bluuebunny/crossref_metadata_2025 huggingface dataset:
Nucleocapsid vaccine elicits spike-independent SARS-CoV-2 protective immunity
Authors: Matchett William E. , Joag Vineet , Stolley J. Michael , Shepherd Frances K. , Quarnstrom Clare F. , Mickelson Clayton K. , Wijeyesinghe Sathi , Soerens Andrew G. , Becker Samuel , Thiede Joshua M. , Weyu Eyob , O’Flanagan Stephen , Walter Jennifer A. , Vu Michelle N. , Menachery Vineet D. , Bold Tyler D. , Vezys Vaiva , Jenkins Marc K. , Langlois Ryan A. , Masopust David
Published: April 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Neutralizing antibodies target the receptor binding domain of the spike (S) protein, a focus of successful vaccine efforts. Concerns have arisen that S-specific vaccine immunity may fail to neutralize emerging variants. We show that vaccination with HAd5 expressing the nucleocapsid (N) protein can establish protective immunity, defined by reduced weight loss and viral load, in both Syrian hamsters and k18-hACE2 mice. Challenge of vaccinated mice was associated with rapid N-specific T cell recall responses in the respiratory mucosa. This study supports the rationale for including additional viral antigens, even if they are not a target of neutralizing antibodies, to broaden epitope coverage and immune effector mechanisms.
Inositol lipid synthesis is widespread in host-associated Bacteroidetes
Authors: Heaver S. L. , Le H. H. , Tang P. , Baslé A. , Marles-Wright J. , Johnson E. L. , Campopiano D. J. , Ley R. E.
Published: April 2021

Ubiquitous in eukaryotes, inositol lipids have finely tuned roles in cellular signaling and membrane homeostasis. In Bacteria, however, inositol lipid production is rare. Recently, the prominent human gut bacteriumBacteroides thetaiotaomicron(BT) was reported to produce inositol lipids, including inositol sphingolipids, but the pathways remain ambiguous and their prevalence unclear. Here, we investigated the gene cluster responsible for inositol lipid synthesis in BT using a novel strain with inducible control of sphingolipid synthesis. We characterized the biosynthetic pathway frommyo-inositol-phosphate (MIP) synthesis to phosphoinositol-dihydroceramide, including structural and kinetic studies of the enzyme MIP synthase (MIPS). We determined the crystal structure of recombinant BT MIPS with bound NAD cofactor at 2.0 Å resolution, and identified the first reported phosphatase for the conversion of bacterially-derived phosphatidylinositol phosphate (PIP) to phosphatidylinositol (PI). Transcriptomic analysis indicated inositol production is nonessential but its loss alters BT capsule expression. Bioinformatic and lipidomic comparisons of Bacteroidetes species revealed a novel second putative pathway for bacterial PI synthesis without a PIP intermediate. Our results indicate that inositol sphingolipid production, via one of the two pathways, is widespread in host-associated Bacteroidetes, and may be implicated in host interactions both indirectly via the capsule and directly through inositol lipid provisioning.
Genomically mined acoustic reporter genes enable real-timein vivomonitoring of tumors and tumor-homing probiotics
Authors: Hurt Robert C. , Buss Marjorie T. , Duan Mengtong , Wong Katie , You Mei Yi , Sawyer Daniel P. , Swift Margaret B. , Dutka Przemysław , Barturen-Larrea Pierina , Mittelstein David R. , Jin Zhiyang , Abedi Mohamad H. , Farhadi Arash , Deshpande Ramya , Shapiro Mikhail G.
Published: April 2021

A major outstanding challenge in the fields of biological research, synthetic biology and cell-based medicine is visualizing the function of natural and engineered cells noninvasively inside opaque organisms. Ultrasound imaging has the potential to address this challenge as a widely available technique with a tissue penetration of several centimeters and spatial resolution below 100 μm. Recently, the first genetically encoded acoustic reporters were developed based on bacterial gas vesicles to link ultrasound signals to molecular and cellular function. However, the properties of these first-generation acoustic reporter genes (ARGs) resulted in limited sensitivity and specificity for imaging gene expressionin vivo.Here, we describe second-generation ARGs with greatly improved acoustic properties and expression characteristics, identified through a phylogenetic screen of candidate gene clusters from diverse bacteria and archaea. The resulting constructs offer major qualitative and quantitative improvements, including much stronger ultrasound contrast, the ability to produce nonlinear signals distinguishable from background tissue, and stable long-term expression. We demonstrate the capabilities of these next-generation ARGs by imagingin situgene expression in mouse models of breast cancer and tumor-homing therapeutic bacteria, noninvasively revealing the unique spatial distributions of tumor growth and colonization by therapeutic cells in living subjects and providing real-time guidance for interventions such as needle biopsies.
Differentiation of speech-induced artifacts from physiological high gamma activity in intracranial recordings
Authors: Bush Alan , Chrabaszcz Anna , Peterson Victoria , Saravanan Varun , Dastolfo-Hromack Christina , Lipski Witold J. , Richardson R. Mark
Published: April 2021

