bluuebunny/crossref_metadata_2025 huggingface dataset:
Disturbed trophoblast transition links preeclampsia progression from placenta to the maternal syndrome
Authors: Nonn Olivia , Debnath Olivia , Valdes Daniela S. , Sallinger Katja , Secener Ali Kerim , Haider Sandra , Fischer Cornelius , Tiesmeyer Sebastian , Nimo Jose , Kuenzer Thomas , Maxian Theresa , Knöfler Martin , Karau Philipp , Bartolomaeus Hendrik , Kroneis Thomas , Frolova Alina , Neuper Lena , Haase Nadine , Kräker Kristin , Kedziora Sarah , Forstner Désirée , Verlohren Stefan , Stern Christina , Coscia Fabian , Sugulle Meryam , Jones Stuart , Tilaganathan Basky , Eils Roland , Huppertz Berthold , El-Heliebi Amin , Staff Anne Cathrine , Müller Dominik N. , Dechend Ralf , Gauster Martin , Ishaque Naveed , Herse Florian
Published: October 2022

Pre-eclampsia (PE) is a syndrome that affects multiple organ systems and is the most severe hypertensive disorder in pregnancy. It frequently leads to preterm delivery, maternal and fetal morbidity and mortality and life-long complications1. We currently lack efficient screening tools2, 3and early therapies4, 5to address PE. To investigate the early stages of early onset PE, and identify candidate markers and pathways, we performed spatio-temporal multi-omics profiling of human PE placentae and healthy controls and validated targets in early gestation in a longitudinal clinical cohort. We used a single-nuclei RNA-seq approach combined with spatial proteo- and transcriptomics and mechanisticin vitrosignalling analyses to bridge the gap from late pregnancy disease to early pregnancy pathomechanisms. We discovered a key disruption in villous trophoblast differentiation, which is driven by the increase of transcriptional coactivator p300, that ultimately ends with a senescence-associated secretory phenotype (SASP) of trophoblasts. We found a significant increase in the senescence marker activin A in preeclamptic maternal serum in early gestation, before the development of clinical symptoms, indicating a translation of the placental syndrome to the maternal side. Our work describes a new disease progression, starting with a disturbed transition in villous trophoblast differentiation. Our study identifies potential pathophysiology-relevant biomarkers for the early diagnosis of the disease as well as possible targets for interventions, which would be crucial steps toward protecting the mother and child from gestational mortality and morbidity and an increased risk of cardiovascular disease later in life.
Molecular Recognition of Itching Neuropeptides by Bombesin Receptors
Authors: Li Changyao , Xu Youwei , Liu Heng , Cai Hongmin , Jiang Yi , Xu H. Eric , Yin Wanchao
Published: October 2022

Neuromedin B (NMB) and gastrin-releasing peptide (GRP), two bombesin analogs, are endogenous itch-specific neuropeptides that induce histaminergic and nonhistaminergic itch, respectively. Their functions are mediated by two G protein-coupled bombesin receptors, NMBR and GRPR. Here we present cryo-electron microscopy(cryo-EM) structures of G protein coupled NMBR and GRPR bound to NMB and GRP, respectively. The structures reveal that both bombesin receptors contain an extended and deep pocket to adopt NMB and GRP, with the conserved C-terminal motif of GH(F/L)M from both peptides to contact the toggle switch residues for the receptor activation. Together with mutational and functional data, our structures reveal the mechanism of ligand selectivity and specific activation of the bombesin receptors. These findings also pave the way to facilitate rational design of therapies targeting bombesin receptors for the treatment of pruritus.
Sex differences in social synchronization of conditioned fear
Authors: Ito Wataru , Morozov Alexei
Published: October 2022

Socially coordinated threat responses support the survival of social groups, and the distinct social roles of males and females predict sex differences in such coordination. However, this study area remains unexplored in mice, the most commonly used laboratory species. Here, we examined two behaviors: a recently reported ‘fear synchrony,’ where paired mice synchronize auditory-conditioned freezing more strongly in males, and a newly identified ‘CS-induced affiliation,’ where mice increase proximity upon a conditioned stimulus. These behaviors necessitate the integration of social cues with emotional CS. To understand how sex influences that process, we manipulated social cues through partner familiarity and emotional states via prior stress. Unfamiliarity moderately reduced synchrony in male dyads but not in females. Whereas stress disrupted male synchrony and contrarily enhanced female synchrony. Unfamiliarity eliminated CS-induced affiliation in both sexes, while stress caused males to distance each other but had no effects in females. Interestingly, heterosexual dyads showed resilience in both coordinated behaviors unaffected by stress or unfamiliarity. These findings reveal sex-specific adaptations in socio-emotional integration when orchestrating socially coordinated behaviors and suggest that the sex-recognition circuits confer stress- and unfamiliarity-resilience, in particular, in heterosexual dyads.
The enzymatic and neurochemical outcomes of a mutation in Mexican cavefish MAO reveal teleost-specific aspects of brain monoamine homeostasis
Authors: Pierre Constance , Callebert Jacques , Launay Jean-Marie , Rétaux Sylvie
Published: October 2022

