we analyze screening data reported by Santé Publique France over 13 metropolitan French regions between 1st of December 2021 and the 30th of January 2022. During the investigated period, the delta variant was replaced by omicron in all metropolitan regions in approximately three weeks. The analysis conducted retrospectively allows us to consider the whole replacement time window and compare regions with different times of omicron introduction and baseline levels of variants’ transmission potential. As large uncertainties regarding cross-immunity among variants persist, uncertainty analyses were carried out to assess its impact on our estimations.

Results

Assuming that 80% of the population was immunized against delta, a cross delta/omicron cross-immunity of 25% and omicron generation time was 3.5 days, the relative strength of omicron to delta, expressed as the ratio of their respective reproduction rates,, was found to range between 1.51 and 1.86 across regions. Uncertainty analysis on epidemiological parameters led ranging over 1.57-2.13 when averaged over the metropolitan French regions, weighting by population size.

Conclusions

Upon introduction, omicron spread rapidly through the French territory and showed a high fitness relative to delta. We documented considerable geographical heterogeneities on the spreading dynamics. The historical reconstruction of variant emergence dynamics provide valuable ground knowledge to face future variant emergence events.
Assessment of Regional Body Composition, Physical Function and Sarcopenia among Peruvian women aging with HIV
Authors: Cabrera Diego M. , Cornejo Mijahil P. , Pinedo Yvett , Garcia Patricia J. , Hsieh Evelyn
Published: June 2022

Background

Management of chronic conditions and optimization of overall health has become a primary global health concern in the care of people living with HIV, particularly in lower-and-middle income countries where infrastructure for chronic disease management may be fragmented. Alterations in body composition (BC) can reflect important changes in musculoskeletal health, particularly among populations at risk for developing fat and muscle redistribution syndromes, such as HIV-infected women. We aimed to explore this issue among Peruvian women aging with HIV.

Methods

Cross-sectional study among HIV-infected and uninfected Peruvian women aged ≥40. Dual X-ray absorptiometry was used to measure trunk and limb lean mass (LM) and fat mass (FM). Physical performance was assessed with the Short Physical Performance Battery (SPPB) and physical strength with a dynamometer. Sarcopenia was assessed based upon EWGSOP criteria. We used linear regression to model associations between BC, sarcopenia and physical scores.

Results

104 HIV-infected and 212 uninfected women were enrolled with a mean age of 55.1±8.8 years. Among the HIV-infected group, years since diagnosis was 11.8±6 and all were on antiretroviral treatment. Mean SPPB score was 9.9 vs 10.8 (p<0.001) between both groups. Sarcopenia spectrum was found in 25.9% of HIV-infected and 23.1% of uninfected women. In multivariate regression analysis, trunk FM and older age were negatively correlated with physical performance among HIV-infected women. An increased percentage of severe sarcopenia was found among the HIV-infected, although our study was not specifically powered for this comparison.

Conclusions

HIV-infected women had significantly lower SPPB scores compared to women without HIV, and trunk FM and upper limb LM were independent predictors for the tests described. Prospective studies are needed in Latin America & the Caribbean to identify individuals at high risk for declines in physical function, and inform prevention guidelines.
Estimating the effect size of a hidden causal factor between SNPs and a continuous trait: a mediation model approach
Authors: Ding Zhuoran , Ritchie Marylyn D. , Voight Benjamin F. , Hwang Wei-Ting
Published: June 2022

Background

Observational studies and Mendelian randomization experiments have been used to identify many causal factors for complex traits in humans. Given a set of causal factors, it is important to understand the extent to which these causal factors explain some, all, or none of the genetic heritability, as measured by single-nucleotide polymorphisms (SNPs) that are associated with the trait. Using the mediation model framework with SNPs as the exposure, a trait of interest as the outcome, and the known causal factors as the mediators, we hypothesize that any unexplained association between the SNPs and the outcome trait is mediated by an additional unobserved, hidden causal factor.

Results

We propose a method to infer the effect size of this hidden mediating causal factor on the outcome trait by utilizing the estimated associations between a continuous outcome trait, the known causal factors, and the SNPs. The proposed method consists of three steps and, in the end, implements Markov chain Monte Carlo to obtain a posterior distribution for the hidden mediator’s effect size. We evaluate our proposed method via extensive simulations and show that when the model assumptions hold, our method estimates the effect size of the hidden mediator well and controls type I error rate if the hidden mediator does not exist.. In addition, we apply the method to the UK Biobank data and find that a potential hidden mediator for waist-hip ratio exists in the European population, and the hidden mediator has a large effect size relatively to the effect size of the known mediator BMI.

Conclusions

We develop a framework to infer the effect of potential, hidden mediators influencing complex traits. This framework can begin to place boundaries on unexplained risk factors contributing to complex traits.
Rapid non-destructive method to phenotype stomatal traits
Authors: Pathoumthong Phetdalaphone , Zhang Zhen , Roy Stuart J. , El Habti Abdeljalil
Published: June 2022

Background

Stomata are tiny pores on the leaf surface that are central to gas exchange. Stomatal number, size and aperture are key determinants of plant transpiration and photosynthesis, and variation in these traits can affect plant growth and productivity. Current methods to screen for stomatal phenotypes are tedious and not high throughput. This impedes research on stomatal biology and hinders efforts to develop resilient crops with optimised stomatal patterning. We have developed a rapid non-destructive method to phenotype stomatal traits in four species: wheat, rice, tomato and Arabidopsis.