There is great interest in identifying the neurophysiological underpinnings of speech production. Deep brain stimulation (DBS) surgery is unique in that it allows intracranial recordings from both cortical and subcortical regions in patients who are awake and speaking. The quality of these recordings, however, may be affected to various degrees by mechanical forces resulting from speech itself. Here we describe the presence of speech-induced artifacts in local-field potential (LFP) recordings obtained from mapping electrodes, DBS leads, and cortical electrodes. In addition to expected physiological increases in high gamma (60-200 Hz) activity during speech production, time-frequency analysis in many channels revealed a narrowband gamma component that exhibited a pattern similar to that observed in the speech audio spectrogram. This component was present to different degrees in multiple types of neural recordings. We show that this component tracks the fundamental frequency of the participant’s voice, correlates with the power spectrum of speech and has coherence with the produced speech audio. A vibration sensor attached to the stereotactic frame recorded speech-induced vibrations with the same pattern observed in the LFPs. No corresponding component was identified in any neural channel during the listening epoch of a syllable repetition task. These observations demonstrate how speech-induced vibrations can create artifacts in the primary frequency band of interest. Identifying and accounting for these artifacts is crucial for establishing the validity and reproducibility of speech-related data obtained from intracranial recordings during DBS surgery.
Effect of Disease Causing Missense Mutations on Intrinsically Disordered Regions in Proteins
Authors: Seera Suryanarayana , Nagarajaram H.A.
Published: April 2021

It is well known that disease-causing missense mutations (DCMMs) reduce the structural stability/integrity of the proteins with well-defined 3D structures thereby impacting their molecular functions. However, it is not known in what way DCMMs affect the intrinsically disordered proteins (IDPs) that do not adopt well defined stable 3D structures. In order to investigate how DCMMs may impact intrinsically disordered regions (IDRs) in proteins we undertook Molecular Dynamics (MD) based studies on three different examples of functionally important IDRs with known DCMMs. Our studies revealed that the functional impact of DCMMs is in reducing the conformational heterogeneity of IDRs which is intrinsic and quintessential for their multi-faceted cellular roles. These results are reinforced by energy landscapes of the wildtype and mutant IDRs where the former is characterized by many local minima separated by low barriers whereas the latter are characterized by one global minimum and several local minima separated by high energy barriers. Our MD based studies also indicate that DCMMs stabilize a very few structural possibilities of IDRs either by the newly formed interactions induced by the substituted side chains or by means of restricted or increased flexibilities of the backbone conformations at the mutation sites. Furthermore, the structural possibilities stabilized by DCMMs do not support the native functional roles of the IDRs thereby leading to disease conditions.
Maternal Western-Style Diet Impairs Bone Marrow Development and Drives a Hyperinflammatory Phenotype in Hematopoietic Stem and Progenitor Cells in Fetal Rhesus Macaques
Authors: Sureshchandra Suhas , Chan Chi N. , Robino Jacob J. , Parmelee Lindsay K. , Nash Michael J. , Wesolowski Stephanie R. , Pietras Eric M. , Friedman Jacob E. , Takahashi Diana , Shen Weining , Hennebold Jon D. , Goldman Devorah , Packwood William , Lindner Jonathan R , Roberts Charles T. , Burwitz Benjamin J. , Messaoudi Ilhem , Varlamov Oleg
Published: April 2021

Background

Maternal obesity adversely impacts the in utero metabolic environment and offspring’s health, but its effect on fetal hematopoiesis and immune cell development remains incompletely understood, particularly in models that resemble human development.

Methods

We studied gestational day 130-135 fetuses derived from rhesus macaque dams chronically exposed to a high-fat Western-style diet (WSD) or a low-fat control diet. Fetal immune cell phenotypes and fetal bone marrow architecture and hematopoietic stem and progenitor cell (FBM HSPC) function were examined using bone computed tomography, histology, flow cytometry, single-cell RNA-sequencing, and HSPC transplantation assays.

Findings

Maternal WSD induced premature FBM cavity opening and a codominant increase in the number of FBM adipocytes. Furthermore, a maternal WSD induced a proinflammatory transcriptional response in FBM HSPCs. FBM macrophages from the WSD group exhibited heightened proinflammatory responses to toll-like receptor agonist stimulation. Maternal WSD exposure suppressed the expression of genes required for B-cell development and decreased the frequencies of FBM B-cells. Finally, maternal WSD led to poor engraftment of FBM HSPCs in nonlethally irradiated immunodeficient NOD/SCID/IL2rγ-/-mice.

Interpretations

Maternal WSD impairs FBM development, drives a hyperinflammatory phenotype, and induces functional and differentiation impairment in FBM HSPCs in a translationally relevant nonhuman primate model.

Funding

National Institute of Health

RESEARCH IN CONTEXT

Evidence before this study

Maternal obesity is associated with increased risk of infections and proinflammatory disease in offspring. The translationally-relevant rhesus macaque model was utilized to address the effects of maternal obesogenic diet on fetal hematopoietic and immune cell development.

Added value of this study

We assessed changes in fetal immune cell phenotypes and fetal hematopoietic stem and progenitor cell function using immunohistochemistry, flow cytometry, single-cell RNA sequencing, and transplantation assays. We determined that chronic consumption of a maternal obesogenic diet induced the development of adipogenic and proinflammatory environments in the fetal bone marrow. Additionally, we detected the impairment in B-cell differentiation program in fetal hematopoietic stem and progenitor cells.

