bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetic reprogramming ameliorates type 1 diabetes by decreasing the generation of Th1 and Th17 subsets and restoring self-tolerance in CD4+ T cells
Authors: Patel Vasu , Jayaraman Arathi , Jayaraman Sundararajan
Published: July 2021

The histone modifier Trichostatin A (TSA) ameliorated diabetes and repressed IFN-γ and IL-17A expression in prediabetic female NOD mice. Purified CD4+ cells could be polarized ex vivo into Th1 and Th17 subsets, which comparably transferred diabetes into NOD.scid mice. Polarized Th1 cells were devoid of IL-17A-producing cells and did not transdifferentiate into Th17 cells in an immunodeficient environment. However, Th17 cells had contaminant Th1 cells, which expressed IFN-γ upon adoptive transfer into lymphopenic recipients. Notably, TSA treatment abrogated the transfer of diabetes by CD4+ T-cells cultured under Th1 or Th17 polarizing conditions accompanied by the absence of Ifng and Il17a expression in NOD.scid recipients. Significantly, the histone modifier restored the ability of CD4+ but not CD8+ T-cells to undergo CD3-mediated apoptosis ex vivo in a caspase-dependent manner. Thus, the histone modifier afforded protection against autoimmune diabetes by negative regulation of signature lymphokines and restitution of self-tolerance in CD4+ T cells.
Protection afforded by the BNT162b2 and mRNA-1273 COVID-19 vaccines in fully vaccinated cohorts with and without prior infection
Authors: Abu-Raddad Laith J. , Chemaitelly Hiam , Ayoub Houssein H. , Yassine Hadi M. , Benslimane Fatiha M. , Al Khatib Hebah A. , Tang Patrick , Hasan Mohammad R. , Coyle Peter , Kanaani Zaina Al , Kuwari Einas Al , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Abdul Rahim Hanan F. , Nasrallah Gheyath K. , Al Kuwari Mohamed Ghaith , Butt Adeel A. , Al Romaihi Hamad Eid , Al-Thani Mohamed H. , Khal Abdullatif Al , Bertollini Roberto
Published: July 2021

Effect of prior SARS-CoV-2 infection on vaccine protection remains poorly understood. Here, we investigated whether persons vaccinated after a prior infection have better protection against future infection than those vaccinated without prior infection. Effect of prior infection was assessed in Qatar’s population, where the Alpha (B.1.1.7) and Beta (B.1.351) variants dominate incidence, using two national retrospective, matched-cohort studies, one for the BNT162b2 (Pfizer-BioNTech) vaccine, and one for the mRNA-1273 (Moderna) vaccine. Incidence rates of infection among BNT162b2-vaccinated persons, with and without prior infection, were estimated, respectively, at 1.66 (95% CI: 1.26-2.18) and 11.02 (95% CI: 9.90-12.26) per 10,000 person-weeks. The incidence rate ratio was 0.15 (95% CI: 0.11-0.20). Analogous incidence rates among mRNA-1273-vaccinated persons were estimated at 1.55 (95% CI: 0.86-2.80) and 1.83 (95% CI: 1.07-3.16) per 10,000 person-weeks. The incidence rate ratio was 0.85 (95% CI: 0.34-2.05). Prior infection enhanced protection of those BNT162b2-vaccinated, but not those mRNA-1273-vaccinated. These findings may have implications for dosing, interval between doses, and potential need for booster vaccination.
The first crested duck genome reveals clues to genetic compensation and crest cushion formation
Authors: Chang Guobin , Yuan Xiaoya , Guo Qixin , Bai Hao , Cao Xiaofang , Liu Meng , Wang Zhixiu , Li Bichun , Wang Shasha , Jiang Yong , Wang Zhiquan , Zhang Yang , Xu Qi , Song Qianqian , Pan Rui , Zheng Shenghan , Qiu Lingling , Gu Tiantian , Wu Xinsheng , Bi Yulin , Cao Zhengfeng , Zhang Yu , Chen Yang , Li Hong , Liu Jianfeng , Dai Wangcheng , Chen Guohong
Published: July 2021

The Chinese crested (CC) duck is a unique indigenous waterfowl breed with a phenotypic crest trait that affects its high survival rate. Therefore, the CC duck is an ideal model to investigate the genetic compensation response to maintain genetic stability. In the present study, we first generated a chromosome-level genome of CC ducks. Comparative genomics revealed genes related to tissue repair, immune function, and tumors were under strong positive selection, which suggested that these adaptive changes might enhance cancer resistance and immune response to maintain the genetic stability of CC ducks. We sub-assembled a Chinese spot-billed duck genome and detected genome-assembled structure variants among three ducks. Functional analysis revealed that a large number of structural variants were related to the immune system, which strongly suggests the occurrence of genetic compensation in the anti-tumor and immune systems to further support the survival of CC ducks. Moreover, we confirmed that the CC duck originated from the mallard ducks. Finally, we revealed the physiological and genetic basis of crest traits and identified a causative mutation in TAS2R40 that leads to crest formation. Overall, the findings of this study provide new insights into the role of genetic compensation in adaptive evolution.
The high-throughput gene prediction of more than 1,700 eukaryote genomes using the software package EukMetaSanity
Authors: Neely Christopher J. , Hu Sarah K. , Alexander Harriet , Tully Benjamin J.
Published: July 2021