Monoamine oxidases (MAO; MAO-A and MAO-B in mammals) are enzymes catalyzing the degradation of biogenic amines, including monoamine neurotransmitters. In humans, coding mutations in MAOs are extremely rare and deleterious. Here, we assessed the structural and biochemical consequences of a point mutation (P106L) in the singlemaogene of the blind cavefishAstyanax mexicanus. This mutation decreased mao enzymatic activity by ~3-fold, probably as a result of decreased flexibility in one of the three loops forming the entrance of the active site, thus reducing the access of substrates. HPLC measurements in brains of mutant and non-mutant larvae and adults of the cave and surface morphs of the species showed major disturbances in serotonin, dopamine and noradrenalin (and metabolites) contents in mutants, demonstrating that the P106Lmaomutation is fully responsible for monoaminergic disequilibrium in the P106Lmaomutant cavefish brain. The outcomes of the mutation were different in the posterior brain (containing the raphe nucleus) and the anterior brain (containing fish-specific hypothalamic serotonergic clusters), revealing contrasting properties in neurotransmitter homeostasis in these different neuronal groups. We also discovered that the effects of the mutation were partially compensated by a decrease in activity of the tph, the serotonin biosynthesis rate-limiting enzyme. Finally, the neurochemical outcomes of themaoP106L mutation differed in many respects from a treatment with deprenyl, an irreversible MAO inhibitor, showing that genetic and pharmacological interference with MAO function are not the same. Our results shade light on our understanding of cavefish evolution, on the specificities of fish monoaminergic systems, and on MAO-dependent homeostasis of brain neurochemistry in general.
Potassium homeostasis and signaling as a determinant ofEchinaceaspecies tolerance to salinity stress
Authors: Ahmadi Fatemeh , Samadi Abbas , Sepehr Ebrahim , Rahimi Amir , Shabala Sergey
Published: October 2022

Salt tolerant is strongly related to potassium (K+) retention in plant tissues under salt stress conditions. However, it is unclear for differentEchinaceaspecies. So, mechanistic basis of fourEchinaceaspecies (i.e.Echinacea purpurea, Echinacea angustifolia, Echinacea pallida, andEchinacea sanguinea) to salinity stress tolerance, and K+retention were assessed in the present study. Non-invasive microelectrode ion flux measuring, DHAR and MDHAR activities, and pharmacological measurements were performed based on the standard methods. Ion flux measurements revealed higher K+efflux inE. pallidaandE. sanguineaspecies compared to theE. purpureaandE. angustifoliaspecies in the elongation zone. Higher salinity-induced H+efflux was found in the elongation zone than mature zone. However,E. angustifoliaandE. purpureahad more Ca2+influx compared toE. pallidaandE. sanguineaspecies. Net K+efflux decreased (> 90%) in the presence of TEA and GdCl3. Increasing of Ca2+uptake and K+loss in fourEchinaceaspecies roots were found in the presence of 0.3 mM Cu/Ascorbate (Cu/Asc). The significant role of H+-ATPase in H+efflux was demonstrated by Sodium orthovanadate. Ultimately, the physiological properties ofEchinaceaspecies have a critical role in salinity-resistant/sensitive differences. Future scientific understanding ofEchinaceaspecies physiognomies may be necessary for better understanding of the plant behavior to salinity stress.

One-sentence summary

Higher K+efflux inE. pallidaandE. sanguineaspecies as a result of NaCl and ROS act as a metabolic switch to save energy for adaptations and repairs in salinity stress conditions.
Novel Pore Size-Controlled, Susceptibility Matched, 3D-Printed MRI Phantoms
Authors: Witherspoon Velencia J. , Komlosh Michal E , Benjamini Dan , Özarslan Evren , Lavrik Nickolay , Basser Peter J.
Published: October 2022

Diffusion magnetic resonance imaging (dMRI) methods are commonly employed to infer changes in tissue microstructure. Quantities like the apparent diffusion coefficient (mADC), and the fractional anisotropy (FA), derived from diffusion tensor imaging (DTI) data, characterize voxel-averaged diffusion properties, whereas double pulse field gradient (dPFG) or double diffusion encoded (DDE) MR methods can be used to characterize heterogeneous diffusion processes occurring within the voxel. Owing to its unique modular design, our novel 3D-printed dMRI phantom exhibits both macroscopic and microscopic anisotropy and can serve to calibrate measures of them. Our phantom susceptibility is close to that of water’s, enabling fast diffusion weighted echo-planar image (DW-EPI) acquisitions to be used to scan it. 3D printed microstructures offer a new medium with which to vet and validate theoretical models of diffusion and pipelines used to estimate it.

Highlights

Research highlight 1: We report the design concept and fabrication of dimensionally stable, uniformly oriented blocks or modules that can be assembled into large-scale MRI phantoms. Waffle-like structures containing blocks of aligned microcapillaries can be stacked into even larger arrays to construct diameter distribution phantoms, or fractured, to create a “powder-averaged” emulsion of randomly oriented blocks.

Research highlight 2: This phantom can be used to vet and calibrate various MRI methods, such as DTI, AxCaliber MRI, MAP-MRI, and various multiple pulsed field gradient (PFG) or multiple diffusion-encoded microstructure imaging methods.