Implications of all the available evidence

These data demonstrate that maternal obesogenic diet modulates fetal hematopoietic development and could impact the offspring’s immune system, including proinflammatory phenotype and a decline in B-cell function.
Engagement of the contralateral limb can enhance the facilitation of motor output by loud acoustic stimuli
Authors: McInnes Aaron N. , Nguyen An T. , Carroll Timothy J. , Lipp Ottmar V. , Marinovic Welber
Published: April 2021

When intense sound is presented during light muscle contraction, inhibition of the corticospinal tract is observed. During action preparation, this effect is reversed, with sound resulting in excitation of the corticospinal tract. We investigated how the combined maintenance of a muscle contraction during preparation for a ballistic action impacts the magnitude of the facilitation of motor output by a loud acoustic stimulus (LAS) – a phenomenon known as the StartReact effect. Participants executed ballistic wrist flexion movements and a LAS was presented simultaneously with the imperative signal in a subset of trials. We examined whether the force level or muscle used to maintain a contraction during preparation for the ballistic response impacted reaction time and/or the force of movements triggered by the LAS. These contractions were sustained either ipsilaterally or contralaterally to the ballistic response. The magnitude of facilitation by the LAS was greatest when low force flexion contractions were maintained in the limb contralateral to the ballistic response during preparation. There was little change in facilitation when contractions recruited the contralateral extensor muscle, or when they were sustained in the same limb that executed the ballistic response. We conclude that a larger network of neurons which may be engaged by a contralateral sustained contraction prior to initiation may be recruited by the LAS, further contributing to the motor output of the response. These findings may be particularly applicable in stroke rehabilitation where engagement of the contralesional side may increase the benefits of a LAS to the functional recovery of movement.
Efficiency of neutral honey as a tissue fixative in histopathology
Authors: Alwahaibi Nasar , Al Dhahli Buthaina , Al Issaei Halima , Al Wahaibi Loai , Al Sinawi Shadia
Published: April 2021

In the routine laboratory, 10% neutral buffered formalin (NBF) is the fixative of choice. However, formalin is a human carcinogen. To the best of our knowledge, neutral honey, not natural or artificial honey, has not been tested to fix histological tissues. This study aimed to examine the efficiency of neutral buffered honey and other types of honey fixatives to fix histological tissues. The most two natural common Omani honey were used as fixatives, namely Sumar and date. We tested samples of rat liver, kidney, and stomach. Nine types of fixatives were used. All tissues were treated equally. The evaluation was performed blindly by three senior biomedical scientists who work in a histopathology laboratory. Hematoxylin and eosin showed adequate staining in all groups when compared to 10% NBF. The intensity and specificity of Jones Methenamine silver stain in 10% Sumer and Date honey and 10% alcoholic Sumer honey showed similar findings of 10% NBF. The specificity and intensity of all groups for Periodic acid–Schiff were comparable with 10% neutral buffered formalin accepts for 10% Sumer honey and 10% Alcoholic Date honey. However, all honey groups showed weak staining for the reticulin fibers using Gordon and Sweets method. Vimentin showed comparable findings with 10% NBF as there were no significant differences. The findings of this study are promising. Further in depth research on honey as a possible safe substitute fixative for formalin should be conducted.
Adjuvant and immunomodulatory potential ofin vivoNatural Killer T (NKT) activation by NKTT320
Authors: Bond Nell G. , Fahlberg Marissa , Yu Shan , Rout Namita , Tran Dollnovan , Fitzpatrick-Schmidt Taylor , Sprehe Lesli , Scheef Elizabeth , Mudd Joseph C. , Schaub Robert , Kaur Amitinder
Published: April 2021

Invariant natural killer T-lymphocytes (iNKT) are unique immunomodulatory innate T-cells with an invariant TCRα recognizing glycolipids presented on MHC class-I-like CD1d molecules. Activated iNKT rapidly secrete pro-and anti-inflammatory cytokines, potentiate innate and adaptive immunity, and modulate inflammation. Here, we report the effects ofin vivoiNKT activation by a novel humanized monoclonal antibody, NKTT320, that binds to the invariant region of the iNKT TCR. NKTT320 led to rapid iNKT activation, increased polyfunctionality, and elevation of multiple plasma analytes within 24 hours of administration. Flow cytometry and RNA-Seq confirmed downstream activation of multiple immune subsets, enrichment of JAK/STAT and PI3K/AKT pathway genes, and upregulation of inflammation-modulating genes CMKLR1, ARG2 and NLRP12. NKTT320 also induced iNKT trafficking to adipose tissue and did not cause iNKT anergy. Our data indicate that NKTT320 has a sustained effect onin vivoiNKT activation, potentiation of innate and adaptive immunity, and resolution of inflammation, which supports its future use as an immunotherapeutic and vaccine adjuvant.

iNKTs are known immunomodulatory cells whose activation is a potential target for immunotherapies and use as an adjuvant. Here we report the potential utility ofin vivoiNKT activation using the novel humanized monoclonal antibody NKTT320 for this purpose.
The genomic basis of domestic colonisation and dispersal in Chagas disease vectors
Authors: Hernandez-Castro Luis E , Villacís Anita G , Jacobs Arne , Cheaib Bachar , Day Casey C , Ocaña-Mayorga Sofía , Yumiseva Cesar A , Bacigalupo Antonella , Andersson Björn , Matthews Louise , Landguth Erin L , Costales Jaime A , Llewellyn Martin S , Grijalva Mario J
Published: April 2021