Gene prediction and annotation for eukaryotic genomes is challenging with large data demands and complex computational requirements. For most eukaryotes, genomes are recovered from specific target taxa. However, it is now feasible to reconstruct or sequence hundreds of metagenome-assembled genomes (MAGs) or single-amplified genomes directly from the environment. To meet this forth-coming wave of eukaryotic genome generation, we introduce EukMetaSanity, which combines state-of-the-art tools into three pipelines that have been specifically designed for extensive parallelization on high-performance computing infrastructure. EukMetaSanity performs an automated taxonomy search against a protein database of 1,482 species to identify phylogenetically compatible proteins to be used in downstream gene prediction. We present the results for intron, exon, and gene locus prediction for 112 genomes collected from NCBI, including fungi, plants, and animals, along with 1,669 MAGs and demonstrate that EukMetaSanity can provide reliable preliminary gene predictions for a single target taxon or at scale for hundreds of MAGs. EukMetaSanity is freely available at https://github.com/cjneely10/EukMetaSanity.
Software for Non-Parametric Image Registration of 2-Photon Imaging Data
Authors: Flotho Philipp , Nomura Shinobu , Kuhn Bernd , Strauss Daniel J.
Published: July 2021

Functional 2-photon microscopy is a key technology for imaging neuronal activity. The recorded image sequences, however, can contain non-rigid movement artifacts which requires high-accuracy movement correction. Variational optical flow (OF) estimation is a group of methods for motion analysis with established performance in many computer vision areas. However, it has yet to be adapted to the statistics of 2-photon neuroimaging data. In this work, we present the motion compensation method Flow-Registration that outperforms previous alignment tools and allows to align and reconstruct even low signal-to-noise ratio 2-photon imaging data and is able to compensate high-divergence displacements during local drug injections. The method is based on statistics of such data and integrates previous advances in variational OF estimation. Our method is available as an easy-to-use ImageJ / FIJI plugin as well as a MATLAB toolbox with modular, object oriented file IO, native multi-channel support and compatibility with existing 2-photon imaging suites.
Monitoring Spore Dispersal and Early Infections of Diplocarpon coronariae Causing Apple Blotch Using Spore Traps and a New qPCR Method
Authors: Boutry Clémence , Bohr Anne , Buchleither Sascha , Ludwig Mathias , Oberhänsli Thomas , Tamm Lucius , Schärer Hans-Jakob , Flury Pascale
Published: July 2021

Apple blotch (AB) is a major disease of apple in Asia and recently emerged in Europe and the USA. It is caused by the fungus Diplocarpon coronariae (Dc) (formerly: Marssonina coronaria; teleomorph: Diplocarpon mali) and leads to severe defoliation of apple trees in late summer resulting in reduced yield and fruit quality. To develop effective disease management strategies, a sound knowledge of the pathogen’s biology is crucial. Data on the early phase of disease development is scarce: no data on spore dispersal in Europe is available. We developed a highly sensitive TaqMan qPCR method to quantify Dc conidia in spore trap samples. We monitored temporal and spatial dispersal of conidia of Dc, and progress of AB in spring and early summer in an extensively managed apple orchard in Switzerland in 2019 and 2020. Our results show that Dc overwinters in leaf litter and spore dispersal and primary infections occur in late April and early May. We provide the first results describing early-season dispersal of conidia of Dc, which, combined with the observed disease progress, helps to understand the disease dynamics and will be a basis for improved disease forecast models. Using the new qPCR method, we detected Dc in buds, on bark and fruit mummies, suggesting that several apple tissues may serve as overwintering habitats for the fungus, in addition to fallen leaves.
Oncogenic c-Myc induces replication stress by increasing cohesins chromatin occupancy
Authors: Peripolli Silvia , Singh Tanya , Patel Harshil , Meneguello Leticia , Kiso Koshiro , Thorpe Peter , Bertoli Cosetta , de Bruin Robertus A.M.
Published: July 2021

Oncogene-induced replication stress is a major driver of genomic instability in cancer cells, with a central role in both cancer initiation and progression (1). Despite its critical role in cancer development, the mechanisms that lay at the basis of oncogene-induced replication stress remains poorly understood. Here, we investigate the mechanism of c-Myc-induced replication stress. Our data shows that c-Myc induces replication stress by increasing the amount of cohesins bound to chromatin in the G1 phase of the cell cycle. This is independent of previously suggested mechanisms involving deregulation of replication initiation and transcriptional interference. Restoring the amount of chromatin-bound cohesins to control levels, or preventing the accumulation of cohesins at CTCF sites, in cells experiencing oncogenic c-Myc activity prevents replication stress. Increased cohesins chromatin occupancy correlates with a c-Myc-dependent increase in the levels of the cohesion loader Mau2. Preventing c-Myc-induced increase in Mau2 reduces oncogene-induced replication stress. Together our data support a novel mechanism for oncogene-induced replication stress. Since c-Myc activation is a crucial event in many human cancers (2), identifying the mechanisms through which this oncogene promotes replication stress provides critical insights into cancer biology.
Phylogenetic distribution and expression pattern analyses identified a divergent basal body assembly protein involved in land plant spermatogenesis
Authors: Koshimizu Shizuka , Minamino Naoki , Nishiyama Tomoaki , Yoro Emiko , Ebine Kazuo , Sakakibara Keiko , Ueda Takashi , Yano Kentaro
Published: July 2021

