bluuebunny/crossref_metadata_2025_split huggingface dataset:
DeepGeni: Deep generalized interpretable autoencoder elucidates gut microbiota for better cancer immunotherapy
Authors: Oh Min , Zhang Liqing 
Published: May 2021

AbstractRecent studies revealed that gut microbiota modulates the response to cancer immunotherapy and fecal microbiota transplantation has clinical benefit in melanoma patients during the treatment. Understanding microbiota affecting individual response is crucial to advance precision oncology. However, it is challenging to identify the key microbial taxa with limited data as statistical and machine learning models often lose their generalizability. In this study, DeepGeni, a deep generalized interpretable autoencoder, is proposed to improve the generalizability and interpretability of microbiome profiles by augmenting data and by introducing interpretable links in the autoencoder. DeepGeni-based machine learning classifier outperforms state-of-the-art classifier in the microbiome-driven prediction of responsiveness of melanoma patients treated with immune checkpoint inhibitors. DeepGeni-based machine learning classifier outperforms state-of-the-art classifier in the microbiome-driven responsiveness prediction of melanoma patients treated with immune checkpoint inhibitors. Also, the interpretable links of DeepGeni elucidate the most informative microbiota associated with cancer immunotherapy response.
Active Surveillance Characterizes Human Intratumoral T Cell Exhaustion
Authors: You Ran , Artichoker Jordan , Fries Adam , Edwards Austin , Combes Alexis , Reeder Gabriella , Samad Bushra , Krummel Matthew F. 
Published: May 2021

AbstractIntratumoral T cells that might otherwise control tumors are often identified in an ‘exhausted’ state, defined by specific epigenetic modifications as well as upregulation of genes such as CD38, CTLA-4 and PD-1. While the term might imply inactivity, there has been little study of this state at the phenotypic level in tumors to understand the extent of their incapacitation. Starting with the observation that T cells move more quickly through mouse tumors as residence time increases and they progress towards exhaustion, we elaborated a non-stimulatory live-biopsy method for real-time study of T cell behaviors within individual patient tumors. Using two-photon microscopy, we studied native CD8 T cells interacting with APCs and with cancer cells in different micro-niches of human tumors, finding that T cell speed was variable by region and by patient, was independent of T cell density and was inversely correlated with local tumor density. Across a range of tumor types, we found a strong relationship between CD8 T cell motility and exhausted T cell state that corresponds to observations made in mouse models where exhausted T cells move faster. While this is a small study, it demonstrates at least two types of T cell dynamic states in individual human tumors and supports the existence of an active program in ‘exhausted’ T cells that extends beyond incapacitating them.
Notch-Induced Endoplasmic Reticulum-Associated Degradation Governs Thymocyte β−Selection
Authors: Liu Xia , Yu Jingjing , Xu Longyong , Umphred-Wilson Katharine , Peng Fanglue , Ding Yao , Barton Brendan M , Lv Xiangdong , Zhao Michael Y , Sun Shengyi , Hong Yuning , Qi Ling , Adoro Stanley , Chen Xi 
Published: May 2021

AbstractSignals from the pre-T cell receptor and Notch coordinately instructβ-selection of CD4−CD8−double negative (DN) thymocytes to generateαβT cells in the thymus. However, how these signals ensure a high-fidelity proteome and safeguard the clonal diversification of the pre- selection TCR repertoire given the considerable translational activity imposed byβ-selection is largely unknown. Here, we identify the endoplasmic reticulum (ER)-associated degradation (ERAD) machinery as a critical proteostasis checkpoint duringβ-selection. Expression of the SEL1L-HRD1 complex, the most conserved branch of ERAD, is directly regulated by the transcriptional activity of the Notch intracellular domain. Deletion ofSel1limpaired DN3 to DN4 thymocyte transition and severely impairedαβT cell development. Mechanistically,Sel1ldeficiency induced unresolved ER stress that triggered thymocyte apoptosis through the PERK pathway. Accordingly, genetically inactivating PERK rescued T cell development fromSel1l- deficient thymocytes. Our study reveals a critical developmental signal controlled proteostasis mechanism that enforces T cell development to ensure a healthy adaptive immunity.
Panacea: a hyperpromiscuous antitoxin protein domain for the neutralisation of diverse toxin domains
Authors: Kurata Tatsuaki , Saha Chayan Kumar , Buttress Jessica A. , Mets Toomas , Brodiazhenko Tetiana , Turnbull Kathryn J. , Awoyomi Ololade F. , Oliveira Sofia Raquel Alves , Jimmy Steffi , Ernits Karin , Delannoy Maxence , Persson Karina , Tenson Tanel , Strahl Henrik , Hauryliuk Vasili , Atkinson Gemma C. 
Published: May 2021

