bluuebunny/crossref_metadata_2025 huggingface dataset:
Interleukin-6 Trajectory and Secondary Infections in Mechanically Ventilated Patients With Coronavirus Disease 2019 Acute Respiratory Distress Syndrome Treated With Interleukin-6 Receptor Blocker
Authors: Vazquez Guillamet M. Cristina , Kulkarni Hrishikesh S. , Montes Kevin , Samant Maanasi , Shaikh Preet A. , Betthauser Kevin , Mudd Philip A. , Reynolds Daniel , O’Halloran Jane , Lyons Patrick , McEvoy Colleen , Vazquez Guillamet Rodrigo
Published: February 2021

Objectives:

To describe the infectious complications and interleukin-6 trajectories in mechanically ventilated patients with coronavirus disease 2019.

Design:

Retrospective cohort study.

Setting:

ICUs at Washington University-Barnes Jewish Hospital in St. Louis, MO.

Participants:

All consecutive patients admitted to the medical ICU and requiring mechanical ventilation from March 12, 2020, to April 21, 2020, were included.

Interventions:

Tocilizumab, an interleukin-6 receptor blocker, was prescribed at the discretion of the treating physicians to patients with a clinical picture compatible with cytokine release syndrome.

Measurements:

All the patients were followed to death or hospital discharge. Demographic and laboratory data were collected retrospectively from the electronic medical record. Interleukin-6 levels were measured at days 0, 3, 7, 14, and 21. Infections were divided into culture positive and culture negative (clinically suspected and treated). The main outcomes were infectious complications and interleukin-6 levels at different points in time.

Results:

Forty-three patients with respiratory failure secondary to coronavirus disease 2019 were on mechanical ventilation during the study period. Twenty-seven (68%) were male, and 31 (72.1%) were African-American. Median Charlson score was 2 (interquartile range, 0–4). Median Pao2/Fio2 was 171.5 (122–221) on the day of mechanical ventilation initiation, and 13 patients (30.2%) required vasopressors. C-reactive protein was 142.7 (97.7–213.7), d-dimer 1,621 (559–13,434), and Acute Physiology and Chronic Health Evaluation-II 11 (9–15). Interleukin-6 levels at admission were 61 pg/mL (interquartile range, 28.6–439 pg/mL). Patients treated with tocilizumab had higher levels of interleukin-6 at each measurement (days 0, 3, 7, 14, and 21) compared with patients receiving standard of care. Both groups reached peak interleukin-6 levels at day 7. Administration of tocilizumab was associated with a trend toward increased risk of infection.

Conclusions:

Interleukin-6 levels peak at day 7 in patients with severe coronavirus disease 2019 pneumonia requiring mechanical ventilation and follows a similar trajectory in patients with coronavirus disease 2019 pneumonia requiring mechanical ventilation irrespective of treatment with interleukin-6R blockers. Interleukin-6 levels continued to rise in nonsurvivors, in comparison with survivors, where the rise in interleukin-6 levels was followed by a decline.
Co-Occurrence of Neurodevelopmental Disorders in Pediatric Sickle Cell Disease
Authors: Lance Eboni I. , Cannon Alicia D. , Shapiro Bruce K. , Lee Li-Ching , Johnston Michael V. , Casella James F.
Published: February 2021

Objective:

The objective of this study is to retrospectively determine the co-occurrence, associated characteristics, and risk factors for neurodevelopmental disorders (NDD) in a pediatric sickle cell disease (SCD) clinic population.

Method:

We investigated the co-occurrence and features of NDD in pediatric SCD through a retrospective cohort study conducted between July 2017 and January 2019. The participants were patients with SCD younger than 18 years of age identified from our institutions' clinic rosters and medical records databases.

Results:

A total of 276 participants were eligible for study inclusion, and 65 participants were found to have various NDD. Children with SCD and NDD were more likely to have a history of multiple SCD-related complications in comparison to children with SCD without NDD. Children with SCD and NDD were more likely to use disease-modifying therapies in comparison to children with SCD without NDD (χ2 27.2, p < 0.001).

Conclusion:

Children with SCD and NDD have higher odds of having certain disease-related complications and higher use of disease-modifying treatments than children with SCD who do not have NDD. Screening and diagnoses of NDD may be relevant to clinical management of pediatric SCD.
Gut Microbiome and Nonalcoholic Fatty Liver Disease (NAFLD)
Authors: Liang Yinji , Zhou Shuang , Chen Xinhe , Yu Lebing , Zhang Dongling , Lin Chenli
Published: February 2021

At present, the incidence of nonalcoholic fatty liver disease (NAFLD) in adults is increasing year by year and at a younger age. Evidence-based healthcare has confirmed that NAFLD is closely related to obesity, cardiovascular disease, type 2 diabetes, metabolic syndrome, and other chronic metabolic diseases. Despite the growing prevalence of NAFLD, little is known about symptoms for patients at risk of NAFLD progression, thus preventing healthcare providers from intervening at an early stage. In addition, these symptoms usually cause problems for patients to cope with other chronic metabolic diseases. Symptoms may have a biological basis; especially as the changes of gut microbes may affect the symptoms of metabolic diseases. This article aims to describe the new role of gut microbes in the development of NAFLD, focusing on the potential relationship between gut microbes and symptoms of NAFLD, as well as the mechanism of action of the “gut–liver–brain” axis. This information can be useful in developing precise nursing interventions for NAFLD patients, restoring the “health” of gut microbes, and alleviating the symptom burden of chronic metabolic disease in NAFLD.
Sociodemographic and Clinical Characteristics of 1350 Patients With Young Onset Dementia
Authors: Ryan Brigid , Martinez Ruiz Adrian , Rivera-Rodriguez Claudia , Curtis Maurice , Cheung Gary
Published: February 2021

Objective:

To determine the sociodemographic and clinical characteristics of a large cohort of patients with young onset dementia (YOD) (aged below 65), and whether they differ from older (age 65+) adults with dementia.