The biology of vector adaptation to the human habitat remains poorly understood for many arthropod-borne diseases but underpins effective and sustainable disease control. We adopted a landscape genomics approach to investigate gene flow, signatures of local adaptation, and drivers of population structure among multiple linked wild and domestic population pairs in Rhodnius ecuadoriensis, an important vector of Chagas Disease. Evidence of high triatomine gene flow (FST) between wild and domestic ecotopes at sites throughout the study area indicate insecticide-based control will be hindered by constant re-infestation of houses. Genome scans revealed genetic loci with strong signal of local adaptation to the domestic setting, which we mapped to annotated regions in the Rhodnius prolixus genome. Our landscape genomic mixed effects models showed Rhodnius ecuadoriensis population structure and connectivity is driven by landscape elevation at a regional scale. Our ecologically- and spatially-explicit vector dispersal model enables targeted vector control and recommends spatially discrete, periodic interventions to local authorities as more efficacious than current, haphazard approaches. In tandem, evidence for parallel genomic adaptation to colonisation of the domestic environment at multiple sites sheds new light on the evolutionary basis of adaptation to the human host in arthropod vectors.
Aerosol Exposure of Cynomolgus Macaques to SARS-CoV-2 Results in More Severe Pathology than Existing Models
Authors: Bixler Sandra L. , Stefan Christopher P. , Jay Alexandra , Rossi Franco , Ricks Keersten M. , Shoemaker Charles J. , Moreau Alicia M. , Zeng Xiankun , Hooper Jay W. , Dyer David , Frick Ondraya , Koehler Jeffrey W. , Kearney Brian , DiPinto Nina , Liu Jun , Tostenson Samantha , Clements Tamara L. , Smith Jeffrey M. , Johnson Joshua A. , Berrier Kerry , Esham Heather , Delp Korey L. , Coyne Susan R. , Bloomfield Holly , Kuehnert Paul , Akers Kristen , Gibson Kathleen , Minogue Timothy D. , Nalca Aysegul , Pitt Margaret L. M.
Published: April 2021

The emergence of SARS-CoV-2 pandemic has highlighted the need for animal models that faithfully recapitulate the salient features of COVID-19 disease in humans; these models are necessary for the rapid down-selection, testing, and evaluation of medical countermeasures. Here we performed a direct comparison of two distinct routes of SARS-CoV-2 exposure, combined intratracheal/intranasal and small particle aerosol, in two nonhuman primate species: rhesus and cynomolgus macaques. While all four experimental groups displayed very few outward clinical signs, evidence of mild to moderate respiratory disease was present on radiographs and at the time of necropsy. Cynomolgus macaques exposed via the aerosol route also developed the most consistent fever responses and had the most severe respiratory disease and pathology. This study demonstrates that while all four models were suitable representations of mild COVID-like illness, aerosol exposure of cynomolgus macaques to SARS-CoV-2 produced the most severe disease, which may provide additional clinical endpoints for evaluating therapeutics and vaccines.
Multidimensional natal isotopic niches reflect migratory patterns in birds
Authors: Franzoi A. , Larsen S. , Franceschi P. , Hobson K.A. , Pedrini P. , Camin F. , Bontempo L.
Published: April 2021

Naturally occurring stable isotope ratios in animal tissues allow estimation of species trophic position and ecological niche. Measuring multiple isotopes of migratory species along flyway bottlenecks offers the opportunity to sample multiple populations and species whose tissues carry information at continental scales.

We measuredδ2H,δ18O,δ13C,δ15N in juvenile feathers of 21 bird species captured at a migratory bottleneck in the Italian Alps.

We examined if trends in individual isotopes reflected known migratory strategies and whether dietary (δ13C-δ15N) and spatially-explicit breeding origin (δ2H-δ18O) niche breadth (NB) differed among long-distance trans-Saharan (TS), short-distance (IP) and irruptive (IR) intra-Palearctic migrants, and whether they correlated with reported populations long-term trends.

In both TS and IP groups, speciesδ2H declined with capture date, indicating that northern populations reached the stopover site later in the season, following a Type-I migration strategy. Values ofδ2H indicated that breeding range of TS migrants extended farther north than IP and IR migrants. The breeding season was longer for IP migrants whoseδ13C andδ15N values declined and increased, respectively, with time of capture.

Average species dietary NB did not differ among migratory groups, but TS migrants displayed wider breeding origin niches, suggesting that long-distant migration is linked to broader ecological niches. Isotope origin NB well reflected species geographic range extent, while dietary NB did not correlate with literature accounts of species’ diet. We found no relationship between species breeding NB and population trends in Europe, implying that conditions in the wintering grounds could be more important for the long-term persistence of species.

We demonstrate that isotopic measurements of passerines migrating through a bottleneck represents a unique opportunity to investigate large-scale life-history phenomena relevant to conservation.
AzuCR RNA modulates carbon metabolism as a dual-function RNA inEscherichia coli
Authors: Raina Medha , Aoyama Jordan J. , Bhatt Shantanu , Paul Brian J. , Storz Gisela
Published: April 2021