AbstractToxin-Antitoxin (TA) gene pairs are ubiquitous in microbial chromosomal genomes and plasmids, as well as bacteriophages. They act as regulatory switches, with the toxin limiting the growth of bacteria and archaea by compromising diverse essential cellular targets, and the antitoxin counteracting the toxic effect. To uncover previously uncharted TA diversity across microbes and bacteriophages, we analysed the conservation of genomic neighbourhoods using our computational tool FlaGs (for Flanking Genes), which allows high-throughput detection of TA-like operons. Focussing on the widespread but poorly experimentally characterised antitoxin domain DUF4065, our in silico analyses indicated that DUF4065-containing proteins serve as broadly distributed antitoxin components in putative TA-like operons with dozens of different toxic domains with multiple different folds. Given the versatility of DUF4065, we have renamed the domain to Panacea (and proteins containing the domain, PanA) after the Greek goddess of universal remedy. We have experimentally validated nine PanA-neutralised TA pairs. While the majority of validated PanA-neutralised toxins act as translation inhibitors or membrane disruptors, a putative nucleotide cyclase toxin from a Burkholderia prophage compromises replication and translation, as well as inducing RelA-dependent accumulation of the nucleotide alarmone (p)ppGpp. We find that Panacea-containing antitoxins form a complex with their diverse cognate toxins, characteristic of the direct neutralisation mechanisms employed by Type II TA systems. Finally, through directed evolution we have selected PanA variants that can neutralise non-cognate TA toxins, thus experimentally demonstrating the evolutionary plasticity of this hyperpromiscuous antitoxin domain.SignificanceToxin-antitoxin systems are enigmatic and diverse elements of bacterial and bacteriophage genomes. We have uncovered remarkable versatility of an antitoxin protein domain, that has evolved to neutralise dozens of different toxin domains. We find that antitoxins carrying this domain – Panacea – form complexes with their cognate toxins, indicating a direct neutralisation mechanism, and that Panacea can be evolved to neutralise a non-cognate and non-homologous toxin with just two amino acid substitutions. This raises the possibility that this domain could be an adaptable universal, or semi-universal protein neutraliser with significant biotechnological and medical potential.
A Comprehensive Human Embryogenesis Reference Tool using Single-Cell RNA-Sequencing Data
Authors: Zhao Cheng , Plaza Reyes Alvaro , Schell John Paul , Weltner Jere , Ortega Nicolás M. , Zheng Yi , Björklund Åsa K. , Baqué-Vidal Laura , Sokka Joonas , Torokovic Ras , Cox Brian , Rossant Janet , Fu Jianping , Petropoulos Sophie , Lanner Fredrik 
Published: May 2021

SummaryStem cell-based embryo models offer unprecedented experimental tools for studying early human development. The usefulness of embryo models hinges on their molecular, cellular and structural fidelities to theirin vivocounterparts. To authenticate human embryo models, single-cell RNA-sequencing has been utilised for unbiased transcriptional profiling. However, a well-organised and integrated human single-cell RNA-sequencing dataset, serving as a universal reference for benchmarking human embryo models, remains unavailable. Herein, we developed such a reference, through integration of six published human datasets covering developmental stages from the zygote to the gastrula. Lineage annotations are contrasted and validated with available human and non-human primate datasets. Using stabilised UMAP we constructed a web tool, where query datasets can be projected on the reference and annotated with predicted cell identities. Using this reference tool, we examined several recent human embryo models, highlighting the risk of misannotation when relevant references are lacking.
Spatial-temporal targeted and non-targeted surveys to assess microbiological composition of drinking water in Puerto Rico following Hurricane Maria
Authors: Sevillano Maria , Vosloo Solize , Cotto Irmarie , Dai Zihan , Jiang Tao , Santiago Santana Jose M. , Padilla Ingrid Y. , Rosario-Pabon Zaira , Vega Carmen Velez , Cordero José F. , Alshawabkeh Akram , Gu April , Pinto Ameet J. 
Published: May 2021