Graphical Abstract
On the causes, consequences, and avoidance of PCR duplicates: towards a theory of library complexity
Authors: Rochette Nicolas C. , Rivera-Colón Angel G. , Walsh Jessica , Sanger Thomas J. , Campbell-Staton Shane C. , Catchen Julian M.
Published: October 2022

Abstract

Library preparation protocols for most sequencing technologies involve PCR amplification of the template DNA, which open the possibility that a given template DNA molecule is sequenced multiple times. Reads arising from this phenomenon, known as PCR duplicates, inflate the cost of sequencing and can jeopardize the reliability of affected experiments. Despite the pervasiveness of this artifact, our understanding of its causes and of its impact on downstream statistical analyses remains essentially empirical. Here, we develop a general quantitative model of amplification distortions in sequencing datasets, which we leverage to investigate the factors controlling the occurrence of PCR duplicates. We show that the PCR duplicate rate is determined by the ratio between library complexity and sequencing depth, and that amplification noise (including in its dependence on the number of PCR cycles) only plays a minor role for this artifact. We confirm our predictions using new and published RAD-seq libraries and provide a method to estimate library complexity and amplification noise in any dataset containing PCR duplicates. We discuss how amplification-related artifacts impact downstream analyses, and in particular genotyping accuracy. The proposed framework unites the numerous observations made on PCR duplicates and will be useful to experimenters of all sequencing technologies where DNA availability is a concern.
Deodorize with Bugs: Inoculation with black soldier fly larvae alters the microbiome and volatile organic compound profile of decomposing food waste
Authors: Michishita Rena , Shimoda Masami , Furukawa Seiichi , Uehara Takuya
Published: October 2022

The black soldier fly (BSF;Hermetia illucens) is used in sustainable processing of many types of organic waste. However, organic waste being decomposed by BSF produces strong odors, hindering more widespread application. The odor components and how they are produced have yet to be characterized. We found that digestion of food waste by BSF significantly alters the microbial flora, based on metagenomic analyses, and the odor components generated, as shown by thermal desorption gas chromatography mass spectrometry analysis. Inoculation with BSF significantly decreased production of volatile organic sulfur compounds (dimethyl disulfide and dimethyl trisulfide), which are known to be released during methionine and cysteine metabolism byLactobacillusandEnterococcusbacteria. BSF inoculation significantly changed the abundance ofLactobacillusandEnterococcusand decreased microbial diversity overall. These findings may help in optimizing use of BSF for deodorization of composting food waste.
Lis1 relieves cytoplasmic dynein-1 auto-inhibition by acting as a molecular wedge
Authors: Karasmanis Eva P. , Reimer Janice M. , Kendrick Agnieszka A. , Rodriguez Jennifer A. , Truong Joey B. , Lahiri Indrajit , Reck-Peterson Samara L. , Leschziner Andres E.
Published: October 2022

Cytoplasmic dynein-1 transports many intracellular cargos towards microtubule minus ends. Dynein is autoinhibited and undergoes conformational changes to form an active complex, consisting of one or two dynein dimers, the dynactin complex and activating adaptor(s)1,2. The Lissencephaly 1 gene,LIS1, is genetically linked to the dynein pathway from fungi to mammals and is mutated in patients with the neurodevelopmental disease lissencephaly3–5. Lis1 is required for active dynein complexes to form6–10, but how it does so is unclear. Here, we present a structure of two dynein motor domains with two Lis1 dimers wedged in-between. The contact sites between dynein and Lis1 in this structure, termed “Chi”, are required for Lis1’s regulation of dynein inSaccharomyces cerevisiaein vivo and the formation of active human dynein–dynactin– activating adaptor complexes in vitro. We propose that this structure represents an intermediate in dynein’s activation pathway, revealing how Lis1 relieves dynein’s autoinhibited state.
Characterization of the HHV-6 U20 immunoevasin
Authors: Schneider Christine L. , Whyte Melissa L. , Konrad Sheryl L. , Hudson Amy W.
Published: October 2022

Roseoloviruses (HHV-6A, -6B, and -7) infect >90% of the human population during early childhood, and are thought to remain latent or persistent throughout the life of the host. As such,these viruses are among the most pervasive and stealthy of all viruses;they must necessarily excel at escaping immune detection throughout the life of the host, and yet very little is known about how these viruses so successfully escape host defenses. Herein, we characterize the HHV6A and HHV6B U20 gene products, which are encoded within a block of genes unique to the roseoloviruses, and therefore of particular interest. Despite 92% amino acid identity, U20 proteins from HHV6A and 6B have been shown to possess different host evasion functions. Here we characterize expression, trafficking, and post-translational modifications of U20 during HHV6A infection. While U20 localized to lysosomes in HHV-6A-infected cells, HHV-6B U20 trafficked to the cell surface and was rapidly internalized. HHV-6B U20 trafficked slowly through the secretory system, receiving several post translational modifications to its N-linked glycans indicative of surface expressed glycoproteins. Interestingly, U20 is also phosphorylated on at least one Ser, Thr, or Tyr residue. These results provide a framework to understand the role(s) of U20 in evading host defenses.