Methods:

Retrospective cross-sectional study. Participants were New Zealanders who were assessed with International Residential Assessment Instrument (interRAI) assessments (including community-dwelling adults and those in long-term care) from 2016 to 2019 and had a diagnosis of dementia. Outcomes were sociodemographic and clinical characteristics captured in the interRAI assessment.

Results:

People with YOD were more likely to be male, of non-European ethnicity, and live in a dwelling other than a private home or be homeless. They were more likely to exhibit problematic behaviors and neuropsychiatric symptoms but were less frail and less dependent for activities of daily living. Financial strain and loneliness were more common in people with YOD. Carers of people with YOD were more likely to feel distress, anger, or depression, and families of people with YOD were more likely to feel overwhelmed.

Conclusions:

YOD patients have different needs than older adults with dementia. These differences must be considered by clinicians and organizations that provide care and support to people living with dementia.
Subtle Changes in Medication-taking Are Associated With Incident Mild Cognitive Impairment
Authors: Dorociak Katherine E. , Mattek Nora , Ferguson John E. , Beattie Zachary T. , Sharma Nicole , Kaye Jeffrey A. , Leese Mira I. , Doane Bridget M. , Hughes Adriana M.
Published: February 2021

Introduction:

Medication-taking is a routine instrumental activity of daily living affected by mild cognitive impairment (MCI) but difficult to measure with clinical tools. This prospective longitudinal study examined in-home medication-taking and transition from normative aging to MCI.

Methods:

Daily, weekly, and monthly medication-taking metrics derived from an instrumented pillbox were examined in 64 healthy cognitively intact older adults (Mage=85.5 y) followed for a mean of 2.3 years; 9 transitioned to MCI during study follow-up.

Results:

In the time up to and after MCI diagnosis, incident MCI participants opened their pillbox later in the day (by 19 min/mo; β=0.46, P<0.001) and had increased day-to-day variability in the first pillbox opening over time (by 4 min/mo) as compared with stable cognitively intact participants (β=4.0, P=0.003).

Discussion:

Individuals who transitioned to MCI opened their pillboxes later in the day and were more variable in their medication-taking habits. These differences increased in the time up to and after diagnosis of MCI. Unobtrusive medication-taking monitoring is an ecologically valid approach for identifying early activity of daily living changes that signal transition to MCI.
Diversity of biological rhythm and food web stability
Authors: Mougi Akihiko
Published: February 2021

How ecosystem biodiversity is maintained remains a persistent question in the field of ecology. Here, I present a new coexistence theory, i.e. diversity of biological rhythm. Circadian, circalunar and circannual rhythms, which control short- and long-term activities, are identified as universal phenomena in organisms. Analysis of a theoretical food web with diel, monthly and annual cycles in foraging activity for each organism shows that diverse biological cycles play key roles in maintaining complex communities. Each biological rhythm does not have a strong stabilizing effect independently but enhances community persistence when combined with other rhythms. Biological rhythms also mitigate inherent destabilization tendencies caused by food web complexity. Temporal weak interactions due to hybridity of multiple activity cycles play a key role toward coexistence. Polyrhythmic changes in biological activities in response to the Earth's rotation may be a key factor in maintaining biological communities.
New insights into large tropical tree mass and structure from direct harvest and terrestrial lidar
Authors: Burt Andrew , Boni Vicari Matheus , da Costa Antonio C. L. , Coughlin Ingrid , Meir Patrick , Rowland Lucy , Disney Mathias
Published: February 2021

A large portion of the terrestrial vegetation carbon stock is stored in the above-ground biomass (AGB) of tropical forests, but the exact amount remains uncertain, partly owing to the lack of measurements. To date, accessible peer-reviewed data are available for just 10 large tropical trees in the Amazon that have been harvested and directly measured entirely via weighing. Here, we harvested four large tropical rainforest trees (stem diameter: 0.6–1.2 m, height: 30–46 m, AGB: 3960–18 584 kg) in intact old-growth forest in East Amazonia, and measured above-ground green mass, moisture content and woody tissue density. We first present rare ecological insights provided by these data, including unsystematic intra-tree variations in density, with both height and radius. We also found the majority of AGB was usually found in the crown, but varied from 42 to 62%. We then compare non-destructive approaches for estimating the AGB of these trees, using both classical allometry and new lidar-based methods. Terrestrial lidar point clouds were collected pre-harvest, on which we fitted cylinders to model woody structure, enabling retrieval of volume-derived AGB. Estimates from this approach were more accurate than allometric counterparts (mean tree-scale relative error: 3% versus 15%), and error decreased when up-scaling to the cumulative AGB of the four trees (1% versus 15%). Furthermore, while allometric error increased fourfold with tree size over the diameter range, lidar error remained constant. This suggests error in these lidar-derived estimates is random and additive. Were these results transferable across forest scenes, terrestrial lidar methods would reduce uncertainty in stand-scale AGB estimates, and therefore advance our understanding of the role of tropical forests in the global carbon cycle.
Cooperation of partially transformed clones: an invisible force behind the early stages of carcinogenesis
Authors: Esposito Alessandro
Published: February 2021