Oogamy is a form of sexual reproduction and evolved independently in animals, fungi, and plants. In streptophyte plants, Charophyceae, Coleochaetophyceae, bryophytes, lycophytes, ferns (monilophytes), and some gymnosperms (Cycads and Ginkgo) utilize spermatozoids as the male gamete. Plant spermatozoids commonly possess characteristic structures such as the spline, which consists of a microtubule array, the multilayered structure (MLS) in which the uppermost layer is continuum of the spline, and multiple flagella. However, the molecular mechanisms underpinning plant spermatogenesis remain to be elucidated. To identify the genes involved in plant spermatogenesis, we performed computational analyses and successfully found deeply divergent BLD10s by combining multiple methods and omics-data. We then validated the functions of candidate genes in the liverwort Marchantia polymorpha and the moss Physcomitrium patens and found that MpBLD10 and PpBLD10 are required for normal basal body and flagella formation. Mpbld10 mutants exhibited defects in remodeling of the cytoplasm and nucleus during spermatozoid formation, thus MpBLD10 should be involved in chromatin reorganization and elimination of the cytoplasm during spermiogenesis. Streptophyte BLD10s are orthologous to BLD10/CEP135 family proteins, which function in basal body assembly, but we found that BLD10s evolved especially fast in land plants and MpBLD10 might obtain additional functions in spermatozoid formation through the fast molecular evolution. This study provides a successful example of combinatorial study from evolutionary and molecular genetic perspectives that elucidated a function of the key protein of the basal body formation that fast evolved in land plants.
Reward-dependent selection of feedback gains impacts rapid motor decisions
Authors: De Comite Antoine , Crevecoeur Frédéric , Lefèvre Philippe
Published: July 2021

Target reward influences motor planning strategies through modulation of movement vigor. Considering current theories of sensorimotor control suggesting that movement planning consists in selecting a goal-directed control strategy, we sought to investigate the influence of reward on feedback control. Here we explored this question in three human reaching experiments. First, we altered the explicit reward associated with the goal target and found an overall increase in feedback gains for higher target rewards, highlighted by larger velocities, feedback responses to external loads, and background muscle activity. Then, we investigated whether the differences in target rewards across multiple goals impacted rapid motor decisions during movement. We observed idiosyncratic switching strategies dependent on both target rewards and, surprisingly, the feedback gains at perturbation onset: the more vigorous movements were less likely to switch to a new goal following perturbations. To gain further insight into a causal influence of the feedback gains on rapid motor decisions, we demonstrated that biasing the baseline activity and reflex gains by means of a background load evoked a larger proportion of target switches in the direction opposite to the background load associated with lower muscle activity. Together, our results demonstrate an impact of target reward on feedback control and highlight the competition between movement vigor and flexibility.

Significance statement

Humans can modulate their movement vigor based on the expected reward. However, a potential influence of reward on feedback control has not been documented. Here we investigated reaching control strategies in different contexts associated with explicit rewards for one or multiple goals, while exposed to external perturbations. We report two strategies: reward could either increase feedback gains, or promote flexible switches between goals. The engagement of peripheral circuits in the modulation of feedback gains was confirmed by the application of a background load that biased feedback vigor directionally, evoking differences in switching behavior in the opposite direction. We conclude that feedback vigor and flexible changes in goal are two competing mechanisms to be selected when interacting with a dynamic environment.
Overexpression of the gene encoding neurosecretory protein GL precursor prevents excessive fat accumulation in the adipose tissue of mice fed a long-term high-fat diet
Authors: Fukumura Keisuke , Narimatsu Yuki , Moriwaki Shogo , Iwakoshi-Ukena Eiko , Furumitsu Megumi , Ukena Kazuyoshi
Published: July 2021

We previously identified a novel small hypothalamic protein, neurosecretory protein GL (NPGL), which induces feeding behavior and fat accumulation in rodents depending on their diet. In the present study, we explored the effects of NPGL on feeding behavior and energy metabolism in mice placed on a long-term high-fat diet with 60% calories from fat (HFD 60). Overexpression of the NPGL precursor gene (Npgl) over 18 weeks increased food intake and body mass. The weekly body mass gain of Npgl-overexpressing mice was higher than that of controls until 7 weeks from induction of overexpression, after which it ceased to be so. Oral glucose tolerance tests showed that Npgl overexpression maintained glucose tolerance and increased blood insulin levels, and intraperitoneal insulin tolerance tests showed that it maintained insulin sensitivity. At the experimental endpoint, Npgl overexpression was associated with increased mass of the perirenal white adipose tissue (WAT) and decreased mass of the epididymal WAT (eWAT), resulting in little effect on the total WAT mass. These results suggest that under long-term HFD 60 feeding, Npgl overexpression may play a role in avoiding metabolic disturbance both by accelerating energy storage and by suppressing excess fat accumulation in certain tissues, such as the eWAT.
Hoslundia oppositaand other Nigerian plants inhibit sickle hemoglobin polymerization and prevent erythrocyte sickling: a virtual screening-guided identification of bioactive plants
Authors: Olori Eric O. , Olubiyi Olujide O. , Babalola Chinedum P.
Published: July 2021