AbstractLoss of basic utilities, such as drinking water and electricity distribution, were sustained for months in the aftermath of Hurricane Maria’s (HM) landfall in Puerto Rico (PR) in September 2017. The goal of this study was to assess if there was deterioration in biological quality of drinking water due to these disruptions. This study characterized the microbial composition of drinking water following HM across nine drinking water systems (DWSs) in PR and utilized an extended temporal sampling campaign to determine if changes in the drinking water microbiome were indicative of HM associated disturbance followed by recovery. In addition to monitoring water chemistry, the samples were subjected to culture independent targeted and non-targeted microbial analysis including quantitative PCR (qPCR) and genome-resolved metagenomics. The qPCR results showed that residual disinfectant was the major driver of bacterial concentrations in tap water with marked decrease in concentrations from early to late sampling timepoints. WhileMycobacterium aviumandPseudomonas aeruginosawere not detected in any sampling locations and timepoints, genetic material fromLeptospiraandLegionella pneumophilawere transiently detected in a few sampling locations. The majority of metagenome assembled genomes (MAGs) recovered from these samples were not associated with pathogens and were consistent with bacterial community members routinely detected in DWSs. Further, whole metagenome-level comparisons between drinking water samples collected in this study with samples from other full-scale DWS indicated no significant deviation from expected community membership of the drinking water microbiome. Overall, our results suggest that disruptions due to HM did not result in significant and sustained deterioration of biological quality of drinking water at our study sites.Graphical Abstract
Combined responses of primary coral polyps and their algal endosymbionts to decreasing seawater pH
Authors: Scucchia Federica , Malik Assaf , Zaslansky Paul , Putnam Hollie M. , Mass Tali 
Published: May 2021

ABSTRACTWith coral reefs declining globally, resilience of these ecosystems hinges on successful coral recruitment. However, knowledge of the acclimatory and/or adaptive potential in response to environmental challenges such as ocean acidification (OA) in earliest life stages is limited. Our combination of physiological measurements, microscopy, computed tomography techniques and gene expression analysis allowed us to thoroughly elucidate the mechanisms underlying the response of early life stages of corals, together with their algal partners, to the projected decline in oceanic pH. We observed extensive physiological, morphological and transcriptional changes in surviving recruits, and the transition to a less-skeleton/more-tissue phenotype. We found that decreased pH conditions stimulate photosynthesis and endosymbiont growth, and gene expression potentially linked to photosynthates translocation. Our unique holistic study discloses the previously unseen intricate net of interacting mechanisms that regulate the performance of these organisms in response to OA.
Limited reciprocal surrogacy of bird and habitat diversity and inconsistencies in their representation in Romanian protected areas
Authors: Geue Julia C. , Rotter Paula J. , Gross Caspar , Benkő Zoltán , Kovács István , Fântână Ciprian , Veres-Szászka Judit , Domşa Cristi , Baltag Emanuel , Daróczi Szilárd J. , Bóné Gábor M. , Popescu Viorel D. , Thomassen Henri A. 
Published: May 2021