Bacteria have evolved small RNAs (sRNAs) to regulate numerous biological processes and stress responses. While sRNAs generally are considered to be “noncoding”, a few have been found to also encode a small protein. Here we describe one such dual-function RNA that modulates carbon utilization inEscherichia coli. The 164 nucleotide RNA was previously shown to encode a 28 amino acid protein (denoted AzuC). We discovered the membrane-associated AzuC protein interacts with GlpD, the aerobic glycerol-3-phosphate dehydrogenase, leading to increased GlpD activity. Overexpression of the RNA encoding AzuC results in a growth defect in glycerol and galactose medium. The defect in galactose medium was still observed for a stop codon mutant derivative, suggesting a potential regulatory role for the RNA. Consistent with this observation, we found thatcadAandgalEare repressed by base pairing with the RNA (denoted AzuCR). Interestingly, translation of AzuC interferes with the observed repression ofcadAandgalEby AzuCR and base pairing interferes with AzuC translation, demonstrating that the translation and base pairing functions compete.
Neonatal neuronal WWOX gene therapy rescuesWwoxnull phenotypes
Authors: Repudi Srinivasarao , Kustanovich Irina , Abu-Swai Sara , Stern Shani , Aqeilan Rami I.
Published: April 2021

WW domain-containing oxidoreductase (WWOX) is an emerging neural gene regulating homeostasis of the central nervous system. Germline biallelic mutations inWWOXcause WWOX-related epileptic encephalopathy (WOREE) syndrome and spinocerebellar ataxia, and autosomal recessive 12 (SCAR12), two devastating neurodevelopmental disorders with highly heterogenous clinical outcomes, the most common being severe epileptic encephalopathy and profound global developmental delay. We recently demonstrated that neuronal ablation of murineWwoxrecapitulates phenotypes ofWwox-null mice leading to intractable epilepsy, hypomyelination and postnatal lethality. Here, we designed and produced an adeno-associated viral vector harboring murineWwoxor humanWWOXcDNA and driven by the human neuronal Synapsin I promoter (AAV-SynI-WWOX). Testing the efficacy of AAV-SynI-WWOX delivery inWwoxnull mice demonstrated that specific neuronal restoration of WWOX expression rescued brain hyperexcitability and seizures, hypoglycemia, and myelination deficits as well as the premature lethality ofWwox-null mice. These findings provide a proof-of-concept forWWOXgene therapy as a promising approach to curing children with WOREE and SCAR12.
OCT4 interprets and enhances nucleosome flexibility
Authors: MacCarthy Caitlin M. , Huertas Jan , Ortmeier Claudia , vom Bruch Hermann , Reinke Deike , Sander Astrid , Bergbrede Tim , Schöler Hans R. , Cojocaru Vlad
Published: April 2021

Pioneer transcription factors are proteins that induce cellular identity transitions by binding to inaccessible regions of DNA in nuclear chromatin. They contribute to chromatin opening and recruit other factors to regulatory DNA elements. The structural features and dynamics modulating their interaction with nucleosomes are still unresolved. From a combination of experiments and molecular simulations, we reveal here how the pioneer factor and master regulator of pluripotency, Oct4, interprets and enhances nucleosome structural flexibility. The magnitude of Oct4’s impact on nucleosome dynamics depends on the binding site position and the mobility of the unstructured tails of nucleosomal histone proteins. Oct4 propagates and stabilizes open nucleosome conformations by specific sequence recognition and nonspecific DNA exploration. Our findings provide a structural basis for the versatility of transcription factors in engaging with nucleosomes and have implications for understanding how pioneer factors induce chromatin dynamics.
H2A ubiquitination is essential for Polycomb Repressive Complex 1-mediated gene regulation in Marchantia polymorpha
Authors: Liu Shujing , Trejo-Arellano Minerva S. , Qiu Yichun , Eklund D. Magnus , Köhler Claudia , Hennig Lars
Published: April 2021

Polycomb repressive complex 1 (PRC1) and PRC2 are chromatin regulators maintaining transcriptional repression. The deposition of H3 lysine 27 tri-methylation (H3K27me3) by PRC2 is known to be required for transcriptional repression, whereas the contribution of H2A ubiquitination (H2Aub) in the Polycomb repressive system remains unclear in plants. We directly tested the requirement of H2Aub for gene regulation in Marchantia polymorpha by generating point mutations in H2A that prevent ubiquitination by PRC1. These mutants show reduced H3K27me3 levels on the same target sites as mutants defective in PRC1 subunits MpBMI1 and the homolog MpBMI1L, revealing that PRC1-catalyzed H2Aub is essential for Polycomb system function. Furthermore, by comparing transcriptome data between mutants in MpH2A and MpBMI1/1L, we demonstrate that H2Aub contributes to the PRC1-mediated transcriptional level of genes and transposable elements. Together, our data demonstrate that H2Aub plays a direct role in H3K27me3 deposition and is required for PRC1-mediated transcriptional changes in both genic and intergenic regions in Marchantia.
A positive correlation between GC content and growth temperature in prokaryotes
Authors: Hu En-Ze , Lan Xin-Ran , Liu Zhi-Ling , Gao Jie , Niu Deng-Ke
Published: April 2021

Background

GC pairs are generally more stable than AT pairs; GC-rich genomes were proposed to be more adapted to high temperatures than AT-rich genomes. Previous studies consistently showed positive correlations between growth temperature and the GC contents of structural RNA genes. However, for the whole genome sequences and the silent sites of the codons in protein-coding genes, the relationship between GC content and growth temperature is in a long-lasting debate.