Importance

HHV6A and HHV6B U20 proteins are virus-encoded integral membrane glycoproteins possessing class I MHC-like folds. As such, it is tempting to speculate that they are involved in host evasion. Indeed, although they share 92% identity, HHV6A U20 has been shown to target NK activating ligands (1) and HHV6B U20 has been shown to inhibit TNF receptor signaling and apoptosis (2). Here, we have performed cell biological and biochemical characterization of the trafficking, glycosylation, and post-translational modifications occurring on HHV6A and -6B U20, and we demonstrate U20 expression in the context of HHV6 infection.
Galectin-3 is Associated with Heart Failure Incidence: A Meta-Analysis
Authors: Baccouche Basil M. , Mahmoud Mattia A. , Nief Corrine , Patel Karan , Natterson-Horowitz B.
Published: October 2022

Introduction

Heart failure (HF) is a leading cause of death worldwide. The global prevalence of heart failure is projected to increase rapidly in the coming decades, and significant attention has turned to improving biomarker-based risk prediction of incident HF. The aim of this paper was to qualitatively and quantitatively evaluate the evidence associating levels of galectin-3 with risk of incident HF.

Methods

A review of PUBMED-indexed peer-reviewed literature was performed. Nine studies met inclusion criteria, and all nine had data eligible for conversion and pooling. A random-effects meta-analysis was performed using hazard ratios and 95% confidence intervals from a minimally adjusted model, a further adjusted model, and from subgroups within the further-adjusted model.

Results

The minimally-adjusted model provided a HR of 1.97 (95% CI 1.74-2.23) when comparing the top quartile of log-gal-3 to the bottom quartile. The further-adjusted model provided a HR of 1.32 (95% CI 1.21-1.44) for the same comparison. The positive, significant association was conserved during sensitivity analysis.

Conclusion

There is a significant positive association between levels of circulating galectin-3 and risk of incident heart failure. Given the complex mechanistic relationship between galectin-3 and cardiovascular pathophysiology, further investigation is recommended for possible implementation of galectin-3 into clinical risk prediction models.
An epigenetic basis of adaptive plasticity inDrosophila melanogaster
Authors: DiVito Evans Abigail , Fairbanks Regina A. , Schmidt Paul , Levine Mia T.
Published: October 2022

Fluctuating environments threaten fertility and viability. To better match the immediate, local environment, many organisms adopt alternative phenotypic states, a phenomenon called “phenotypic plasticity”. Local adaptation shapes phenotypic plasticity: natural populations that predictably encounter fluctuating environments tend to be more plastic than conspecific populations that encounter a constant environment. Despite pervasive evidence of such “adaptive phenotypic plasticity,” the evolution of the gene regulatory mechanisms underlying plasticity remains poorly understood. Here we test the hypothesis that environment-dependent phenotypic plasticity is mediated by epigenetic factors and that these epigenetic factors vary across naturally occurring genotypes. To test these hypotheses, we exploit the adaptive reproductive arrest ofDrosophila melanogasterfemales, called diapause. Using an inbred line from a natural population with high diapause plasticity, we demonstrate that diapause is determined epigenetically: only a subset of genetically identical individuals enter diapause and this diapause plasticity is epigenetically transmitted for at least three generations. Upon screening a suite of epigenetic marks, we discovered that the active histone marks H3K4me3 and H3K36me1 are depleted in diapausing ovaries. Using ovary-specific knockdown of histone mark writers and erasers, we demonstrate that H3K4me3 and H3K36me1 depletion promotes diapause. Given that diapause is highly polygenic – distinct suites of alleles mediate diapause plasticity across distinct genotypes – we investigated the potential for genetic variation in diapause-determining epigenetic marks. Specifically, we asked if these histone marks were similarly depleted in diapause of a geographically distinct, comparatively less plastic genotype. We found evidence of genotypic divergence in both the gene expression program and histone mark abundance. This study reveals chromatin determinants of adaptive plasticity and suggests that these determinants are genotype-dependent, offering new insight into how organisms may exploit and evolve epigenetic mechanisms to persist in fluctuating environments.
Quantification of differential toxin expressions and their relation to distinct lifespans of bacterial subpopulations associated with diverse host immune mechanisms
Authors: Santra Shweta , Nayak Indrani , Das Dibyendu , Banerjee Anirban
Published: October 2022

An assortment of robust intracellular defence mechanisms are critical for restricting proliferation of pathogens and maintaining sanctity of the cytosol. Defect in these mechanisms could be exploited by the pathogens for creation of a safe sanctuary which can act as a transient reservoir for periodic dissemination into the host. While residing inside the host cell, pore forming toxins secreted by the pathogens compromises the integrity of the vacuole and exposes the microbe to diverse intracellular defence mechanisms. However, the correlation between toxin expression levels and consequent pore dynamics, fostering pathogen’s intracellular life, remains largely unexplored. In this study, usingStreptococcus pneumoniae(SPN) and its secreted pore forming toxin pneumolysin (Ply), as model systems, we explored various facets of host-pathogen interactions in host cytosol, governed by the toxin expression and the resultant pore formation. The extent of damage on the endosomal membrane was found to dictate subsequent interaction with different host endosomal damage sensors. This in turn governed the routes of SPN clearance, revealing multiple layers of defence mechanisms at host’s disposal for counteracting invaded pathogens. A subset of SPN population producing extremely low amount of Ply inflicted minimal damage to the endomembrane, precluding decoration by endomembrane damage sensors and significantly prolonging its intracellular persistence. Such long persisting bacterial population could be key for pathogenic transmission or ensuing invasive disease. Using time-lapse fluorescence imaging, we monitored lifespans of different pneumococcal population subsets inside host cells. After quantitative analysis of various timescales such as pore formation time, vacuolar or cytosolic residence time and total degradation time, we developed a mathematical model that could correlate these to intravacuolar accumulation of Ply monomers. By proposing events like pore formation and vacuolar degradation of SPN as first passage processes, our theoretical modelling yields estimates of Ply production rate, burst size, and threshold Ply quantities which triggers these outcomes. Collectively, we present a general method by which intracellular lifespans of pathogens could be correlated to differential levels of toxins that they produce.
Population structure and genetic variance among local populations of an non-native earthworm species in Minnesota, USA
Authors: Heimburger Bastian , Klein Andreas , Roth Alex , Scheu Stefan , Eisenhauer Nico , Schaefer Ina
Published: October 2022