Most tumours exhibit significant heterogeneity and are best described as communities of cellular populations competing for resources. Growing experimental evidence also suggests that cooperation between cancer clones is important as well for the maintenance of tumour heterogeneity and tumour progression. However, a role for cell communication during the earliest steps in oncogenesis is not well characterized despite its vital importance in normal tissue and clinically manifest tumours. Here, we present a simple analytical model and stochastic lattice-based simulations to study how the interaction between the mutational process and cell-to-cell communication in three-dimensional tissue architecture might contribute to shape early oncogenesis. We show that non-cell-autonomous mechanisms of carcinogenesis could support and accelerate pre-cancerous clonal expansion through the cooperation of different, non- or partially transformed mutants. We predict the existence of a ‘cell-autonomous time horizon', a time before which cooperation between cell-to-cell communication and DNA mutations might be one of the most fundamental forces shaping the early stages of oncogenesis. The understanding of this process could shed new light on the mechanisms leading to clinically manifest cancers.
Kin relationships in cultural species of the marine realm: case study of a matrilineal social group of sperm whales off Mauritius island, Indian Ocean
Authors: Sarano Francois , Girardet Justine , Sarano Véronique , Vitry Hugues , Preud'homme Axel , Heuzey René , Garcia-Cegarra Ana M. , Madon Bénédicte , Delfour Fabienne , Glotin Hervé , Adam Olivier , Jung Jean-Luc
Published: February 2021

Understanding the organization and dynamics of social groups of marine mammals through the study of kin relationships is particularly challenging.Here, we studied a stable social group of sperm whales off Mauritius, using underwater observations, individual-specific identification, non-invasive sampling and genetic analyses based on mitochondrial sequencing and microsatellite profiling. Twenty-four sperm whales were sampled between 2017 and 2019. All individuals except one adult female shared the same mitochondrial DNA (mtDNA) haplotype—one that is rare in the western Indian Ocean—thus confirming with near certainty the matrilineality of the group. All probable first- and second-degree kin relationships were depicted in the sperm whale social group: 13 first-degree and 27 second-degree relationships were identified. Notably, we highlight the likely case of an unrelated female having been integrated into a social unit, in that she presented a distinct mtDNA haplotype and no close relationships with any members of the group. Investigating the possible matrilineality of sperm whale cultural units (i.e. vocal clans) is the next step in our research programme to elucidate and better apprehend the complex organization of sperm whale social groups.
Onset of energy equipartition among surface and body waves
Authors: Borcea L. , Garnier J. , Sølna K.
Published: February 2021

We derive a radiative transfer equation that accounts for coupling from surface waves to body waves and the other way around. The model is the acoustic wave equation in a two-dimensional waveguide with reflecting boundary. The waveguide has a thin, weakly randomly heterogeneous layer near the top surface, and a thick homogeneous layer beneath it. There are two types of modes that propagate along the axis of the waveguide: those that are almost trapped in the thin layer, and thus model surface waves, and those that penetrate deep in the waveguide, and thus model body waves. The remaining modes are evanescent waves. We introduce a mathematical theory of mode coupling induced by scattering in the thin layer, and derive a radiative transfer equation which quantifies the mean mode power exchange. We study the solution of this equation in the asymptotic limit of infinite width of the waveguide. The main result is a quantification of the rate of convergence of the mean mode powers toward equipartition.
Cell-growth gene expression reveals a direct fitness cost of grazer-induced toxin production in red tide dinoflagellate prey
Authors: Park Gihong , Dam Hans G.
Published: February 2021

Induced prey defences against consumers are conspicuous in microbes, plants and animals. In toxigenic prey, a defence fitness cost should result in a trade-off between defence expression and individual growth. Yet, previous experimental work has failed to detect such induced defence cost in toxigenic phytoplankton. We measured a potential direct fitness cost of grazer-induced toxin production in a red tide dinoflagellate prey using relative gene expression (RGE) of a mitotic cyclin gene (cyc), a marker that correlates to cell growth. This approach disentangles the reduction in cell growth from the defence cost from the mortality by consumers. Treatments where the dinoflagellateAlexandrium catenellawere exposed to copepod grazers significantly increased toxin production while decreasing RGE ofcyc, indicating a defence-growth trade-off. The defence fitness cost represents a mean decrease of the cell growth rate of 32%. Simultaneously, we estimate that the traditional method to measure mortality loss by consumers is overestimated by 29%. The defence appears adaptive as the prey population persists in quasi steady state after the defence is induced. Our approach provides a novel framework to incorporate the fitness cost of defence in toxigenic prey–consumer interaction models.
Sum of fears among intraguild predators drives the survival of green sea turtle (
Chelonia mydas
) eggs
Authors: Liao Chen-Pan , Hsu Jung-Ya , Huang Shi-Ping , Clark Rulon W. , Lin Jhan-Wei , Tseng Hui-Yun , Huang Wen-San
Published: February 2021

