bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel ‘GaEl antigenic patches’ identified by ‘reverse epitomics’ approach to design multi-patch vaccines against NIPAH infection, a silent threat to global human health
Authors: Srivastava Sukrit , Kolbe Michael 
Published: September 2022

AbstractBackgroundNipah virus (NiV) is a zoonotic virus that causes lethal encephalitis and respiratory disease with the symptom of endothelial cell-cell fusion. Several NiV outbreaks have been reported since 1999 with nearly annual occurrences in Bangladesh. The outbreaks had high mortality rates ranging from 40 to 90%. No specific vaccine has yet been reported against NiV.MethodologyRecently, several vaccine candidates and different designs of vaccines composed of epitopes against NiV were proposed. Most of the vaccines target single protein or protein complex subunits of the pathogen. The Multi-epitope vaccines proposed also cover a largely limited number of epitopes and hence their efficiency is still pending. To address the urgent need for a specific and effective vaccine against NiV infection in the present study, we have utilized the ‘Reverse Epitomics’ approach (“overlapping-epitope-clusters-to-patches” method) to identify ‘antigenic patches’ (Ag-Patches) and utilize them as immunogenic composition for Multi-Patch vaccine (MPV) design. The designed MPVs were analyzed for immunologically crucial parameters, physiochemical properties and interaction with Toll-like receptor 3 ectodomain.ResultsIn total 30 CTL (Cytotoxic T lymphocyte) and 27 HTL (Helper T lymphocytes) antigenic patches were identified from the entire NiV proteome based on the clusters of overlapping epitopes. These identified Ag-Patches cover a total of discreet 362 CTL and 414 HTL epitopes from entire proteome of NiV. The antigenic patches were utilized as immunogenic composition for the design of two CTL and two HTL multi-patch vaccines. The 57 antigenic patches utilized here cover 776 overlapping epitopes targeting 52 different HLA class I and II alleles providing a global ethnically distributed human population coverage of 99.71%. Such large number of epitope coverage resulting in large human population coverage cannot be reached with single protein/subunit or multi-epitope based vaccines. The reported antigenic patches also provide potential immunogenic composition for early detection diagnostic kits for NiV infection. Further, all the MPVs & Toll-Like Receptor ectodomain complexes show stable nature of molecular interaction with numerous hydrogen bonds, salt bridges and non-bounded contacts formation and acceptable root mean square deviation and fluctuation. The cDNA analysis show a favorable large scale expression of the MPV constructs in human cell line.ConclusionBy utilizing the novel ‘Reverse epitomics’ approach highly immunogenic novel ‘GaEl antigenic patches’ (GaEl Ag-Patches) a synonym term for ‘antigenic patches’, were identified and utilized as immunogenic composition to design four MPVs against NiV. We conclude that the novel Multi-Patch Vaccines is a potential candidate to combat NiV, with greater effectiveness, high specificity and large human population coverage worldwide.
Positive effects of tree diversity on tropical forest restoration in a field-scale experiment
Authors: Veryard Ryan , Wu Jinhui , O’Brien Michael J. , Anthony Rosila , Both Sabine , Burslem David F.R.P. , Chen Bin , Cagigal Elena Fernandez-Miranda , J. Godfray H. Charles , Godoong Elia , Liang Shunlin , Saner Philippe , Schmid Bernhard , Wai Yap Sau , Xie Jun , Reynolds Glen , Hector Andy 
Published: September 2022