A variety of human activities have been identified as driving factors for the release and spread of invasive earthworm species in North America. Population genetic markers can help to identify locally relevant anthropogenic vectors and provide insights into the processes of population dispersal and establishment. We sampled the invasive European earthworm speciesLumbricus terrestrisat nine sites and several bait shops within the metropolitan area of Minneapolis-St. Paul in Minnesota, USA. We used microsatellite markers to infer genetic diversity and population structure, and 16S rDNA to address multiple introduction events, including bait dumping, which is a common source ofL. terrestrisintroductions into the wild. Our results indicate multiple introductions but not from current bait dumping. Overall, genetic structure was low and earthworms >5000 m apart were genetically differentiated, except for one sampling location, indicating jump-dispersal followed by population establishment. Further, earthworms at one location north of Minneapolis established from one or few founder individuals, suggesting that earthworm invasions are ongoing. We therefore encourage further monitoring of earthworm populations using molecular markers, in order to disentangle the different human-related vectors contributing to the spread of earthworms and their establishment, which is essential to develop adequate management strategies.
Designed active-site library reveals thousands of functional GFP variants
Authors: Weinstein Jonathan Yaacov , Martí-Gómez Carlos , Lipsh-Sokolik Rosalie , Hoch Shlomo Yakir , Liebermann Demian , Nevo Reinat , Weissman Haim , Petrovich-Kopitman Ekaterina , Margulies David , Ivankov Dmitry , McCandlish David , Fleishman Sarel Jacob
Published: October 2022

Mutations in a protein active site can lead to dramatic and useful changes in protein activity. The active site, however, is extremely sensitive to mutations due to a high density of molecular interactions, drastically reducing the likelihood of obtaining functional multipoint mutants. We introduce an atomistic and machine-learning-based approach, called htFuncLib, to design a sequence space in which mutations form low-energy combinations that mitigate the risk of incompatible interactions. We applied htFuncLib to the GFP chromophore-binding pocket, and, using fluorescence readout, recovered >16,000 unique designs encoding as many as eight active-site mutations. Many designs exhibit substantial and useful diversity in functional thermostability (up to 96 °C), fluorescence lifetime, and quantum yield. By eliminating incompatible active-site mutations, htFuncLib generates a large diversity of functional sequences. We envision that htFuncLib will be useful for one-shot optimization of activity in enzymes, binders, and other proteins.
FBXL4 deficiency promotes mitophagy by elevating NIX
Authors: Elcocks Hannah , Brazel Ailbhe J. , McCarron Katy R. , Kaulich Manuel , Husnjak Koraljka , Mortiboys Heather , Clague Michael J. , Urbé Sylvie
Published: October 2022

The selective autophagy of mitochondria is linked to mitochondrial quality control and is critical to a healthy organism. We have conducted a CRISPR/Cas9 screen of human E3 ubiquitin ligases for influence on mitophagy under both basal cell culture conditions and following acute mitochondrial depolarisation. We identify two Cullin RING ligases, VHL and FBXL4 as the most profound negative regulators of basal mitophagy. We show that these converge through control of the mitophagy adaptors BNIP3 and BNIP3L/NIX through different mechanisms. FBXL4 suppression of BNIP3 and NIX levels is mediated via direct interaction and protein destabilisation rather than suppression of HIF1α-mediated transcription. Depletion of NIX but not BNIP3 is sufficient to restore mitophagy levels. Our study enables a full understanding of the aetiology of early onset mitochondrial encephalomyopathy that is supported by analysis of a disease associated mutation. We further show that the compound MLN4924, which globally interferes with Cullin RING ligase activity, is a strong inducer of mitophagy providing a research tool in this context and a candidate therapeutic agent for conditions linked to mitochondrial dysfunction.
Distinct roles for canonical and variant histone H3 lysine 36 in Polycomb silencing
Authors: Salzler Harmony R. , Vandadi Vasudha , McMichael Benjamin D. , Brown John C. , Boerma Sally A. , Leatham-Jensen Mary P. , Adams Kirsten M. , Meers Michael P. , Simon Jeremy M. , Duronio Robert J. , McKay Daniel J. , Matera A. Gregory
Published: October 2022

Polycomb complexes regulate cell-type specific gene expression programs through heritable silencing of target genes. Trimethylation of histone H3 lysine 27 (H3K27me3) is essential for this process. Perturbation of H3K36 is thought to interfere with H3K27me3. We show that mutants ofDrosophilareplication-dependent(H3.2K36R)or -independent(H3.3K36R)histone H3 genes generally maintain Polycomb silencing and reach later stages of development. In contrast, combined(H3.3K36RH3.2K36R)mutants display widespread Hox gene misexpression and fail to develop past the first larval stage. Chromatin profiling revealed that theH3.2K36Rmutation disrupts H3K27me3 levels broadly throughout silenced domains, whereas these regions are mostly unaffected inH3.3K36Ranimals. Analysis of H3.3 distributions showed that this histone is enriched at presumptive PREs (Polycomb Response Elements) located outside of silenced domains but relatively depleted from those inside. We conclude that H3.2 and H3.3 K36 residues collaborate to repress Hox genes using different mechanisms.