Ecologists have long theorized that apex predators stabilize trophic systems by exerting a net protective effect on the basal resource of a food web. Although experimental and observational studies have borne this out, it is not always clear what behavioural mechanisms among the trophically connected species are responsible for this stability. Fear of intraguild predation is commonly identified as one such mechanism in models and mesocosm studies, but empirical evidence in natural systems remains limited, as the complexity of many trophic systems renders detailed behavioural studies of species interactions challenging. Here, we combine long-term field observations of a trophic system in nature with experimental behavioural studies of how all the species in this system interact, in both pairs and groups. The results demonstrate how an abundant, sessile and palatable prey item (sea turtle eggs,
Chelonia mydas
) survives when faced by three potential predators that all readily eat eggs: an apex predator (the stink ratsnake,
Elaphe carinata
) and two mesopredators (the brown rat,
Rattus norvegicus
, and kukri snake,
Oligodon formosanus
). Our results detail how fear of intraguild predation, conspecific cannibalism, habitat structure and territorial behaviour among these species interact in a complex fashion that results in high egg survival.
Cutting across structural and transcriptomic scales translates time across the lifespan in humans and chimpanzees
Authors: Charvet Christine J.
Published: February 2021

How the unique capacities of human cognition arose in evolution is a question of enduring interest. It is still unclear which developmental programmes are responsible for the emergence of the human brain. The inability to determine corresponding ages between humans and apes has hampered progress in detecting developmental programmes leading to the emergence of the human brain. I harness temporal variation in anatomical, behavioural and transcriptional variation to determine corresponding ages from fetal to postnatal development and ageing, between humans and chimpanzees. This multi-dimensional approach results in 137 corresponding time points across the lifespan, from embryonic day 44 to approximately 55 years of age, in humans and their equivalent ages in chimpanzees. I used these data to test whether developmental programmes, such as the timeline of prefrontal cortex (PFC) maturation, previously claimed to differ between humans and chimpanzees, do so once variation in developmental schedules is controlled for. I compared the maturation of frontal cortex projections from structural magnetic resonance (MR) scans and from temporal variation in the expression of genes used to track long-range projecting neurons (i.e. supragranular-enriched genes) in chimpanzees and humans. Contrary to what has been suggested, the timetable of PFC maturation is not unusually extended in humans. This dataset, which is the largest with which to determine corresponding ages across humans and chimpanzees, provides a rigorous approach to control for variation in developmental schedules and to identify developmental programmes responsible for unique features of the human brain.
Comparison of drug-susceptibility patterns and gene sequences associated with clarithromycin and azithromycin resistance in Mycobacterium abscessus complex isolates and evaluation of the accumulation of intrinsic macrolide resistance
Authors: Yoshida Shiomi , Tsuyuguchi Kazunari , Kobayashi Takehiko , Inoue Yoshikazu , Suzuki Katsuhiro
Published: February 2021

Introduction.

Mycobacterium abscessus

complex (MABC) is an infectious agent associated with macrolide resistance and treatment failure.

Hypothesis/Gap Statement. Despite drug-susceptibility testing for MABC isolates including clarithromycin (CAM), long-term treatment with azithromycin (AZM) for MABC disease is recommended.

Aim. We compared phenotypic and genotypic resistance to AZM and CAM in clinical isolates and evaluated the accumulation of intrinsic macrolide resistance (AIM) and morphological changes by macrolides exposure.

Methodology. Forty-nine isolates were characterized regarding erm(41) sequevars. Sequencing data were compared to the nucleotide sequence of rrl and whiB7. The AIM MIC was performed in three reference strains and 15 isolates were randomized [each set of five isolates with

M. abscessus

subsp.

abscessus

(MAA) T28, MAA C28 and subsp. massiliense (MAM)].

Results. The 49 isolates were distributed as 24 MAA T28, 5 MAA C28 and 20 MAM. The MIC50 values to CAM at day 3 in MAA T28, C28 and MAM were 1, 0.12 and 0.12 µg ml−1, while those at day 14 were 32, 0.5 and 0.12 µg ml−1, respectively. The AZM-MIC50 values at day 3 of the above isolates were 4, 0.25 and 0.5 µg ml−1, while those at day 14 were >64, 0.5 and 0.5 µg ml−1, respectively. Neither mutations in rrl of MAA T28 with acquired resistance nor deletions in whiB7 of MAA T28 without inducible resistance were observed . For AIM MIC, MAA T28 showed that the time-to-detection of AZM resistance was significantly faster over that of CAM (P<0.05). Morphological changes were not determined in all isolates.

Conclusion. Our findings did not support the suggestion for the preferential use of AZM for, at least, MAA T28 disease due to the high-level MIC value and the increased AIM. The long duration of AZM-based treatment eventually may favour the emergence of isolates with a high-level of intrinsic resistance.
Soil Microbial Composition and Structure Allow Assessment of Biological Product Effectiveness and Crop Yield Prediction
Authors: Imam Nabeel , Belda Ignacio , Duehl Adrian J. , Doroghazi James R. , Almonacid Daniel E. , Thomas Varghese P. , Acedo Alberto
Published: February 2021

Understanding the effectiveness and potential mechanism of action of agricultural biological products under different soil profiles and crops will allow more precise product recommendations based on local conditions and will ultimately result in increased crop yield. This study aimed to use bulk and rhizosphere soil’s microbial composition and structure to evaluate the effect of aBacillus amyloliquefaciensstrain QST713 inoculant on potatoes, and to explore its relationship with crop yield. We implemented NGS and bioinformatics approaches to assess the bacterial and fungal biodiversity in 185 soil samples, distributed over four different time points -from planting to harvest -from three different geographical regions in the United States.