AbstractExperiments under controlled conditions have established that ecosystem functioning is generally positively related to levels of biodiversity, but it is unclear how widespread these effects are in real-world settings and whether they can be harnessed for ecosystem restoration. We used a long-term, field-scale tropical restoration experiment to test how the diversity of planted trees affected recovery measured across a 500 ha area of selectively logged forest using multiple sources of satellite data. Replanting with species rich mixtures of tree seedlings that had higher phylogenetic and functional diversity accelerated restoration rates. Our results are consistent with a positive relationship between biodiversity and ecosystem functioning in the lowland dipterocarp rainforests of SE Asia and demonstrate that using diverse mixtures of species can enhance initial recovery after logging.
Loss of FBXO11 function establishes a stem cell program in acute myeloid leukemia through dysregulation of mitochondrial LONP1
Authors: Mo Angela Ya-Chi , Kincross Hayle , Wang Xuan , Chang Linda Ya-Ting , Duns Gerben , Mey Franziska , Zhu Zurui , Kwan Harwood , Lau Tammy , Docking T. Roderick , Tran Jessica , Colborne Shane , Cheng Se-Wing Grace , Huang Shujun , Gharaee Nadia , Willie Elijah , Jiang Jihong , Parker Jeremy , Bridgers Joshua , Wood Davis , Geltink Ramon Klein , Morin Gregg B. , Karsan Aly 
Published: September 2022

SummaryAcute myeloid leukemia (AML) is an aggressive cancer with very poor outcomes. To identify additional drivers of leukemogenesis, we analyzed sequence data from 1,727 unique individual AML patients, which revealed mutations in ubiquitin ligase family genes in 11.2% of adult AML samples with mutual exclusivity. The Skp1/Cul1/Fbox (SCF) E3 ubiquitin ligase complex geneFBXO11was the most significantly downregulated gene of the SCF complex in AML. FBXO11 catalyzes K63-linked ubiquitination of a novel target, LONP1, which promotes entry into mitochondria, thereby enhancing mitochondrial respiration. Reduced mitochondrial respiration secondary toFBXO11depletion imparts myeloid-biased stem cell properties in primary CD34+hematopoietic stem progenitor cells (HSPC). In a human xenograft model, depletion of FBXO11 cooperated withAML1-ETOand mutantKRASG12Dto generate serially transplantable AML enriched for primitive cells. Our findings suggest that reduced FBXO11 primes HSPC for myeloid-biased self-renewal through attenuation of LONP1-mediated regulation of mitochondrial respiration.
Transiently heritable fates and quorum sensing drive early IFN-I response dynamics
Authors: Van Eyndhoven Laura C. , Verberne Vincent P.G. , Bouten Carlijn V.C. , Singh Abhyudai , Tel Jurjen 
Published: September 2022

AbstractType I Interferon (IFN-I)-mediated antiviral responses are central to host defense against viral infections. Crucial is the tight and well-orchestrated control of cellular decision-making leading to the production of IFN-Is. Innovative single-cell approaches revealed that the initiation of IFN-I production is only limited to a fraction of 1-3% of the total population, both found in vitro and in vivo, which were thought to be stochastically regulated. To challenge this dogma, we addressed the influence of various host-intrinsic factors, both stochastic and epigenetic, on dictating early IFN-I responses. Hypomethylating drugs increased the percentage of responding cells. Next, with the classical Luria-Delbrück fluctuation test, we provided evidence that the fate of becoming a responding cell is transiently heritable. Finally, while studying varying cell-densities, we substantiated an important role for quorum sensing, which was verified by mathematical modeling. Together, this systems immunology approach opens up new avenues to progress the fundamental understanding of cellular decision-making during early IFN-I responses, which can be translated to other (immune) signaling systems, and ultimately will improve IFN-I based immune therapies.
Fanconi anemia-isogenic head and neck cancer cell line pairs - a basic and translational science resource
Authors: Nguyen H. Tai , Tang Weiliang , Webster Andrew L.H. , Whiteaker Jeffrey R. , Chandler Christopher M. , Errazquin Ricardo , Sullivan Lucas B. , Jonlin Erica , Hoskins Elizabeth E. , Chen Eleanor Y. , Fritzke Madeline , Paulovich Amanda G. , Wells Susanne I. , Roohollahi Khashayar , Dorsman Josephine , Brakenhoff Ruud , Garcia-Escudero Ramon , Smogorzewska Agata , Wakefield Leslie , Grompe Markus , Monnat Raymond J. 
Published: September 2022