In sickle cell disease, a hereditary hemoglobinopathy, clinically observed disease presentations are the endpoint of a point mutation involving the substitution of glutamic acid with valine at the position 6 of the beta globin chain. With about 4.4 million people globally being affected, and another 43 million people bearing the sickle cell trait, several research efforts have been made to discover new and affordable treatment and possibly cure for the disease. Africa is endowed with a large flora population and traditional healers and citizens have over time depended on the use of herbs in folkloric medicine for different ailments including sickle cell disease (SCD). Such native knowledge has often formed the basis for different research exploration into the anti-sickling activities of selected African plants. These plants that have been so far investigated for their anti-sickling properties represent about 0.05 % of the 45,000 plant species enriching the flora landscape in Sub-Saharan Africa. Some of these have yielded potent anti-sickling profiles. In the current work we seek to achieve a more extensive search of the African plant diversity with anti-sickling properties: for this we have adopted a hybrid computational-cum-experimental protocol that employed computer-aided drug design (CADD) means for identifying plants with at least one constituent capable of interacting with the sickle hemoglobin, followed by extractive procedures and anti-sickling experiments for validating the predictions. Over two thousand (or 2,000) African natural products, representing over 200 plant species, were first virtually screened against the crystal structure of the dimerized human sickle hemoglobin. The natural products with the best computed sickle hemoglobin interaction energetics were found to belong to five plant species includingCatharanthus roseus, Rauvolfia vomitoria, Hoslundia opposita, Lantana camara and Euphorbia hirta. The leaves of these plants were each collected subsequently and subjected to standard processing and extraction procedures. Using both HbSS polymerization inhibition and sickling reversal tests significant reductions in polymerization of erythrocyte hemolysate of the HbSS genotype were observed with the methanolic extracts of the plants, as well as sickling reversal levels of up to 68.50 % (H. opposita) was observed.
Artificial Intelligence Resolves Kinetic Pathways of Magnesium Binding to RNA
Authors: Neumann Jan , Schwierz Nadine
Published: July 2021

Magnesium is an indispensable cofactor in countless vital processes. In order to understand its functional role, the characterization of the binding pathways to biomolecules such as RNA is crucial. Despite the importance, a molecular description is still lacking since the transition from the water-mediated outer-sphere to the direct inner-sphere conformation is on the millisecond timescale and therefore out of reach for conventional simulation techniques. To fill this gap, we use transition path sampling to resolve the binding pathways and to elucidate the role of the solvent in the reaction. The results reveal that the molecular void provoked by the leaving phosphate oxygen of the RNA is immediately filled by an entering water molecule. In addition, water molecules from the first and second hydration shell couple to the concerted exchange. To capture the intimate solute-solvent coupling, we perform a committor analysis as basis for a machine learning algorithm that derives the optimal deep learning model from thousands of scanned architectures using hyperparameter tuning. The results reveal that the properly optimized deep network architecture recognizes the important solvent structures, extracts the relevant information and predicts the commitment probability with high accuracy. Our results provide a quantitative description of solute-solvent coupling which is ubiquitous for kosmotropic ions and governs a large variety of biochemical reactions in aqueous solutions.
Specialized subsets of innate-like T cells and dendritic cells protect from lethal pneumococcal infection in the lung
Authors: Murray Mallory Paynich , Crosby Catherine M. , Marcovecchio Paola , Hartmann Nadine , Chandra Shilpi , Zhao Meng , Khurana Archana , Zahner Sonja P. , Clausen Björn E. , Coleman Fadie T. , Mizgerd Joseph P. , Mikulski Zbigniew , Kronenberg Mitchell
Published: July 2021

Innate-like T cells, including invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells and γδ T cells, are present in various barrier tissues, including the lung. They carry out protective responses during infections, but the mechanisms for protection are not completely understood. Here, we investigated their roles during pulmonary infection with Streptococcus pneumoniae. Following infection, innate-like T cells rapidly increased in lung tissue, in part through recruitment, but TCR activation and cytokine production occurred mostly in IL-17-producing NKT17 and γδ T cells. NKT17 cells were preferentially located outside the vasculature prior to infection, as were CD103+ dendritic cells (cDC1), which were important both for antigen presentation to NKT17 cells and γδ T cell activation. Whereas IL-17A-producing γδ T cells also were numerous, GM-CSF was exclusive to NKT17 cells and contributed to iNKT cell-mediated protection. These studies demonstrate how particular cellular interactions and responses of functional subsets of innate-like T cells contribute to protection from pathogenic lung infection.
Supra-physiological levels of gibberellins/DELLAs modify the root cell size/number and the root architecture in root tips of A. thaliana seedlings. Connections to the root hair patterning and abundance
Authors: McCarthy-Suárez Iva
Published: July 2021

A previous study (McCarthy-Suárez, 2021) showed that growing A. thaliana seedlings for 5 days under excessive levels of gibberellins (GAs)/DELLAs altered the arrangement, shape and frequency of root hairs in root tips. Because no changes in the distribution or number of root hairs occurred when the gai-1 (gibberellin-insensitive-1) DELLA was over-expressed at the root epidermis, it was concluded that the GAs/DELLAs might regulate the root hair patterning and abundance in A. thaliana seedlings by acting from the root sub-epidermal tissues. In the present study, microscopy analyses showed that excessive levels of GAs/DELLAs also modified the size and number of root tip cells in A. thaliana seedlings. While excessive DELLAs shortened and widened the root epidermal, cortical, endodermal and pericycle cells, excessive GAs, excepting the epidermal cells, generally narrowed them. However, no changes of root cell size occurred when gai-1 was over-expressed at the root epidermis. In addition, high levels of DELLAs often induced extra cells at the root epidermis, cortex, endodermis and pericycle, whereas high levels of GAs sometimes induced extra cells at the root cortex and pericycle. On the other hand, excessive levels of DELLAs enhanced the outgrowth of lateral roots in root tips, unlike excessive levels of GAs. Thus, the results of this study suggest that supra-physiological levels of GAs/DELLAs might modify the size/number of root tip cells by acting from the root sub-epidermal tissues. This, in turn, might impact on the patterning and abundance of root hairs and on the root architecture.
First record ofTemnothorax convexus(Forel, 1894) in Portugal (Hymenoptera: Formicidae) with an updated checklist of ants from the country
Authors: Arcos Javier , Chaves Diogo , Alarcón Paco , Rosado Ángel
Published: July 2021