AbstractBecause it is impossible to comprehensively characterize biodiversity at all levels of organization, conservation prioritization efforts need to rely on surrogates. As species distribution maps of relished groups as well as high-resolution remotely sensed data increasingly become available, both types of surrogates are commonly used. A good surrogate should represent as much of biodiversity as possible, but it often remains unclear to what extent this is the case. Here, we aimed to address this question by assessing how well bird species and habitat diversity represent one another. We conducted our study in Romania, a species-rich country with high landscape heterogeneity where bird species distribution data have only recently started to become available. First, we prioritized areas for conservation based on either 137 breeding bird species or 36 habitat classes, and then evaluated their reciprocal surrogacy performance. Second, we examined how well these features are represented in already existing protected areas. Finally, we identified target regions of high conservation value for the potential expansion of the current network of reserves (as planned under the new EU Biodiversity Strategy for 2030). We found that bird species were a better surrogate for habitat diversity than vice versa. Highly ranked areas based on habitat diversity were represented better than areas based on bird species, which varied considerably between species. Our results highlight that taxonomic and environmental (i.e., habitat types) data may perform rather poorly as reciprocal surrogates, and multiple sources of data are required for a full evaluation of protected areas expansion.
A novel system for classifying tooth root phenotypes
Authors: Gellis Jason , Foley Robert 
Published: May 2021

AbstractHuman root and canal number and morphology are highly variable, and internal root canal form and count does not necessarily co-vary directly with external morphology. While several typologies and classifications have been developed to address individual components of teeth, there is a need for a comprehensive system, that captures internal and external root features across all teeth. Using CT scans, the external and internal root morphologies of a global sample of humans are analysed (n=945). From this analysis a method of classification that captures external and internal root morphology in a way that is intuitive, reproducible, and defines the human phenotypic set is developed. Results provide a robust definition of modern human tooth root phenotypic diversity. Our method is modular in nature, allowing for incorporation of past and future classification systems. Additionally, it provides a basis for analysing hominin root morphology in evolutionary, ecological, genetic, and developmental contexts.
Efficacy of double-stranded RNA for the large-scale control and prevention of sacbrood virus in Apis cerana (Hymenoptera: Apidae) apiaries
Authors: Yoo Mi-Sun , Truong A-Tai , Jeong Hana , Hahn Do Hyun , Lee Ju Seong , Yoon Soon-Seek , Cho Yun Sang 
Published: May 2021

AbstractSacbrood virus (SBV) infection in Apis cerana has caused tremendous damage in India, Thailand, Vietnam, and China since the 1970s. The disease caused by this virus results in colony collapse disorder in A. cerana and is also a devastating disease affecting A. cerana in South Korean apiaries. It has almost resulted in the elimination of the species. Therefore, control measures for this emerging threat are urgently needed. SBV RNA interference (RNAi) targeting VP1 was prepared to test the safety and efficacy of protection and treatment in artificially infected larvae and in infected colonies in South Korean apiaries. The efficacy of VP1 double-stranded RNA (dsRNA) was confirmed for the protection and treatment of infected larvae by increasing the survival rate in comparison with that in untreated larvae. Furthermore, an optimal application procedure was established for the large-scale RNAi treatment of SBV in apiaries. The protection of healthy colonies from SBV by RNAi was demonstrated in 100% of apiaries, and the treatment results showed that after five administrations, the SBV in infected colonies was mitigated to a safe level at which no symptoms of the disease were observed. Importantly, the low cost of dsRNA production in this study enables its application as a specific drug in large scale in South Korean apiculture.
AgMESH, a peritrophic matrix-associated protein embedded inAnopheles gambiaemelanotic capsules modulates malaria parasite infection
Authors: Camacho Emma , Dong Yuemei , Anglero-Rodriguez Yesseinia , Smith Daniel F. Q. , de Souza Jacomini Ricardo , McConnell Scott A. , Dimopoulos George , Casadevall Arturo 
Published: May 2021