Short summary

Histone H3.2 and H3.3 K36 residues ensure Hox gene silencing and enable development by different, but synergistic mechanisms.
A novel Single Alpha-Helix-DNA-binding domain in CAF-1 promotes gene silencing and DNA damage survival through tetrasome-length DNA selectivity and spacer function
Authors: Rosas Ruben , Aguilar Rhiannon R. , Arslanovic Nina , Tyler Jessica K. , Churchill Mair E. A.
Published: October 2022

The histone chaperone chromatin assembly factor 1 (CAF-1) deposits nascent histone H3/H4 dimers onto newly replicated DNA forming the central core of the nucleosome known as the tetrasome. How CAF-1 ensures there is sufficient space for the assembly of tetrasomes remains unknown. Structural and biophysical characterization of the lysine/glutamic acid/arginine-rich (KER) region of CAF-1 revealed a 128 Å single alpha helix (SAH) motif with unprecedented DNA binding properties. Distinct KER sequence features and length of the SAH drive the selectivity of CAF-1 for tetrasome-length DNA and facilitate function in budding yeast.In vivo, the KER cooperates with the DNA-binding winged helix domain in CAF-1 to overcome DNA damage sensitivity and maintain silencing of gene expression. We propose that the KER SAH links functional domains within CAF-1 with structural precision, acting as a DNA binding spacer element during chromatin assembly.
Breadth of Fc-mediated effector function delineates grades of clinical immunity following human malaria challenge
Authors: Nkumama Irene N. , Odera Dennis , Musasia Fauzia , Mwai Kennedy , Nyamako Lydia , Murungi Linda , Tuju James , Fürle Kristin , Rosenkranz Micha , Kimathi Rinter , Njuguna Patricia , Hamaluba Mainga , Kapulu Melissa C. , Frank Roland ,   CHMI-SIKA study Team, Osier Faith H. A.
Published: October 2022

Controlled human malaria challenge studies in semi-immune volunteers provide an unparalleled opportunity to robustly identify mechanistic correlates of protection. We leveraged this platform to undertake a head-to-head comparison of seven functional antibody assays that are relevant to immunity against the erythrocytic merozoite stage ofPlasmodium falciparum. Fc-mediated effector functions were strongly associated with protection from clinical symptoms of malaria and exponential parasite multiplication while the gold standard growth inhibition assay was not. The breadth of Fc-mediated effector function clearly discriminated grades of clinical immunity following challenge. These findings present a paradigm shift in the understanding of the mechanisms that underpin immunity to malaria and have important implications for vaccine development.
The SARS-CoV-2 envelope (E) protein forms a calcium- and voltage-activated calcium channel
Authors: Antonides Lysbeth H. , Hurst Quenton W. , Ives Callum M. , Ramberg Kiefer , Ostrovitsa Nikitas , Scanlan Eoin , Caffrey Martin , Pitt Samantha J. , Zachariae Ulrich
Published: October 2022

The function of ion channels is essential in the infectious cycle of many viruses. To facilitate viral uptake, maturation and export, viruses must modify the ionic balance of their host cells, in particular of calcium ions (Ca2+). Viroporins encoded in the viral genome play a key part in altering the cell’s ionic homeostasis. In SARS-Coronavirus-2 (SARS-CoV-2) – the causative agent of Covid-19 – the envelope (E) protein is considered to form ion channels in ERGIC organellar membranes, whose function is closely linked to disease progression and lethality. Deletion, blockade, or loss-of-function mutation of coronaviral E proteins results in propagation-deficient or attenuated virus variants. The exact physiological function of the E protein, however, is not sufficiently understood. Since one of the key features of the ER is its function as a Ca2+storage compartment, we investigated the activity of E in the context of this cation. Molecular dynamics simulations and voltage-clamp electrophysiological measurements show that E exhibits ion channel activity that is regulated by increased luminal Ca2+concentration, membrane voltage, post-translational protein modification, and negatively charged ERGIC lipids. Particularly, calcium ions bind to a distinct region at the ER-luminal channel entrance, where they activate the channel and maintain the pore in an open state. Also, alongside monovalent ions, the E protein is highly permeable to Ca2+. Our results suggest that the physiological role of the E protein is the release of Ca2+from the ER, and that the distinct Ca2+activation site may serve as a promising target for channel blockers, potentially inhibiting the infectious cycle of coronaviruses.
Comparative genomics and phylogenomics ofCampylobacterunveil potential novel species and provide insights into niche segregation
Authors: Henaut-Jacobs Sarah , Passarelli-Araujo Hemanoel , Venancio Thiago M.
Published: October 2022