In addition to variety, phenological stage of the potato plant and geography being important factors defining the microbiome composition and structure, the microbial inoculant applied as a treatment also had a significant effect. However, treatment preserved the native communities without causing a detectable long-lasting effect on the alpha- and beta-diversity patterns after harvest. Specific taxonomic groups, and most interestingly the structure of the fungal and bacterial communities (measured using co-occurrence and co-exclusion networks), changed after inoculation. Additionally, using information about the application of the microbial inoculant and considering microbiome composition and structure data we were able to train a Random Forest model to estimate if a bulk or rhizosphere soil sample came from a low or high yield block with relatively high accuracy, concluding that the structure of fungal communities is a better estimator of potato yield than the structure of bacterial communities.

IMPORTANCE

The manuscript’s results reinforce the notion that each crop variety on each location recruits a unique microbial community and that these communities are modulated by the vegetative growth stage of the plant. Moreover, inoculation of aBacillus amyloliquefaciensstrain QST713-based product on potatoes also changed specific taxonomic groups and, most interestingly, the structure of local fungal and bacterial networks in bulk and rhizosphere soil. The data obtained, coming from in-field assays performed in three different geographical locations, allowed training a predictive model to estimate the yield of a certain block, identifying microbiome variables -especially those related to microbial community structure- with a higher predictive power than the variety and geography of the block. The methods described here can be replicated to fit new models predicting yield in any other crop, and to evaluate the effect of any Ag-input product in the composition and structure of the soil microbiome.
Structural variants in Chinese population and their impact on phenotypes, diseases and population adaptation
Authors: Wu Zhikun , Jiang Zehang , Li Tong , Xie Chuanbo , Zhao Liansheng , Yang Jiaqi , Ouyang Shuai , Liu Yizhi , Li Tao , Xie Zhi
Published: February 2021

A complete characterization of genetic variation is a fundamental goal of human genome research. Long-read sequencing (LRS) improves the sensitivity for structural variant (SV) discovery and facilitates a better understanding of the SV spectrum in human genomes. Here, we conduct the first LRS-based SV analysis in Chinese population. We perform whole-genome LRS for 405 unrelated Chinese, with 68 phenotypic and clinical measurements. We discover a complex landscape of 132,312 non-redundant SVs, of which 53.3% are novel. The identified SVs are of high-quality validated by the PacBio high-fidelity sequencing and PCR experiments. The total length of SVs represents approximately 13.2% of the human reference genome. We annotate 1,929 loss-of-function SVs affecting the coding sequences of 1,681 genes. We discover new associations of SVs with phenotypes and diseases, such as rare deletions inHBA1/HBA2/HBBassociated with anemia and common deletions inGHRassociated with body height. Furthermore, we identify SV candidates related to human immunity that differentiate sub-populations of Chinese. Our study reveals the complex landscape of human SVs in unprecedented detail and provides new insights into their roles contributing to phenotypes, diseases and evolution. The genotypic and phenotypic resource is freely available to the scientific community.
T cell derived HB-EGF prevents Th17 cell differentiation in an autocrine way
Authors: Macdonald Felicity , van Loosdregt Jorg , Zaiss Dietmar M W
Published: February 2021

CD4 T cells critically contribute to host immunity against infections, but can also contribute to the development of autoimmune diseases. The underlying mechanisms that govern differentiation of naïve CD4 T cells into different effector populations remain poorly understood. Here, we show that the expression of the Epidermal Growth Factor (EGF)-like growth factor HB-EGF by CD4 T cells sustained their expression of Interleukin (IL)-2 and reduced their capacity to differentiate into T Helper 17 (Th17) cells. Concordantly, mice with a T cell specific deficiency of HB-EGF showed an enhanced differentiation of naïve CD4 T cells into Th17 cells and a more rapid onset of experimental autoimmune encephalomyelitis (EAE). Furthermore, transfer of naïve HB-EGF-deficient CD4 T cells intoRag1-/-mice led to the rapid induction of multi-organ inflammation in recipient mice. Together, our data reveal a novel mechanism by which an HB-EGF-mediated constrain on Th17 differentiation prevents the development of autoimmune diseases.

CD4 T cell activation induces the expression of the EGFR and its high-affinity ligand HB-EGF. HB-EGF sustains IL-2 expression in an autocrine manner, preventing the differentiation of Th17 cells and the subsequent induction of Th17 cell-mediated autoimmune diseases.
Desert lizard diversity worldwide: effects of environment, time, and evolutionary rate
Authors: Tejero-Cicuéndez Héctor , Tarroso Pedro , Carranza Salvador , Rabosky Daniel
Published: February 2021

Aim

Biodiversity is not uniformly distributed across the Earth’s surface, even among physiographically comparable biomes in different biogeographic regions. For lizards, the world’s large desert regions are characterized by extreme heterogeneity in species richness, spanning some of the most species-rich (arid Australia) and species-poor (central Asia) biomes overall. Regional differences in species diversity may arise as a consequence of the interplay of several factors (e.g., evolutionary time, diversification rate, environment), but their relative importance for biogeographic patterns remains poorly known. Here we use distributional and phylogenetic data to assess the evolutionary and ecological drivers of large-scale variation in desert lizard diversity.