The arboreal antTemnothorax convexus(Forel, 1894) is reported for the first time in Portugal. A single colony was found nesting inside an abandoned gall near Lisbon. A full morphometric evaluation of the specimens is provided, including a small sample from the recently discovered population in South Iberia. High-definition photographs of the worker caste are given, together with a comparison with the most similar species in Iberia and an update of the Portuguese ant checklist.
Opposing roles of blood-borne monocytes and tissue-resident macrophages in limbal stem cell damage after ocular injury
Authors: Zhou Chengxin , Lei Fengyang , Mittermaier Mirja , Ksander Bruce , Dana Reza , Dohlman Claes H. , Vavvas Demetrios G. , Chodosh James , Paschalis Eleftherios I.
Published: July 2021

Limbal stem cell (LSC) deficiency is a frequent and severe complication after chemical injury to the eye. Previous studies have assumed that this is mediated directly by the caustic agent. Here we show that LSC damage occurs through immune cell mediators, even without direct injury to LSCs. In particular, pH elevation in the anterior chamber (AC) causes acute uveal stress, release of inflammatory cytokines at the basal limbal tissue, and subsequent LSC loss. Peripheral CCR2+ CX3CR1- monocytes are the key mediators of LSC damage, through the upregulation of tumor necrosis factor alpha (TNF-α) at the limbus. In contrast to peripherally-derived monocytes, CX3CR1+ CCR2- tissue-resident macrophages have a protective role and their depletion prior to injury exacerbates LSC loss and increases LSC vulnerability to TNF-α-mediated apoptosis independently of CCR2+ cell infiltration into the tissue. Consistently, repopulation of the tissue by new resident macrophages not only restores the protective M2-like phenotype of macrophages but also suppresses LSC loss after exposure to inflammatory signals. These findings may have clinical implication in patient with chemical burns.

Significance

Limbal stem cell (LSC) loss after chemical burn is a significant clinical problem that has long been thought to be the result of direct chemical injury. This study demonstrates the existence of competing inflammatory mechanism responsible for LSC death, mediated by infiltrating peripheral monocytes that antagonize and overcome the protective role of tissue-resident macrophages. Thus, enhancing the role of tissue-resident macrophages while suppressing that of infiltrating monocytes could be a novel therapeutic strategy for LSC survival.
Eukaryotic genomes from a global metagenomic dataset illuminate trophic modes and biogeography of ocean plankton
Authors: Alexander Harriet , Hu Sarah K. , Krinos Arianna I. , Pachiadaki Maria , Tully Benjamin J. , Neely Christopher J. , Reiter Taylor
Published: July 2021

Metagenomics is a powerful method for interpreting the ecological roles and physiological capabilities of mixed microbial communities. Yet, many tools for processing metagenomic data are not designed to consider eukaryotes, nor are they built for an increasing amount of sequence data. EukHeist is an automated pipeline to retrieve eukaryotic and prokaryotic metagenome assembled genomes (MAGs) from large-scale metagenomic datasets. We developed the EukHeist workflow to specifically process large amounts of both metagenomic and/or metatranscriptomic sequence data in an automated and reproducible fashion. Here, we applied EukHeist to the large-size fraction data (0.8-2000µm) fromTaraOceans to recover both eukaryotic and prokaryotic MAGs, which we refer to as TOPAZ (TaraOceans Particle-Associated MAGs). The TOPAZ MAGs consisted of >900 environmentally-relevant eukaryotic MAGs and >4,000 bacterial and archaeal MAGs. The bacterial and archaeal TOPAZ MAGs expand the known marine phylogenetic diversity through the increase in coverage of likely particle- and host-associated taxa. We also demonstrate an approach to infer the putative functional mode of the recovered eukaryotic MAGs. A global survey of the TOPAZ MAGs enabled the identification of ecological cohorts, driven by specific environmental factors, and putative host-microbe associations.

Importance

Despite the ecological importance of single-celled eukaryotic organisms in marine environments, the majority are difficult to cultivate in the lab. Sequencing genetic material extracted from environmental samples enables researchers to document naturally-occurring protistan communities. However, conventional sequencing methodologies cannot separate out the genomes of individual organisms. To more completely capture the entire genomic content of mixed protistan community, we can create bins of sequences that represent the same organism. We developed a pipeline that enables scientists to bin individual organisms out of metagenomic reads, and show results that provide exciting insights into what protistan communities are present in the ocean and what roles they play in the ecosystem. Here, a global survey of both eukaryotic and prokaryotic MAGs enabled the identification of ecological cohorts, driven by specific environmental factors, and putative host-microbe associations. Accessible and scalable computational tools, such as EukHeist, are likely to accelerate the identification of meaningful genetic signatures from large datasets, ultimately expanding the eukaryotic tree of life.
Intermittent hypoxia enhances the expression of HIF1A by increasing the quantity and catalytic activity of KDM4A-C and demethylating H3K9me3 at the HIF1A locus
Authors: Martinez Chloe-Anne , Bal Neha , Cistulli Peter A , Cook Kristina M
Published: July 2021