AbstractFanconi anemia (FA) is a heritable malformation, bone marrow failure and cancer predisposition syndrome that confers an exceptionally high risk of developing carcinomas arising in squamous mucosal epithelia lining the mouth, proximal esophagus, vulva and anus. The origin of these cancers is not understood, and no effective way has been identified to prevent or delay their appearance. FA-associated carcinomas are also therapeutically challenging, as they may be multi-focal and stage-advanced at diagnosis making surgical control challenging. Moreover, individuals with FA have systemic DNA damage hypersensitivity and thus an elevated risk of toxicity when treated with standard-of-care therapies such as DNA cross-linking drugs and ionizing radiation.We developed the Fanconi Anemia Cancer Cell Line Resource (FA-CCLR) in order to foster new research on the origins, treatment, and prevention of FA-associated cancers. The FA-CCLR consists of FANC-isogenic head and neck squamous cell carcinoma (HNSCC) cell line pairs from cancers arising in individuals with FA, or newly engineered from sporadic HNSCC cell lines. Molecular, cellular, and biochemical analyses were used to demonstrate the causal dependence of key FA-associated phenotypes on FANC genotype, expression and pathway activity. These FANC-isogenic cell line pairs are available to academic and non-profit investigators, with ordering information available at the ‘Fanconi Anemia Research Materials’ Resource and Repository at Oregon Health & Sciences University, Portland OR.SignificanceWe have generated new isogenic cancer cell line models to investigate the origins, treatment and prevention of Fanconi anemia-associated squamous carcinomas that target the oral mucosa, proximal esophagus, and anogenital region.
Ecological succession revisited from a temporal beta-diversity perspective
Authors: Nakadai Ryosuke , Suzuki Satoshi N. 
Published: September 2022

AbstractEcological succession, which is the community re-assembly process after a disturbance, is a study topic receiving renewed attention in relation to anthropogenic disturbance as well as one of the most classical ones in ecology. Previous studies occasionally revealed that compositional shifts decrease toward late succession stages and discussed the potential links with species life history and longevity. However, clear empirical evidence is not available until now because of limited analytical approaches. Therefore, traditional approaches used in previous studies could not quantify the relative contribution of demographic processes to apparent compositional shifts in communities.In the present study, we aimed to understand ecological succession processes by revealing the patterns of temporal beta diversity based on both conventional Bray-Curtis dissimilarity and recently developed individual-based dissimilarity indices using a long-term dataset. Specifically, we used published forest inventory data from permanent forest plots in cool temperate forests along a secondary successional chronosequence, with stands at 17 to 106 years post clear-cutting.We clearly demonstrated the detailed patterns of temporal beta-diversity indices (i.e., conventional Bray–Curtis dissimilarity and individual-based dissimilarity indices) based on stem number and stem basal area along long-term chronosequences across approximately one hundred years.Synthesis. Using a long-term forest inventory dataset, this study demonstrated the link between the apparent compositional shifts and the changes in each component of the demographic processes (i.e., recruitment, growth, and mortality) during secondary forest succession in the context of temporal beta diversity. As done in this study, future research on changes in community composition during ecological successions at various sites and systems will help elucidate the relationships between temporal changes in global biodiversity and the impact of anthropogenic environmental changes.
Tumor microenvironment impaired T cell antigen recognition and function were restored by Lovastatin therapy
Authors: Yuan Zhou , O’Melia Meghan J. , Li Kaitao , Lyu Jintian , Rosado Aaron M. , Watson Valencia E. , Ashkezari Amir Hossein Kazemipour , Zhou Fangyuan , Kansal Vikash , Kinney Brendan , Travaglino Stefano , Doudy Larissa O. , Noel Richard K. , Lucas Samuel N. , Kong Steven Lingyang , Jothikumar Prithiviraj , Rohner Nathan A. , Manspeaker Margaret P. , Francis David M. , Bai Ke , Ge Chenghao , Rushdi Muaz N. , Chingozha Loice , Ruipérez-Campillo Samuel , Jiang Ning , Lu Hang , Schmitt Nicole C. , Thomas Susan N. , Zhu Cheng 
Published: September 2022