Location

Deserts worldwide.

Major taxa studied

Lizards (non-snake squamates).

Methods

We specifically test whether diversity patterns are best explained by differences in the ages of arid-adapted lineages (evolutionary time hypothesis), by regional variation in speciation rate, by geographic area of the arid systems, and by spatial variation related to environment (climate, topography, and productivity).

Results

We found no effect of recent speciation rate and geographic area on differences in desert lizard diversity. We demonstrate that the extreme species richness of the Australian deserts cannot be explained by greater evolutionary time, because species began accumulating more recently there than in more species-poor arid regions. We found limited support for relationships between regional lizard richness and environmental variables, but these effects were inconsistent across deserts, showing a differential role of the environment in shaping the lizard diversity in different arid regions.

Main conclusions

Our results provide evidence against several classic hypotheses for interregional variation in species richness, but also highlight the complexity of processes underlying vertebrate community richness in the world’s great arid systems.
Fluctuations in TCR and pMHC interactions regulate T cell activation
Authors: Egan Joseph R. , Abu-Shah Enas , Dushek Omer , Elliott Tim , MacArthur Ben D.
Published: February 2021

Adaptive immune responses depend on interactions between T cell receptors (TCRs) and peptide major-histocompatibility complex (pMHC) ligands located on the surface of T cells and antigen presenting cells (APCs) respectively. As TCRs and pMHCs are often only present at low copy-numbers their interactions are inherently stochastic, yet the role of stochastic fluctuations on T cell function is unclear. Here we introduce a minimal stochastic model of T cell activation that accounts for serial TCR-pMHC engagement, reversible TCR conformational change and TCR aggregation. Analysis of this model indicates that it is not the strength of binding between the T cell and the APC cellper sethat elicits an immune response, but rather the information imparted to the T cell from the encounter, as assessed by the entropy rate of the TCR-pMHC binding dynamics. This view provides an information-theoretic interpretation of T cell activation that explains a range of experimental observations. Based on this analysis we propose that effective T cell therapeutics may be enhanced by optimizing the inherent stochasticity of TCR-pMHC binding dynamics.
Emergent Oscillation Induced by Nutrient-Modulating Growth Feedback
Authors: Melendez-Alvarez Juan , He Changhan , Zhang Rong , Kuang Yang , Tian Xiao-Jun
Published: February 2021

Growth feedback, the inherent coupling between the synthetic gene circuit and the host cell growth, could significantly change the circuit behaviors. Previously, a diverse array of emerged behaviors, such as growth bistability, enhanced ultrasensitivity, and topology-dependent memory loss, were reported to be induced by growth feedback. However, the influence of the growth feedback on the circuit functions remains underexplored. Here, we reported an unexpected oscillatory behavior of a self-activation gene circuit induced by nutrient-modulating growth feedback. Specifically, after dilution of the activated self-activation switch into the fresh medium with moderate nutrient, its gene expression first decreases as the cell grows and then shows a significant overshoot before it reaches the steady states, leading to oscillation dynamics. Fitting the data with a coarse-grained model suggests a nonmonotonic growth-rate regulation on gene production rate. The underlying mechanism of the oscillation was demonstrated by a molecular mathematical model, which includes the ribosome allocation towards gene production, cell growth, and cell maintenance. Interestingly, the model predicted a counterintuitive dependence of oscillation amplitude on the nutrition level, where the highest peak was found in the medium with a moderate nutrient but was not observed in rich nutrient. We experimentally verified this prediction by tuning the nutrient level in the culture medium. We did not observe significant oscillatory behavior for toggle switch, suggesting that the emergence of oscillatory behavior depends on circuit network topology. Our results demonstrated a new nonlinear emergent behavior mediated by growth feedback, which depends on the ribosome allocation between gene circuit and cell growth.
Sequence neighborhoods enable reliable prediction of pathogenic mutations in cancer genomes
Authors: Banerjee Shayantan , Raman Karthik , Ravindran Balaraman
Published: February 2021

Identifying cancer-causing mutations from sequenced cancer genomes hold much promise for targeted therapy and precision medicine. “Driver” mutations are primarily responsible for cancer progression, while “passengers” are functionally neutral. Although several computational approaches have been developed for distinguishing between driver and passenger mutations, very few have concentrated on utilizing the raw nucleotide sequences surrounding a particular mutation as potential features for building predictive models. Using experimentally validated cancer mutation data in this study, we explored various string-based feature representation techniques to incorporate information on the neighborhood bases immediately 5’ and 3’ from each mutated position. Density estimation methods showed significant distributional differences between the neighborhood bases surrounding driver and passenger mutations. Binary classification models derived using repeated cross-validation experiments gave comparable performances across all window sizes. Integrating sequence features derived from raw nucleotide sequences with other genomic, structural and evolutionary features resulted in the development of a pan-cancer mutation effect prediction tool, NBDriver, which was highly efficient in identifying pathogenic variants from five independent validation datasets. An ensemble predictor obtained by combining the predictions from NBDriver with two other commonly used driver prediction tools (CONDEL and Mutation Taster) outperformed existing pan-cancer models in prioritizing a literature-curated list of driver and passenger mutations. Using the list of true positive mutation predictions derived from NBDriver, we identified a list of 138 known driver genes with functional evidence from various sources. Overall, our study underscores the efficacy of utilizing raw nucleotide sequences as features to distinguish between driver and passenger mutations from sequenced cancer genomes.
Validating a high-throughput tracking system: ATLAS as a regional-scale alternative to GPS
Authors: Beardsworth Christine E. , Gobbens Evy , van Maarseveen Frank , Denissen Bas , Dekinga Anne , Nathan Ran , Toledo Sivan , Bijleveld Allert I.
Published: February 2021