Cellular oxygen-sensing pathways are primarily regulated by hypoxia inducible factor-1 (HIF-1) in chronic hypoxia and are well studied. Intermittent hypoxia also occurs in many pathological conditions, yet little is known about its biological effects. In this study, we investigated how two proposed cellular oxygen sensing systems, HIF-1 and KDM4A-C, respond to cells exposed to intermittent hypoxia and compared to chronic hypoxia. We found that intermittent hypoxia increases HIF-1 activity through a pathway distinct from chronic hypoxia, involving the KDM4A, -B and -C histone lysine demethylases. Intermittent hypoxia increases the quantity and activity of KDM4A-C resulting in a decrease in H3K9 methylation. This contrasts with chronic hypoxia, which decreases KDM4A-C activity, leading to hypermethylation of H3K9. Demethylation of histones bound to the HIF1A gene in intermittent hypoxia increases HIF1A mRNA expression, which has the downstream effect of increasing overall HIF-1 activity and expression of HIF target genes. This study highlights how multiple oxygen-sensing pathways can interact to regulate and fine tune the cellular hypoxic response depending on the period and length of hypoxia.
Understanding associative false memories in aging using multivariate analyses
Authors: Dennis Nancy A. , Overman Amy A. , Carpenter Catherine M. , Gerver Courtney R.
Published: July 2021

Age-related declines in associative memory are ubiquitous, having been observed across a wide array of stimuli and experimental paradigms. Research further shows that such decreases in behavioral discriminability arise from increases in false memories for recombined lures. The current study examined the underlying neural basis of associative false memories by using representational similarity analyses to examine both age differences in the reactivation of encoded representations during retrieval and the neural overlap in the similarity of neural patterns underlying targets and related lures during retrieval. Behaviorally, we observed an age-related reduction in d’, which was shown to be driven by increased false alarms in the older adults. While we found no age difference in the relationship between patterns of neural activity underlying hits across memory phases (as measured by ERS), the similarity of neural patterns underlying targets and lures was affected by age. Specifically, while younger and older adults exhibited overall higher pattern similarity between hits and CRs compared to hits and FAs (as measured by RSA), this difference was reduced in older adults within occipital cortices. Additionally, greater Hit-FA representational similarity correlated with increases in associative FAs across occipital, frontal, and parietal cortices. Results suggest that while neural representations underlying targets may not differ across age, greater pattern similarity between the neural representation of targets and lures may reflect reduced distinctiveness of the information encoded in memory, such that old and new items are more difficult to discriminate, leading to more false alarms.
Inhibition of striatal SEZ6 by miR-3594-5p is a drug-specific marker for late-stage heroin intake escalation
Authors: Lenoir Magalie , Bondi Isabella , Clemenceau Loïc , Nondier Isabelle , Ballé Margaux , Jacques Sébastien , Duché Angéline , Canestrelli Corinne , Martin-Lannerée Séverine , Mouillet-Richard Sophie , Gunnersen Jenny M. , Ahmed Serge H. , Marie Nicolas , Noble Florence
Published: July 2021

Escalation of drug use is a hallmark stage in the transition to addiction and uncovering its underlying brain molecular mechanisms constitutes a considerable challenge. Here, we report in rats with extended access to heroin for self-administration that miR-3594-5p was upregulated in the dorsal striatum at late, but not early, stages during escalation when excessive heroin intake plateaued. Striatal miR-3594-5p bound directly to the 3’UTR region ofSez6transcript and inhibited its expression, thereby decreasing the mature form of the translated SEZ6 protein. This miR-3594-5p/Sez6interaction was specific to heroin, as it was not observed with cocaine, and correlated with the severity of heroin intake escalation. Our findings reveal that miRNA alterations during escalation of drug self-administration are spatially and temporally regulated and drug-specific.
LAMP2A regulates the loading of proteins into exosomes
Authors: Ferreira João Vasco , da Rosa Soares Ana , Ramalho José , Carvalho Catarina Máximo , Cardoso Maria Helena , Pintado Petra , Carvalho Ana Sofia , Beck Hans Christian , Matthiesen Rune , Zuzarte Mónica , Girão Henrique , van Niel Guillaume , Pereira Paulo
Published: July 2021

Exosomes are extracellular vesicles of endosomal origin released by virtually all cell types across metazoans. Exosomes are active vehicles of intercellular communication and can transfer lipids, RNAs and proteins between different cells, tissues or organs. However, the mechanisms that regulate the selective loading of cytosolic proteins into these vesicles are still largely unknow. Here we describe a mechanism whereby proteins containing a pentapeptide sequence, biochemically related to the KFERQ-motif, are loaded into a subpopulation of exosomes in a process that is dependent on the membrane protein LAMP2A. Moreover, this mechanism is independent of the ESCRT machinery components TSG101 and VPS4b and dependent on HSC70, CD63, Alix, Syntenin-1, Rab31 and ceramides. The transcription factor and master regulator of hypoxia HIF1A is loaded into exosomes by this mechanism to transport hypoxia signaling to normoxic cells. Additionally, by tagging fluorescent proteins with KFERQ-like sequences we were able to follow inter-organ transfer of exosomes in zebrafish larvae. Our findings identify LAMP2A as a key component in exosome biogenesis while opening new avenues for exosome engineering by allowing the loading of bioactive proteins by tagging them with KFERQ-like motifs.
ABlooper: Fast accurate antibody CDR loop structure prediction with accuracy estimation
Authors: Abanades Brennan , Georges Guy , Bujotzek Alexander , Deane Charlotte M.
Published: July 2021