Results

With a dataset much larger than previous studies (681 bacteria and 155 archaea with completely assembled genomes), our phylogenetic comparative analyses showed positive correlations between optimal growth temperature (Topt) and GC content both in bacterial and archaeal structural RNA genes and in bacterial whole genome sequences, chromosomal sequences, plasmid sequences, core genes, and accessory genes. However, in the 155 archaea, we did not observe a significant positive correlation of Topt with whole-genome GC content (GCw) or GC content at four-fold degenerate sites. We randomly drew 155 samples from the 681 bacteria for 1000 rounds. In most cases (> 95%), the positive correlations between Topt and genomic GC contents became statistically nonsignificant (P > 0.05). This result suggested that the small sample sizes might account for the lack of positive correlations between growth temperature and genomic GC content in the 155 archaea and the bacterial samples of previous studies. Comparing the GC content among four categories (psychrophiles/psychrotrophiles, mesophiles, thermophiles, and hyperthermophiles) also revealed a positive correlation between GCw and growth temperature in bacteria. By including the GCw of incompletely assembled genomes, we expanded the sample size of archaea to 303. Positive correlations between GCw and Topt appear especially after excluding the halophilic archaea whose GC contents might be are strongly shaped by intense UV radiation.

Conclusions

This study explains the previous contradictory observations and ends a long debate. Prokaryotes growing in high temperatures have higher GC contents. Thermal adaptation is one possible explanation for the positive association. Meanwhile, we propose that the elevated efficiency of DNA repair in response to heat mutagenesis might have the by-product of increasing GC content like that happens in intracellular symbionts and marine bacterioplankton.
Influenca: a gamified assessment of value-based decision-making for longitudinal studies
Authors: Neuser Monja P. , Kräutlein Franziska , Kühnel Anne , Teckentrup Vanessa , Svaldi Jennifer , Kroemer Nils B.
Published: April 2021

Reinforcement learning is a core facet of motivation and alterations have been associated with various mental disorders. To build better models of individual learning, repeated measurement of value-based decision-making is crucial. However, the focus on lab-based assessment of reward learning has limited the number of measurements and the test-retest reliability of many decision-related parameters is therefore unknown. Here, we developed an open-source cross-platform applicationInfluencathat provides a novel reward learning task complemented by ecological momentary assessment (EMA) for repeated assessment over weeks. In this task, players have to identify the most effective medication by selecting the best option after integrating offered points with changing probabilities (according to random Gaussian walks). Participants can complete up to 31 levels with 150 trials each. To encourage replay on their preferred device, in-game screens provide feedback on the progress. Using an initial validation sample of 127 players (2904 runs), we found that reinforcement learning parameters such as the learning rate and reward sensitivity show low to medium intra-class correlations (ICC: 0.22-0.52), indicating substantial within- and between-subject variance. Notably, state items showed comparable ICCs as reinforcement learning parameters. To conclude, our innovative and openly customizable app framework provides a gamified task that optimizes repeated assessments of reward learning to better quantify intra- and inter-individual differences in value-based decision-making over time.
Activation of proneuronal transcription factorAscl1in maternal liver ensures a healthy pregnancy
Authors: Lee Joonyong , Garcia Veronica , Nambiar Shashank M. , Jiang Huaizhou , Dai Guoli
Published: April 2021

Background & Aims

Maternal liver exhibits robust adaptations to pregnancy to accommodate the metabolic needs of developing and growing placenta and fetus by largely unknown mechanisms. We found that achaete-scute homolog-like 1 (Ascl1), a basic helix-loop-helix transcription factor essential for neuronal development, is highly activated in maternal hepatocytes during the second half of gestation in mice.

Methods

To investigate whether and howAscl1plays a pregnancy-dependent role, we deleted theAscl1gene specifically in maternal hepatocytes from mid-gestation until term.

Results

As a result, we identified multipleAscl1-dependent phenotypes. Maternal livers lackingAscl1exhibited aberrant hepatocyte structure, increased hepatocyte proliferation, enlarged hepatocyte size, reduced albumin production, and elevated release of liver enzymes, indicating maternal liver dysfunction. Simultaneously, maternal pancreas and spleen and the placenta displayed marked overgrowth; and the maternal ceca microbiome showed alterations in relative abundance of several bacterial subpopulations. Moreover, litters born from maternal hepaticAscl1-deficient dams experienced abnormal postnatal growth after weaning, implying an adverse pregnancy outcome. Mechanistically, we found that maternal hepatocytes deficient forAscl1exhibited robust activation ofinsulin-like growth factor 2expression, which may contribute to theAscl1-dependent phenotypes widespread in maternal and uteroplacental compartments.

Conclusion

In summary, we demonstrate that maternal liver, via activatingAscl1expression, modulates the adaptations of maternal organs and the growth of the placenta to maintain a healthy pregnancy. Our studies revealAscl1as a novel and critical regulator of the physiology of pregnancy.

Synopsis

How the maternal liver adapts to pregnancy remains elusive. We found that maternal liver activates the expression ofAscl1, a gene encoding a proneuronal transcription factor, to coordinate the adaptations of maternal organs and the growth of the placenta, enabling a healthy pregnancy and normal postnatal growth of the offspring.