Fine-scale tracking of animal movement is important to understand the proximate mechanisms of animal behaviour. While GPS tracking is an excellent tool for measuring animal movement, trade-offs between tag weight, cost and lifespan limit its application to relatively large species, a small number of individuals or short tracking durations, respectively. The reverse-GPS system – ATLAS – uses lighter, cheaper tags compared to GPS tags, that can also last long periods of time at high sampling frequencies. Six systems are now operational worldwide and have successfully tracked over 50 species in various landscape types. This growing use of ATLAS to track animal movement motivates further refinement of best-practice application and an assessment of its accuracy.

Here, we test the accuracy and precision of the largest ATLAS system, located in the Dutch Wadden Sea using concurrent GPS measurements as a reference. This large-scale ATLAS system consists of 26 receivers and covers 1326 km2of intertidal region, with almost no physical obstacles for radio signals, providing a useful baseline for other systems. To measure accuracy, we calculated the distance between ATLAS and GPS location estimates for a route (mobile test) and 16 fixed locations (stationary test) on the Griend mudflat.

ATLAS-derived location estimates differed on average 4.2 m from GPS-estimated stationary test sites and 5.7 m from GPS tracks taken whilst moving between them. Signals that were collected by more receiver stations were more accurate, although even 3-receiver localisations were comparable with GPS localisations (∼10 m difference). Higher receiver stations detected the tag at longer distances.

Future ATLAS users should consider the height of receivers, their spatial arrangement, density and the movement mode of the study species (e.g., ground-dwelling or flying). In conclusion, ATLAS provides an accurate, regional-scale alternative to global GPS-based tracking with which hundreds of relatively small-bodied species can be tracked simultaneously for long periods of time. Our study shows that ATLAS is a valid alternative, providing comparable location estimates to GPS.
The seasonal dynamics of bud dormancy in grapevine suggest a regulated checkpoint prior to acclimation
Authors: Velappan Yazhini , Chabikwa Tinashe G , Considine John A , Agudelo-Romero Patricia , Foyer Christine H , Signorelli Santiago , Considine Michael J
Published: February 2021

Grapevine (Vitis viniferaL.) displays wide plasticity to climate and seasonality, ranging from strongly deciduous to evergreen. Understanding the physiology of decisions to grow or quiesce is critical for improved crop management, prediction, and the adaptability of production to alternative climate scenarios. The perenniating bud (N+2) is a major economic unit and focus of study. Here we investigated the physiology and transcriptome of cv. Merlot buds grown in a temperate maritime climate from summer to spring in two consecutive years. The changes in bud respiration, hydration and internal tissue oxygen data were consistent with the transcriptome data. ABA-responsive gene processes prevailed upon the transition to a deep metabolic and cellular quiescence in the bud during autumn. Light, together with hypoxia and redox signalling presided over the resumption of nuclear and cellular growth in the transition to spring. Comparisons with transcriptome data from bud burst studies revealed a number of regulatory candidates for the orderly resumption of growth in spring, including components that may integrate light and temperature signalling. Importantly however, the bud burst forcing data, which is widely used as a measure of bud dormancy, were not consistent with the physiological and transcription data. We hypothesise the existence of a physiological checkpoint following bud set in summer, which if not met results in extreme quiescence. Collectively this is the most integrated developmental dataset of the latent bud of cultivated grapevine, and establishes a platform for systems approaches to study seasonal plasticity.

One sentence summary

Physiology and transcriptome data provide strong evidence of a regulatory checkpoint prior to acclimation and dormancy in latent grapevine buds.
New multiscale characterisation methodology for effective determination of isolation-structure-function relationship of extracellular vesicles
Authors: Phan Thanh Huyen , Divakarla Shiva Kamini , Yeo Jia Hao , Lei Qingyu , Tharkar Priyanka , Pansani Taisa Nogueira , Leslie Kathryn G. , Tong Maggie , Coleman Victoria A. , Jämting Åsa , Du Plessis Mar-Dean , New Elizabeth J. , Kalionis Bill , Demokritou Philip , Woo Hyun-Kyung , Cho Yoon-Kyoung , Chrzanowski Wojciech
Published: February 2021