Results

The method consists of two steps. The first is the non-destructive capture of images of the leaf surface from plants in their growing environment using a handheld microscope; a process which only takes a few seconds compared to minutes for other methods. The second is to analyse stomatal features using a machine learning model that automatically detects, counts and measures stomatal number, size and aperture. The accuracy of the machine learning model in detecting stomata ranged from 76% to 99%, depending on the species, with a high correlation between measures of number, size and aperture between measurements using the machine learning models and by measuring them manually. The rapid method was applied to quickly identify contrasting stomatal phenotypes.

Conclusions

We developed a method that combines rapid non-destructive imaging of leaf surfaces with automated image analysis. The method provides accurate data on stomatal features while significantly reducing time for data acquisition and analysis. It can be readily used to phenotype stomata in large populations in the field and in controlled environments.
Host age-dependent evolution of a plant RNA virus
Authors: Melero Izan , González Rubén , Elena Santiago F.
Published: June 2022

Viruses are obligate pathogens that entirely rely on their host resources to complete their infectious cycle. The availability of such resources depends upon external and internal factors, being host age one of the most relevant ones. The interplay between host age and virus evolution has not been thoroughly studied in plants. Here, we have used the Arabidopsis thaliana - turnip mosaic virus (TuMV) pathosystem to study plant-virus interactions and virus evolution at three different host ages: vegetative (juvenile), bolting (transition) and reproductive (mature) stages. After infecting plants with a naïve and a well-adapted TuMV isolates, we observed that the older the host the faster and more severe the infections were. The same trend was observed for several other viruses. Thereafter, we experimentally evolved lineages of the naïve and the well-adapted TuMV isolates in plants from each of the three developmental stages. All evolved viruses enhanced their infection phenotypes, being this increase more intense on viruses evolved in younger hosts. The genomic changes of the evolved viral lineages revealed mutation patterns that strongly depended on the founder viral isolate as well as on the age of the host wherein the lineages evolved.
Ancient Trans-Species Polymorphism at the Major Histocompatibility Complex in Primates
Authors: Fortier Alyssa Lyn , Pritchard Jonathan K
Published: June 2022

Classical genes within the Major Histocompatibility Complex (MHC) are responsible for peptide presentation to T cells, thus playing a central role in immune defense against pathogens. These genes are subject to strong selective pressures including both balancing and directional selection, resulting in exceptional genetic diversity—thousands of alleles per gene in humans. Moreover, some alleles appear to be shared between primate species, a phenomenon known as trans-species polymorphism (TSP) or incomplete lineage sorting, which is rare in the genome overall. However, despite the clinical and evolutionary importance of MHC diversity, we currently lack a full picture of primate MHC evolution. To start addressing this gap, we explore variation across genes and species in our companion paper Fortier2024a and here we explore variation within individual genes. We used Bayesian phylogenetic methods to determine the extent of TSP at 17 MHC genes, including classical and non-classical Class I and Class II genes. We find strong support for deep TSP in 7 of 10 classical genes, including—remarkably—between humans and old-world monkeys in MHC-DQB1. Despite the long-term persistence of ancient lineages, we additionally observe rapid evolution at nucleotides encoding the proteins' peptide-binding domains. The most rapidly-evolving amino acid positions are extremely enriched for autoimmune and infectious disease associations. Together, these results suggest complex selective forces—arising from differential peptide binding—that drive short-term allelic turnover within lineages while also maintaining deeply divergent lineages for at least 31 million years.
Taxonomic assessment of two wild house mouse subspecies using whole-genome sequencing
Authors: Lawal Raman Akinyanju , Mathis Verity L. , Barter Mary E. , Charette Jeremy R. , Garretson Alexis , Dumont Beth L.
Published: June 2022

House mice (Mus musculus) are comprised of three primary subspecies. A large number of secondary subspecies have also been suggested on the basis of divergent morphology and molecular variation at limited numbers of markers. While the phylogenetic relationships among the primary M. musculus subspecies are well-defined, the relationships among the secondary subspecies, and their relationships to primary subspecies, remain poorly understood. Here, we integrate de novo genome sequencing of museum-stored specimens of house mice from one secondary subspecies (M. m. bactrianus) and publicly available genome sequences of house mice previously characterized as M. m. helgolandicus, with whole-genome sequences from diverse representatives of the three primary house mouse subspecies. We show that mice assigned to the secondary M. m. bactrianus and M. m. helgolandicus subspecies are not genetically differentiated from the contemporary M. m. castaneus and M. m. domesticus, respectively. Overall, our work suggests that the M. m. bactrianus and M. m. helgolandicus subspecies are not well-justified taxonomic entities, emphasizing the importance of leveraging whole-genome sequence data to inform subspecies designations. Additionally, our investigation has established experimental procedures for generating whole-genome sequences from air-dried museum specimens and provides key genomic resources to inform future genomic investigations of wild mouse diversity.
Testing the Growth Rate and Temperature Compensation Hypotheses in Marine Bacterioplankton
Authors: Givati Shira , Yang Xingyu , Sher Daniel , Rahav Eyal
Published: June 2022