AbstractMelanins are structurally complex pigments produced by organisms in all domains of life. In insects, melanins are essential for survival and have key roles in cuticle sclerotization, wound healing and innate immunity. In this study, we used a diverse set of molecular, biochemical, and imaging approaches to characterize mosquito melanin involved in innate immune defense (melanotic capsules). We observed that melanotic capsules enclosingPlasmodium bergheiookinetes were composed of an acid-resistant and highly hydrophobic material with granular appearance, which are characteristic properties of melanins. Spectroscopical analyses reveal chemical signatures of eumelanins and pheomelanin. Furthermore, we identified a set of 14 acid-resistant mosquito proteins embedded within the melanin matrix possibly related to an anti-Plasmodiumresponse. Among these,AgMESH, a mucin-related protein highly conserved among insects that is associated with the midgut brush border microvilli proteome ofAnopheles gambiaeandA. albimanus. AgMESHgene silencing in mosquitos was associated with reducedPlasmodiumparasite infection, compromised integrity of the peritrophic matrix, and inability to synthesize a dityrosine network. Our results provide a new approach to study aspects of insect melanogenesis that revealed proteins associated with melanotic capsule, one of which was strongly implicated in the stabilization of the peritrophic matrix and pathogenesis ofPlasmodiumspp. mosquito infection. Given the conservation ofAgMESH among disease-transmitting insect vector species, future analysis of this protein could provide fertile ground for the identification of strategies that block transmission of vector borne diseases to humans.Significance StatementMalaria is a parasitic disease transmitted by mosquito bites. Here, we adapt methodologies to study fungal melanogenesis to explore the melanin-based immune response ofAnopheles gambiaeagainst malaria parasites. We reveal that melanotic capsules againstPlasmodiumare composed of pheomelanin and eumelanin. We demonstrate that melanin-encapsulatedPlasmodiumis associated to acid-resistant mosquito gut proteins and identify several putative factors of the melanin-mediated immunity. Disruption ofAgMESH, a surface-associated protein conserved among other mosquito vectors, demonstrates its ability to impaired formation of the dityrosine network and peritrophic matrix compromising parasite development within the mosquito gut. Our study provides a new approach to investigate the melanin-based defense mechanism in insects and identified a potential host molecule for developing novel universal vector-control schemes.
Deciphering the role of mucosal immune responses and cervicovaginal microbiome in resistance to HIV infection in HIV-exposed seronegative (HESN) women
Authors: Ponnan Sivasankaran Munusamy , Thiruvengadam Kannan , Tellapragada Chaitanya , Ambikan Anoop T , Narayanan Aswathy , Kathirvel Sujitha , Shankar Janani , Rajaraman Akshaya , Amanulla Mehar Afsan , Dinesha Thongadi Ramesh , Poongulali Selvamuthu , Saravanan Shanmugam , Murugavel Kailapuri Gangatharan , Swaminathan Soumya , Velu Vijayakumar , Shacklett Barbara , Neogi Ujjwal , Hanna Luke Elizabeth 
Published: May 2021

AbstractThe female genital tract (FGT) is an essential site of HIV infection. Discerning the nature of HIV-specific local immune responses is crucial for identifying correlates of protection in HIV-exposed seronegative (HESN) individuals. The present study involved a comprehensive analysis of soluble immune mediators, secretory immunoglobulins (sIg) and levels of natural killer (NK) cells, CXCR5+CD8+T cells, T follicular helper cells (Tfh) and T regulatory cells (T regs) in the vaginal mucosa, as well as the nature and composition of the cervicovaginal microbiome in HESN women. We found significantly elevated antiviral cytokines, soluble immunoglobulins, and increased frequencies of activated NK cells, CXCR5+CD8+T cells and Tfh cells in HESN females as compared to HIV unexposed healthy (UH) women. Analysis of the genital microbiome of HESN women revealed a greater bacterial diversity and increased abundance ofGardnerella sppin the mucosa of HESN women. The findings suggest the female genital tract of HESN females represents a microenvironment equipped with innate immune factors, antiviral mediators and critical T cells subsets that protect against HIV infection.
Instant three color multi-plane fluorescence microscopy
Authors: Gregor Ingo , Butkevich Eugenia , Enderlein Jörg , Mojiri Soheil 
Published: May 2021

AbstractOne of the most widely used microscopy techniques in biology and medicine is fluorescence microscopy, offering high specificity in labeling as well as maximum sensitivity. For live cell imaging, the ideal fluorescence microscope should offer high spatial resolution, fast image acquisition, three-dimensional sectioning, and multi-color detection. However, most existing fluorescence microscopes have to compromise between these different requirements. Here, we present a multi-plane multi-color wide-field microscope that uses a dedicated beam-splitter for recording volumetric data in eight focal planes and for three emission colors with frame rates of hundreds of volumes per second. We demonstrate the efficiency and performance of our system by three-dimensional imaging of multiply labeled fixed and living cells.