Graphical Abstract
A synthetic protein as efficient multitarget regulator against complement over-activation
Authors: Ruiz-Molina Natalia , Parsons Juliana , Müller Madeleine , Hoernstein Sebastian N.W , Bohlender Lennard L. , Pumple Steffen , Zipfel Peter F. , Häffner Karsten , Reski Ralf , Decker Eva L.
Published: April 2021

The complement system constitutes the innate defense against pathogens. Its dysregulation leads to diseases and is a critical determinant in many viral infections, e.g.COVID-19. Factor H (FH) is the main regulator of the alternative pathway of complement activation and could be a therapy to restore homeostasis. However, recombinant FH is not available. Engineered FH versions may present alternative therapeutics. Here, we designed a synthetic protein, MFHR13, as a multitarget complement regulator. It combines the dimerization and C5-regulatory domains of human FH-related protein 1 (FHR1) with the C3-regulatory and cell surface recognition domains of human FH. MFHR13 includes the FH variant I62, which we characterized to induce improved C3b binding and cofactor activity compared to the variant V62. After comparative protein structure modelling, we introduced the SCR FH13, which includes anN-glycosylation site for higher protein stability. In summary, the fusion protein MFHR13 comprises SCRs FHR11-2:FH1-4:FH13:FH19-20. It shows an enhanced heparin binding and protects sheep erythrocytes from complement attack exhibiting 26 and 4-fold the regulatory activity of eculizumab and human FH, respectively. Furthermore, it also blocks the terminal pathway of complement activation and we demonstrate that MFHR13 and FHR1 bind to all proteins forming the membrane attack complex, which contributes to the mechanistic understanding of FHR1. We consider MFHR13 a promising candidate as a therapeutic for complement-associated diseases.
Genetic resistance to stripe rust infection of the wheat ear is controlled by genes controlling foliar resistance and flowering time
Authors: Bouvet Laura , Percival-Alwyn Lawrence , Berry Simon , Fenwick Paul , Holdgate Sarah , Mackay Ian J. , Cockram James
Published: April 2021

Yellow rust (YR), or stripe rust, is a fungal infection of wheat (Triticum aestivumL.) caused by the pathogenPuccinia striiformisWestend f. sp.tritici(Pst). While much research has focused on YR infection of wheat leaves, we are not aware of reports investigating the genetic control of YR resistance in other wheat structures, such as the ears. Here we use an eight-founder population to undertake genetic analysis of glume YR infection in wheat ears. Five quantitative trait loci (QTL) were identified, each explaining between ~3-7% of the phenotypic variation. Of these, three (QYrg.niab-2D.2, QYrg.niab-4D.1andQYrg.niab-5A.1) co-located with QTL for leaf YR resistance previously identified in the same population, with evidence suggestingQYrg.niab-5A.1may correspond to the adult plant resistance locusYr34which originates fromT. monococcumssp.monococcumand that resistance atQYrg.niab-2D.2may be conferred by chromosomal introgression from a wheat relative. Additional leaf YR resistance QTL previously identified in the population were not detected as controlling glume resistance, with the remaining two glume YR QTL linked to genetic loci controlling flowering time. The first of these,QYrg.niab-2D.1, mapped to the major flowering time locusPhotoperiod-D1(Ppd-D1), with the early-flowering allele from the MAGIC founder Soissons conferring reduced glume YR resistance. The second,QYrg.niab-4A.1, was identified in one trial only, and was located close to a flowering time QTL. This indicates earlier flowering results in increased glume YR susceptibility, likely due to exposure of tissues during environmental conditions more favourable forPstinfection. Collectively, our results provide first insights into the genetic control of YR resistance in glumes, controlled by subsets of QTL for leaf YR resistance and flowering time. This work provides specific genetic targets for the control of YR resistance in both the leaves and the glumes, and may be especially relevant inPst-proneagricultural environments where earlier flowering is favoured.

Core ideas

Puccinia striiformisWestend f. sp.tritici(Pst) causes yellow rust (YR) in wheat leaves and ears.

We present the first reports for the genetic control of YR on the wheat ear.

Ear YR infection is controlled by subsets of QTL controlling leaf resistance and flowering time.

The findings are relevant to wheat breeding forPst-prone environments.
A broadly neutralizing antibody protects against SARS-CoV, pre-emergent bat CoVs, and SARS-CoV-2 variants in mice
Authors: Martinez David R. , Schaefer Alexandra , Gobeil Sophie , Li Dapeng , De la Cruz Gabriela , Parks Robert , Lu Xiaozhi , Barr Maggie , Manne Kartik , Mansouri Katayoun , Edwards Robert J. , Yount Boyd , Anasti Kara , Montgomery Stephanie A. , Shen Shaunna , Zhou Tongqing , Kwong Peter D. , Graham Barney S. , Mascola John R. , Montefiori David. C. , Alam Munir , Sempowski Gregory D. , Wiehe Kevin , Saunders Kevin O. , Acharya Priyamvada , Haynes Barton F. , Baric Ralph S.
Published: April 2021

SARS-CoV in 2003, SARS-CoV-2 in 2019, and SARS-CoV-2 variants of concern (VOC) can cause deadly infections, underlining the importance of developing broadly effective countermeasures against Group 2B Sarbecoviruses, which could be key in the rapid prevention and mitigation of future zoonotic events. Here, we demonstrate the neutralization of SARS-CoV, bat CoVs WIV-1 and RsSHC014, and SARS-CoV-2 variants D614G, B.1.1.7, B.1.429, B1.351 by a receptor-binding domain (RBD)-specific antibody DH1047. Prophylactic and therapeutic treatment with DH1047 demonstrated protection against SARS-CoV, WIV-1, RsSHC014, and SARS-CoV-2 B1.351infection in mice. Binding and structural analysis showed high affinity binding of DH1047 to an epitope that is highly conserved among Sarbecoviruses. We conclude that DH1047 is a broadly neutralizing and protective antibody that can prevent infection and mitigate outbreaks caused by SARS-like strains and SARS-CoV-2 variants. Our results argue that the RBD conserved epitope bound by DH1047 is a rational target for pan Group 2B coronavirus vaccines.
Vivarium: an Interface and Engine for Integrative Multiscale Modeling in Computational Biology
Authors: Agmon Eran , Spangler Ryan K. , Skalnik Christopher J. , Poole William , Peirce Shayn M. , Morrison Jerry H. , Covert Markus W.
Published: April 2021