Campylobacteris a bacterial genus associated with community outbreaks and gastrointestinal symptoms. Studies onCampylobactergenerally focus on specific pathogenic species such asC. coliandC. jejuni. Currently, there are thousands of publicly availableCampylobactergenomes, allowing a more complete assessment of the genus diversity. In this work, we report a network-based analysis of all availableCampylobactergenomes to explore the genus structure and diversity, revealing potentially new species and elucidating genus features. We also hypothesize that the previously established Clade III ofC. coliis in fact a novel species (referred here asCampylobacter spp12). Finally, we found a negative correlation between pangenome fluidity and saturation coefficient, with potential implications to the lifestyles of distinctCampylobacterspecies. Since pangenome analysis depends on the number of available genomes, this correlation could help estimate pangenome metrics ofCampylobacterspecies with less sequenced genomes, helping understand their lifestyle and niche adaptation. Together, our results indicate that theCampylobactergenus should be re-evaluated, with particular attention to the interplay between genome structure and niche segregation.
Host and Water Microbiota are Differentially Linked to Potential Human Pathogen Accumulation in Oysters
Authors: Diner Rachel E. , Zimmer-Faust Amy , Cooksey Emily , Allard Sarah , Kodera Sho M. , Kunselman Emily , Garodia Yash , Allen Andrew E. , Griffith John , Gilbert Jack A.
Published: October 2022

Oysters play an important role in coastal ecology and are a globally popular seafood source. However, their filter feeding lifestyle enables coastal pathogens, toxins, and pollutants to accumulate in their tissues, potentially endangering human health. For example, bacterial pathogens from both marine and terrestrial sources concentrate in oysters and can cause human illness when oysters are consumed raw. While pathogen concentrations in coastal waters are often linked to environmental conditions and runoff events, these do not always correlate with pathogen concentrations in oysters. Additional factors related to oyster hosts and the microbial ecology of pathogenic bacteria likely play a role in accumulation but are poorly understood. In this study, we investigated whether microbial communities in water and oysters were linked to accumulation of fecal indicators,Vibrio parahaemolyticus, andVibrio vulnificus. Site-specific environmental conditions significantly influenced the composition and diversity of water microbial communities, which were linked to the highest concentrations of bothVibriospp. and fecal indicator bacteria. Oyster microbial communities, however, were less impacted by environmental variability and exhibited less variability in microbial community diversity and accumulation of target bacteria. Instead, changes in specific microbial taxa in oyster and water samples, particularly in oyster digestive glands, were linked to elevated potential pathogens in oysters, especiallyV. parahaemolyticus. This included an increase in cyanobacteria in both water and oyster digestive gland microbial communities, which could represent an environmental vector forVibriospp. transport and decreased relative abundance ofMycoplasmaand other key members of the oyster digestive gland microbiota. These findings suggest that host and microbial factors, in addition to environmental variables, may influence pathogen accumulation in oysters.
The clock genePer1expression may exert diurnal control over hippocampal memory consolidation
Authors: Bellfy Lauren , Smies Chad W. , Bernhardt Alicia R. , Bodinayake Kasuni K. , Sebastian Aswathy , Stuart Emily M. , Wright Destiny S. , Lo Chen-Yu , Murakami Shoko , Boyd Hannah M. , von Abo Megan J. , Albert Istvan , Kwapis Janine L.
Published: October 2022

The circadian system influences many different biological processes, including memory performance. While the suprachiasmatic nucleus (SCN) functions as the brain’s central pacemaker, satellite clocks have also been identified in other brain regions, such as the memory-relevant dorsal hippocampus. Although it is unclear how these satellite clocks contribute to brain function, one possibility is that they may serve to exert diurnal control over local processes. Within the hippocampus, for example, the local clock may contribute to time-of-day effects on memory. Here, we used the hippocampus-dependent Object Location Memory task to determine how memory is regulated across the day/night cycle in mice. First, we systematically determined which phase of memory (acquisition, consolidation, or retrieval) is modulated across the 24h day. We found that mice show better long-term memory performance during the day than at night, an effect that was specifically attributed to diurnal changes in memory consolidation, as neither memory acquisition nor memory retrieval fluctuated across the day/night cycle. Using RNA-sequencing we identified the circadian clock genePeriod1(Per1) as a key mechanism capable of supporting this diurnal fluctuation in memory consolidation, asPer1oscillates in tandem with memory performance. We then show that local knockdown ofPer1within the dorsal hippocampus has no effect on either the circadian rhythm or sleep behavior, although previous work has shown this manipulation impairs memory. Thus,Per1may independently function within the dorsal hippocampus to regulate memory in addition to its known role in regulating the circadian rhythm within the SCN.Per1may therefore exert local diurnal control over memory consolidation within the dorsal hippocampus.
Stochastic chain termination in bacterial pilus assembly
Authors: Giese Christoph , Puorger Chasper , Ignatov Oleksandr , Bečárová Zuzana , Weber Marco E. , Schärer Martin A. , Capitani Guido , Glockshuber Rudi
Published: October 2022