Two different hypotheses have been raised as to how temperature affects resource allocation in microorganisms. The translation-compensation hypothesis (TCH) predicts that the increase in enzymatic efficiency with temperature results in fewer required ribosomes per cell and lower RNA:protein ratio. In contrast, the growth rate hypothesis (GRH) predicts that increasing growth rate with temperature requires more ribosomes and hence a higher cellular RNA:protein. We tested these two hypotheses in lab cultures ofProchlorococcusandAlteromonasas well as over an annual cycle in the Eastern Mediterranean Sea. The RNA:protein ofAlteromonasmostly decreased with temperature in accordance with the TCH, while that ofProchlorococcusincreased with temperature, as predicted by the GRH. No support was found for either hypotheses in surface waters from the Eastern Mediterranean, whereas the fraction of phosphorus in RNA was positively correlated with per-cell bacterial production in the deep chlorophyll maximum, supporting the GRH in this niche. A considerable part of the cellular phosphorus was not allocated to RNA, DNA, phospholipids or polyphosphate, raising the question which cellular molecules contain these P reserves. While macromolecular quotas differed significantly between laboratory cultures and field samples, these were connected through a power law, suggesting common rules of resource allocation.

Originality-Significance statement

We investigated whether the translation-compensation hypothesis (TCH) or growth rate hypothesis (GRH) affect the macromolecular composition and phosphorus allocation in both lab cultures ofProchlorococcusandAlteromonasas well as in seawater with natural microbial communities. Our results highlight that the TCH and GRH may each be applicable to different organisms (autotroph or heterotroph), physiological states or environmental conditions. Testing the applicability of theoretical models such as the TCH and GRH in lab cultures and field samples is an important step toward mechanistic models of bacterial physiology. This is especially important to our understanding of how bacterioplankton allocate resources in response to changes in environmental conditions such as temperature and nutrient stress, which are likely to expand due to the predicted global changes.
Genomic regions insertion and deletion in Monkeypox virus causing multi-country outbreak-2022
Authors: Desingu Perumal Arumugam , Nagarajan K.
Published: June 2022

The genetic diversity and evolutionary origin of the Monkeypox virus (MPXV) that is currently creating a multi-country outbreak-2022 is not fully understood. Here we report that the MPXVs that cause outbreak-2022 (MPXVs-2022) have deletion/insertion of ∼500 to 2000bp nucleotide in multiple genomic regions. Our analyses revealed that MPXVs-2022 are very close to the West African Clade of MPXVs (WA-MPXVs) that caused the Outbreak in Nigeria in 2017-2018. Furthermore, we classified the WA-MPXVs detected before 2017 that could not be transmitted from human-to-human as WA-MPXVs-I and WA-MPXVs detected after 2017 that could be transmitted from human-to-human as WA-MPXVs-II (including MPXVs-2022), and human-to-human transmissible Central African MPXVs (CA-MPXV) remained as a separate clade. Overall our results suggest that although WA-MPXVs-II are almost identical to WA-MPXVs-I throughout the genome and two large genomic insertions (∼500, 2000bp size insertion), they differ from WA-MPXVs-I in 5’-inverted terminal repeat (5’-ITR) (deletion of the last-2000bp-5’-ITR) and 13 proteins that of CA-MPXVs, and the presence of seven unique proteins in WA-MPXVs-II is likely to be a significant cause of outbreak-2022. This study shed light on the genetic diversity and evolutionary origin of MPXVs causing outbreak-2022.
PipeIT2: A tumor-only somatic variant calling workflow for Molecular Diagnostic Ion Torrent sequencing data
Authors: Schnidrig Desiree , Garofoli Andrea , Benjak Andrej , Rätsch Gunnar , Rubin Mark A. ,   SOCIBP consortium, Piscuoglio Salvatore , Ng Charlotte K. Y.
Published: June 2022

Precision oncology relies on the accurate identification of somatic mutations in cancer patients. While the sequencing of the tumoral tissue is frequently part of routine clinical care, the healthy counterparts are rarely sequenced. We previously published PipeIT, a somatic variant calling workflow specific for Ion Torrent sequencing data enclosed in a Singularity container. PipeIT combines user-friendly execution, reproducibility and reliable mutation identification, but relies on matched germline sequencing data to exclude germline variants. Expanding on the original PipeIT, here we describe PipeIT2 to address the clinical need to define somatic mutations in the absence of germline control. We show that PipeIT2 achieves a >95% recall for variants with variant allele fraction >10%, reliably detects driver and actionable mutations and filters out most of the germline mutations and sequencing artifacts. With its performance, reproducibility and ease of execution, PipeIT2 is a valuable addition to molecular diagnostics laboratories.