Extracellular vesicles (EVs) have been lauded as next generation medicines, but very few EV-based therapeutics have progressed to clinical use. Limited clinical translation is largely due to technical barriers that hamper our ability to mass-produce EVs,i.e.to isolate, purify and characterise them effectively. Technical limitations in comprehensive characterisation of EVs leads to unpredicted biological effects of EVs. Here, using a range of optical and non-optical techniques, we showed that the differences in molecular composition of EVs isolated using two isolation methods correlated with the differences in their biological function. Our results demonstrated that the isolation method determines the composition of isolated EVs at single and sub-population levels. Besides the composition, we measured for the first time the dry mass and predicted sedimentation of EVs. These parameters were shown to correlate well with the biological and functional effects of EVs on single cell and cell cultures. We anticipate that our new multiscale characterisation approach, which goes beyond traditional experimental methodology, will support fundamental understanding of EVs as well as elucidate the functional effects of EVs inin vitroandin vivostudies. Our findings and methodology will be pivotal for developing optimal isolation methods and establishing EVs as mainstream therapeutics and diagnostics. This innovative approach is applicable to a wide range of sectors including biopharma and biotechnology as well as to regulatory agencies.
Genome-wide prediction and integrative functional characterization of Alzheimer’s disease-associated genes
Authors: Lin Cui-Xiang , Li Hong-Dong , Deng Chao , Liu Weisheng , Erhardt Shannon , Wu Fang-Xiang , Zhao Xing-Ming , Wang Jun , Wang Daifeng , Hu Bin , Wang Jianxin
Published: February 2021

The mechanism of Alzheimer’s disease (AD) remains elusive, partly due to the incomplete identification of risk genes. We developed an approach to predict AD-associated genes by learning the functional pattern of curated AD-associated genes from brain gene networks. We created a pipeline to evaluate disease-gene association by interrogating heterogeneous biological networks at different molecular levels. Our analysis showed that top-ranked genes were functionally related to AD. We identified gene modules associated with AD pathways, and found that top-ranked genes were correlated with both neuropathological and clinical phenotypes of AD on independent datasets. We also identified potential causal variants for genes such asFYNandPRKAR1Aby integrating brain eQTL and ATAC-seq data. Lastly, we created the ALZLINK web interface, enabling users to exploit the functional relevance of predicted genes to AD. The predictions and pipeline could become a valuable resource to advance the identification of therapeutic targets for AD.
The biogenesis and function of nucleosome arrays
Authors: Singh Ashish Kumar , Schauer Tamás , Pfaller Lena , Straub Tobias , Mueller-Planitz Felix
Published: February 2021

Numerous chromatin remodeling enzymes position nucleosomes in eukaryotic cells. Aside from these factors, transcription, DNA sequence, and statistical positioning of nucleosomes also shapes the nucleosome landscape. Precise contributions of these processes remain unclear due to their functional redundancyin vivo. By incisive genome engineering, we radically decreased their redundancy inSaccharomyces cerevisiae. The transcriptional machinery is strongly disruptive of evenly spaced nucleosomes, and proper nucleosome density and DNA sequence critical for their biogenesis. The INO80 remodeling complex spaces nucleosomesin vivoand positions the first nucleosome over genes in an H2A.Z-independent fashion. INO80 requires its Arp8 subunit but unexpectedly not the Nhp10 module for spacing. Spaced nucleosomes prevent cryptic transcription and protect cells against genotoxic stress such as DNA damage, recombination and transpositions. We derive a unifying model of the biogenesis of the nucleosome landscape and suggest that it evolved not only to regulate but also to protect the genome.
Spinal premotor interneurons controlling antagonistic muscles are spatially intermingled
Authors: Ronzano Remi , Skarlatou Sophie , Barriga Bianca K. , Bannatyne B. Anne , Bhumbra Gardave S. , Foster Joshua D. , Moore Jeffrey D. , Lancelin Camille , Pocratsky Amanda , Özyurt Mustafa Görkem , Smith Calvin C. , Todd Andrew J. , Maxwell David J. , Murray Andrew J. , Pfaff Samuel L. , Brownstone Robert M. , Zampieri Niccolò , Beato Marco
Published: February 2021

Elaborate behaviours are produced by tightly controlled flexor-extensor motor neuron activation patterns. Motor neurons are regulated by a network of interneurons within the spinal cord, but the computational processes involved in motor control are not fully understood. The neuroanatomical arrangement of motor and premotor neurons into topographic patterns related to their controlled muscles is thought to facilitate how information is processed by spinal circuits. Rabies retrograde monosynaptic tracing has been used to label premotor interneurons innervating specific motor neuron pools, with previous studies reporting topographic mediolateral positional biases in flexor and extensor premotor interneurons. To more precisely define how premotor interneurons contacting specific motor pools are organized we used multiple complementary viral-tracing approaches to minimize systematic biases associated with each method. Contrary to expectations, we found that premotor interneurons contacting motor pools controlling flexion and extension of the ankle are highly intermingled rather than segregated into specific domains like motor neurons. Thus, premotor spinal neurons controlling different muscles process motor instructions in the absence of clear spatial patterns among the flexor-extensor circuit components.

The paper can be downloaded in executable format as a MATLAB live script fromhttps://github.com/marcobeato/Spinal_premotor_interneurons_controlling_antagonistic_muscles_are_spatially_intermingled, where all the data are available An R version of the executable paper is available athttps://mybinder.org/v2/gh/rronzano/Spinal_premotor_interneurons_controlling_antagonistic_muscles_are_spatially_intermingled.git/HEAD?urlpath=rstudio