Antibodies are a key component of the immune system and have been extensively used as biotherapeutics. Accurate knowledge of their structure is central to understanding their antigen binding function. The key area for antigen binding and the main area of structural variation in antibodies is concentrated in the six complementarity determining regions (CDRs), with the most important for binding and most variable being the CDR-H3 loop. The sequence and structural variability of CDR-H3 make it particularly challenging to model. Recently deep learning methods have offered a step change in our ability to predict protein structures. In this work we present ABlooper, an end-to-end equivariant deep-learning based CDR loop structure prediction tool. ABlooper rapidly predicts the structure of CDR loops with high accuracy and provides a confidence estimate for each of its predictions. On the models of the Rosetta Antibody Benchmark, ABlooper makes predictions with an average CDR-H3 RMSD of 2.49Å, which drops to 2.05Å when considering only its 76% most confident predictions.
Impact of neurite alignment on organelle motion
Authors: Mytiliniou Maria , Wondergem Joeri A. J. , Schmidt Thomas , Heinrich Doris
Published: July 2021

Intracellular transport is pivotal for cell growth and survival. Malfunctions in this process have been associated with devastating neurodegenerative diseases, posing a need for deeper understanding of the involved mechanisms. Here, we used an experimental methodology that lead neurites of differentiated PC12 cells in either of two configurations: an one-dimensional, where the neurites align along lines, or a two-dimensional configuration, where the neurites adopt a random orientation and shape on a fiat substrate. We subsequently monitored the motion of functional organelles, the lysosomes, inside the neurites. Implementing a time-resolved analysis of the mean-squared displacement, we quantitatively characterized distinct motion modes of the lysosomes. Our results indicate that neurite alignment gives rise to faster diffusive and super-diffusive lysosomal motion in comparison to the situation where the neurites are randomly oriented. After inducing lysosome swelling through an osmotic challenge by sucrose, we confirmed the predicted slowdown in diffusive mobility. Surprisingly we found that the swelling-induced mobility change affected each of the (sub-/super-) diffusive motion modes differently and depended on the alignment configuration of the neurites. Our findings imply that intracellular transport is significantly and robustly dependent on cell morphology, which might be in part controlled by the extracellular matrix.
A highly conserved host lipase deacylates oxidized phospholipids and ameliorates acute lung injury
Authors: Zou Benkun , Goodwin Michael , Saleem Danial , Jiang Wei , Tang Jianguo , Chu Yiwei , Munford Robert , Lu Mingfang
Published: July 2021

Oxidized phospholipids have diverse biological activities, many of which can be pathological, yet how they are inactivatedin vivois not fully understood. Here we present evidence that a previously unsuspected host lipase, acyloxyacyl hydrolase (AOAH), can play a significant role in reducing the pro-inflammatory activities of two prominent products of phospholipid oxidation, 1-palmitoyl-2-glutaryl-sn-glycero-3- phosphocholine (PGPC) and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC). AOAH removed the sn-2 and sn-1 acyl chains from both lipids and reduced their ability to induce macrophage inflammasome activation and cell deathin vitroand acute lung injuryin vivo. In addition to transforming Gram-negative bacterial lipopolysaccharide from stimulus to inhibitor, its most studied activity, AOAH can inactivate these important danger-associated molecular pattern (DAMP) molecules and reduce tissue inflammation and cell death.
Evaluating Differences in Elastic Modulus of Regenerated and Uninjured Mouse Digit Bone through microCT Density-Elasticity Calculation and Nanoindentation Testing
Authors: Hoffseth Kevin F , Busse Emily , Lacey Michelle , Sammarco Mimi C
Published: July 2021

Bone is an essential, healing structure in vertebrates that ensures daily function. However, the regenerative capacity of bone declines with age, compromising quality of life in the elderly and increasing cost of care. Here, for the first time, the elasticity of regenerated bone in a mouse digit amputation model is evaluated in order to better investigate biomechanics of skeletal regeneration. Amputation of the distal one third of the digit (third phalangeal element – P3) results in de novo regeneration of the digit, where analyzing the structural quality of this regenerated bone is a challenging task due to its small scale and triangular shape. To date, the evaluation of structural quality of the P3 bone has primarily focused on mineral density and bone architecture. This work describes an image-processing based method for assessment of elasticity in the whole P3 bone by using microcomputed tomography-generated mineral density data to calculate spatially discrete elastic modulus values across the entire P3 bone volume. Further, we validate this method through comparison to nanoindentation-measured values for elastic modulus. Application to a set of regenerated and unamputated digits shows that regenerated bone has a lower elastic modulus compared to the uninjured digit, with a similar trend for experimental hardness values. This method will be impactful in predicting and evaluating the regenerative outcomes of potential treatments and heightens the utility of the P3 regenerative model.
Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma
Authors: Urtatiz Oscar , Haage Amanda , Tanentzapf Guy , Van Raamsdonk Catherine D.
Published: July 2021