Abstract

Motivation

This paper introduces Vivarium – software born of the idea that it should be as easy as possible for computational biologists to define any imaginable mechanistic model, combine it with existing models, and execute them together as an integrated multiscale model. Integrative multiscale modeling confronts the complexity of biology by combining heterogeneous datasets and diverse modeling strategies into unified representations. These integrated models are then run to simulate how the hypothesized mechanisms operate as a whole. But building such models has been a labor-intensive process that requires many contributors, and they are still primarily developed on a case-by-case basis with each project starting anew. New software tools that streamline the integrative modeling effort and facilitate collaboration are therefore essential for future computational biologists.

Results

Vivarium is a Pythonic software for building integrative multiscale models. It provides an interface that makes individual models into modules that can be wired together in large composite models, parallelized across multiple CPUs, and run with Vivarium’s simulation engine. Vivarium’s utility is demonstrated by building composite models that combine several modeling frameworks: agent based models, ordinary differential equations, stochastic reaction systems, constraint-based models, solid-body physics, and spatial diffusion. This demonstrates just the beginning of what is possible – future efforts can integrate many more types of models and at many more biological scales.

Availability

The models, simulation pipelines, and notebooks developed for this paper are available at the vivarium-notebooks repository:https://github.com/vivarium-collective/vivarium-notebooks. Vivarium-core is available athttps://github.com/vivarium-collective/vivarium-core, and has been released on PyPI. The Vivarium Collective (https://vivarium-collective.github.io) is a repository of freely-available Vivarium processes and composites, including the processes used in Section 3. Supplementary materials provide with an extensive methodology section, with several code listings that demonstrate the basic interfaces.
Enhanced lipogenesis through Pparγ helps cavefish adapt to food scarcity
Authors: Xiong Shaolei , Wang Wei , Kenzior Alexander , Olsen Luke , Krishnan Jaya , Persons Jenna , Medley Kyle , Peuß Robert , Wang Yongfu , Chen Shiyuan , Zhang Ning , Thomas Nancy , Miles John M. , Sánchez Alvarado Alejandro , Rohner Nicolas
Published: April 2021

Nutrient availability varies seasonally and spatially in the wild. The resulting nutrient limitation or restricted access to nutrients pose a major challenge for every organism. While many animals, such as hibernating animals, evolved strategies to overcome periods of nutrient scarcity, the cellular mechanisms of these strategies are poorly understood. Cave environments represent an extreme example of nutrient deprived environments since the lack of sunlight and therefore primary energy production drastically diminishes the nutrient availability. Here, we usedAstyanax mexicanus, which includes river-dwelling surface fish and cave adapted cavefish populations to study the genetic adaptation to nutrient limitations. We show that cavefish populations store large amounts of fat in different body regions when fed ad libitum in the lab. We found higher expression of lipogenesis genes in cavefish livers when fed the same amount of food as surface fish, suggesting an improved ability of cavefish to use lipogenesis to convert available energy into triglycerides for storage into adipose tissue. Moreover, the lipid metabolism regulator, Peroxisome proliferator-activated receptor γ (Pparγ), is upregulated at both transcript and protein levels in cavefish livers. Chromatin Immunoprecipitation sequencing (ChIP seq) showed that Pparγ binds cavefish promoter regions of genes to a higher extent than surface fish. Finally, we identified two possible regulatory mechanisms of Pparγ in cavefish: higher amounts of ligands of the nuclear receptor, and nonsense mutations inper2, a known repressor of Pparγ. Taken together, our study reveals that upregulated Pparγ promotes higher levels of lipogenesis in the liver and contributes to higher body fat accumulation in cavefish populations, an important adaptation to nutrient limited environments.
Liver Endothelium Promotes HER3-mediated Cell Survival inKRASWild-type and Mutant Colorectal Cancer Cells
Authors: Rathore Moeez , Wright Michel’le , Bhattacharya Rajat , Fan Fan , Vaziri-Gohar Ali , Winter Jordan , Wang Zhenghe , Markowitz Sanford D , Willis Joseph , Ellis Lee M. , Wang Rui
Published: April 2021

We previously showed that liver endothelial cells (ECs) secreted soluble factors in a paracrine fashion and activated human epidermal growth factor receptor 3 (HER3, also known as ERBB3) for promoting colorectal cancer (CRC) growth and chemoresistance. However, RAS proteins play a critical role in receptor tyrosine kinase signaling pathways, andKRASmutations mediate CRC resistance to therapies targeting EGFR, another HER protein. Therefore, the role ofKRASmutation status in EC-induced HER3 activation and CRC survival was investigated as it has therapeutic implications. We used CRC cell lines and patient-derived xenografts harboringKRASwild-type or mutant genes and demonstrated that liver EC-secreted factors promoted HER3-mediated CRC cell growth independent ofKRASmutation status. Also, blocking HER3 in CRC cells by siRNAs or a HER3 antibody seribantumab blocked EC-induced CRC survival. Our findings highlight the potential of utilizing HER3 targeted therapies for treating patients with mCRC independent ofRASmutational status.