Adhesive type 1 pili from uropathogenicEscherichia colistrains are filamentous, supramolecular protein complexes consisting of a short tip fibrillum and a long, helical rod formed by up to several thousand copies of the major pilus subunit FimA. Here, we reconstituted the entire type 1 pilus rod assembly reactionin vitro, using all constituent protein subunits in the presence of the assembly platform FimD, and identified the so-far uncharacterized subunit FimI as an irreversible assembly terminator. We provide a complete, quantitative model of pilus rod assembly kinetics based on the measured rate constants of FimD-catalyzed subunit incorporation. The model reliably predicts the length distribution of assembled pilus rods as a function of the ratio between FimI and the main pilus subunit FimA and is fully consistent with the length distribution of membrane-anchored pili assembledin vivo. The results show that the natural length distribution of adhesive pili formed via the chaperone-usher pathway results from a stochastic chain termination reaction.
An optimized messenger RNA vaccine candidate protects non-human primates from Zika virus infection
Authors: Bollman Brooke , Nunna Naveen , Bahl Kapil , Hsiao Chiaowen Joyce , Bennett Hamilton , Butler Scott , Foreman Bryant , Burgomaster Katherine E. , Aleshnick Maya , Kong Wing-Pui , Fisher Brian E. , Ruckwardt Tracy J. , Morabito Kaitlyn M. , Graham Barney S. , Dowd Kimberly A. , Pierson Theodore C. , Carfi Andrea
Published: October 2022

Zika virus (ZIKV), an arbovirus transmitted by mosquitoes, was identified as a cause of congenital disease during a major outbreak in the Americas in 2016. Vaccine design strategies relied on limited available isolate sequence information due to the rapid response necessary. The first-generation ZIKV mRNA vaccine, mRNA-1325, was initially generated and, as additional strain sequences became available, a second mRNA vaccine, mRNA-1893, was developed. Herein, we compared the immune responses following mRNA-1325 and mRNA-1893 vaccination and reported that mRNA-1893 generated comparable neutralizing antibody titers to mRNA-1325 at 1/20thof the dose and provided complete protection from ZIKV challenge in non-human primates. In depth characterization of these vaccines indicated that the observed immunologic differences could be attributed to a single amino acid residue difference that compromised mRNA-1325 virus-like particle formation.
Research on the relationship between industrial agglomeration and regional innovation from the dynamic perspective: evidence from China
Authors: Yang Boxu , Liu Xielin , Liu Wen
Published: October 2022

Purpose

The purpose of this paper is to reveal the paradox between diversification and specialization from a dynamic perspective. More precisely, this paper will analyze the impact of diversification and specialization as well as their interaction on regional innovation in different development stages.

Design/methodology/approach

Based on the principles of new economic geography and innovation geography, data from 30 provinces from 2001 to 2017 was used to explore the relationship. Least squares regressions with fix effect were used to examine the hypotheses.

Findings

The results show that both diversification and specialization have a significant and positive impact on regional innovation. The interaction of diversification and specialization also significantly and positively impacts regional innovation. The effect of industrial agglomeration is heterogeneity under different development stages.

Practical implications

This paper verifies the positive role of diversification and specialization and their interaction in promoting regional innovation. The impact of industrial agglomeration on innovation is dynamic and changes with the regional development process. Emerging economies should make appropriate industrial agglomeration strategies according to their development stages.

Originality/value

This paper introduces diversification, specialization and their interaction into the research framework at the same time to analyze their impact on innovation performance which deepened the research of industrial agglomeration. Taking China as an example, this paper also examines the impact of industrial agglomeration on regional innovation in different development stages that expands the dynamic perspective of industrial agglomeration.
Examining the effect of interoperability factors on building information modelling (BIM) adoption in Malaysia
Authors: Ahmed Yunis Ali , Shehzad Hafiz Muhammad Faisal , Khurshid Muhammad Mahboob , Abbas Hassan Omayma Husain , Abdalla Samah Abdelsalam , Alrefai Nashat
Published: October 2022

Purpose

Building information modelling (BIM) has transformed the traditional practices of the Architecture, Engineering and Construction (AEC) industry. BIM creates a collaborative digital representation of built environment data. Competitive advantage can be achieved with collaborative project delivery and rich information modelling. Despite the abundant benefits, BIM’s adoption in the AEC is susceptible to confrontation. A substantial impediment to BIM adoption often cited is data interoperability. Other facets of interoperability got limited attention. Other academic areas, including information systems, discuss the interoperability construct ahead of data interoperability. These interoperability factors have yet to be surveyed in the AEC industry. This study aims to investigate the effect of interoperability factors on BIM adoption and develop a comprehensive BIM adoption model.

Design/methodology/approach

The theoretical foundations of the proposed model are based on the European interoperability framework (EIF) and technology, organization, environment framework (TOE). Quantitative data collection from construction firms is gathered. The model has been thoroughly examined and validated using partial least squares structural equation modelling in SmartPLS software.

Findings

The study’s findings indicate that relative advantage, top management support, government support, organizational readiness and regulation support are determinants of BIM adoption. Financial constraints, complexity, lack of technical interoperability, semantic interoperability, organizational interoperability and uncertainty are barriers to BIM adoption. However, compatibility, competitive pressure and legal interoperability do not affect BIM adoption.

Practical implications

Finally, this study provides recommendations containing the essential technological, organizational, environmental and interoperability factors that AEC stakeholders can address to enhance BIM adoption.

Originality/value

To the best of the authors’ knowledge, this paper is one of the first studies to combine TOE and EIF in a single research model. This research provides empirical evidence for using the proposed model as a guide to promoting BIM adoption. As a result, the highlighted determinants can assist organizations in developing and executing successful policies that support BIM adoption in the AEC industry.