Different melanoma subtypes exhibit specific and non-overlapping sets of oncogene and tumor suppressor mutations, despite a common cell of origin in melanocytes. For example, activation of the Gαq/11signaling pathway is a characteristic initiating event in primary melanomas that arise in the dermis, uveal tract or central nervous system. It is rare in melanomas arising in the epidermis. Here, we present evidence that in the mouse, crosstalk with the epidermal microenvironment actively impairs the survival of melanocytes expressing the GNAQQ209Loncogene, providing a new model for oncogene specificity in cancer. The presence of epidermal cells inhibited cell division and fragmented dendrites of melanocytes expressing GNAQQ209Lin culture, while they promoted the growth of normal melanocytes. Differential gene expression analysis of FACS sorted epidermal melanocytes showed that cells expressing GNAQQ209Lexhibit an oxidative stress and apoptosis signature previously linked to vitiligo. Furthermore, PLCB4, the direct downstream effector of Gαq/11signaling, is frequently mutated in cutaneous melanoma alongside P53 and NF1. Our results suggest that a deficiency of PLCB4 promotes cutaneous melanomagenesis by reducing GNAQ driven signaling. Hence, our studies reveal the flip side of the GNAQ/PLCB4 signaling pathway, which was hitherto unsuspected. In the future, understanding how epidermal crosstalk restrains the GNAQQ209Loncogene could suggest novel melanoma therapies.
Conformational control through co-operative nonconventional C—H...N hydrogen bonds
Authors: Bosch Eric , Bowling Nathan P. , Oburn Shalisa M.
Published: July 2021

We report the design, synthesis, and crystal structure of a conjugated aryleneethynyl molecule, 2-(2-{4,5-dimethoxy-2-[2-(2,3,4-trifluorophenyl)ethynyl]phenyl}ethynyl)-6-[2-(pyridin-2-yl)ethynyl]pyridine, C30H17F3N2O2, that adopts a planar rhombus conformation in the solid state. The molecule crystallizes in the space group P-1, with Z = 2, and features two intramolecular sp2
-C—H...N hydrogen bonds that co-operatively hold the arylethynyl molecule in a rhombus conformation. The H atoms are activated towards hydrogen bonding since they are situated on a trifluorophenyl ring and the H...N distances are 2.470 (16) and 2.646 (16) Å, with C—H...N angles of 161.7 (2) and 164.7 (2)°, respectively. Molecular electrostatic potential calculations support the formation of C—H...N hydrogen bonds to the trifluorophenyl moiety. Hirshfeld surface analysis identifies a self-complementary C—H...O dimeric interaction between adjacent 1,2-dimethoxybenzene segments that is shown to be common in structures containing that moiety.
Corrosion behavior of carbon steel in H2S-CO2-H2O-methyldiethanolamine (MDEA) solution under the presence of chloride ions
Authors: Wu Guiyang , Gu Xikui , Zhao Wanwei , Fan Rui , Mao Ting
Published: July 2021

Purpose

This paper aims to study the effect of chloride ions concentration on the corrosion behavior of carbon steel in methyldiethanolamine (MDEA) aqueous solution in the sight of different process parameters of purification plant.

Design/methodology/approach

Due to the decrease of filtration efficiency and separation efficiency, the chloride ion in the desulfurization solution is enriched. The corrosion behavior of carbon steel under chloride ion enrichment environment was studied by weight-loss method, electrochemical impedance spectroscopy, cyclic polarization curve, X-ray photoelectron spectroscopy and scanning electron microscopy.

Findings

The results show that temperature and hydrogen sulfide loads are the main factors of corrosion in CO2-MDEA-H2O-H2S environment. The enrichment of chloride ions reduces the corrosion rate at low temperature but promotes the corrosion rate at high temperature. The chloride concentration should be controlled below 3000 mg/L, and no pitting corrosion was found under the experimental conditions.

Originality/value

The effect of chloride ion enrichment on MDEA solution corrosion shows that at low temperature, the increase of chloride ion will reduce the acid gas load and increase the density of corrosion products, so as to reduce the corrosion; on the contrary, at high temperature, the density of corrosion products will decrease and the corrosion will be intensified as well. It is believed that the chloride ion should be controlled below 3000 mg/L according to the results of the tests.
Barriers for homeless with dual diagnosis: lessons learned from intensive mobile psychosocial assertive community treatment program
Authors: Zolnikov Tara Rava , Hammel Michael , Furio Frances , Eggleston Brandon
Published: July 2021

Purpose

Dual diagnosis is a term that describes the co-occurrence of mental health disorders or illness and substance use or abuse disorders. Because this co-occurrence results in multiple diseases, layers of treatment are often needed to successfully create positive change in the individual. The purpose of this study is to explore factors of treatment that could facilitate improvements in functionality and quality of life for those with a dual diagnosis.

Design/methodology/approach

A secondary data analysis, using both quantitative and qualitative data, was completed. Secondary analysis is an empirical exercise that applies the same basic research principles as studies using primary data and has steps to be followed, including the evaluative and procedural steps commonly associated with secondary data analysis. Documentation data from the intensive mobile psychosocial assertive community treatment program was gathered for this analysis; this program was used because of the intensive and community-based services provided to patients with a dual diagnosis.

Findings

The major findings from this secondary analysis suggested that significant barriers included “denial” (e.g. evasion, suspension or avoidance of internal awareness) of diagnoses, complicated treatment and other barriers related to housing. Ultimately, these findings provided greater insight into potential effective treatment interventions for people living with a dual diagnosis.

Originality/value

This study adds to the growing body of literature showing that patient-centered care allows for more effective treatment and ultimately, improved health outcomes.