AbstractCD8+T cells underpin effective anti-tumor immune responses in melanoma; however, their functions are attenuated due to various immunosuppressive factors in the tumor microenvironment (TME), resulting in disease progression. T cell function is elicited by the T cell receptor (TCR), which recognizes antigen peptide-major histocompatibility complex (pMHC) expressed on tumor cells via direct physical contact, i.e., two-dimensional (2D) interaction. TCR–pMHC 2D affinity plays a central role in antigen recognition and discrimination, and is sensitive to both the conditions of the T cell and the microenvironment in which it resides. Herein, we demonstrate that CD8+T cells residing in TME have lower 2D TCR–pMHC bimolecular affinity and TCR–pMHC–CD8 trimolecular avidity, pull fewer TCR–pMHC bonds by endogenous forces, flux lower level of intracellular calcium in response to antigen stimulation, exhibit impairedin vivoactivation, and show diminished anti-tumor effector function. These detrimental effects are localized in the tumor and tumor draining lymph node (TdLN), and affect both antigen-inexperienced and antigen-experienced CD8+T cells irrespective of their TCR specificities. These findings implicate impaired antigen recognition as a mechanism of T cell dysfunction in the TME.
Tumor suppressor p53 deficiency increases tumor immunogenicity through promoting IL33-mediated anti-tumor immune responses
Authors: Li Yang , Gao David Shihong , Yi Lixian , Gao Fei , Sun Runzi , Lu Kevin Kai , Xu Junchi , Shoush Jason , Kykrou Zoi , Liang Minxin , Lu Binfeng 
Published: September 2022

AbstractRecent studies have shown that p53 contributes to poor survival during immune checkpoint blockade (ICB) therapy. Lung cancer patients with p53 mutations have significantly improved response rates to PD-1 ICB therapy. While previous studies have shown that tumor-derived IL-33 is required for the anti-tumor immune response and efficacy of ICB therapies, the relationship between p53 and IL-33 during ICB therapy is unknown. In this study, we characterized the role of the p53/IL-33 axis in regulating the tumor microenvironment (TME) in response to ICB therapy. CRISPR-Cas9-mediated deletion of Trp53 in tumor cells combined with PD-1 ICB therapy synergistically inhibited tumor growth in a murine MC38 colon adenocarcinoma model. We observed increased CD4+ and CD8+ T cell infiltration, as well as reduced Treg infiltration. IL-33 was upregulated and its expression increased with time and response to treatment. Simultaneous deletion of Il33 in the MC38 tumor cells reversed the efficacy of PD-1 ICB therapy. ST2-/-(IL-33 receptor) mice with Trp53-deficient MC38 tumors also showed no response to PD-1 ICB. Our findings depict a novel mechanism by which the loss of p53 in tumors treated with ICB therapy induces upregulation of tumoral IL-33 and host ST2 signaling. p53 mutations may be a double-edged sword for cancer, i.e. loss of the tumor suppressor initially facilitates tumorigenesis, but also leads to upregulation of danger signals in the tumor. These danger signals, such as IL-33, mediate the anti-tumor effect of ICB.
Transcriptome analysis of the necrotrophic pathogen Alternaria brassicae reveals a biphasic mode of pathogenesis in Brassica juncea
Authors: Rajarammohan Sivasubramanian 
Published: September 2022

ABSTRACTAlternaria blight or leaf spot caused by Alternaria brassicae has an enormous economic impact on the Brassica crops grown worldwide. Although the genome of A. brassicae has been sequenced, little is known about the genes that play a role during the infection of the host species. In this study, the transcriptome expression profile of A. brassicae during growth and infection was determined. Differential expression analysis revealed that 3921 genes were differentially expressed during infection. Weighted gene co-expression network analysis helped identify nine modules, which were highly correlated with growth and infection. Subsequent gene ontology (GO) enrichment analysis of the modules highlighted the involvement of biological processes such as toxin metabolism, ribosome biogenesis, polysaccharide catabolism, copper ion transport, and vesicular trafficking during infection. Additionally, 194 CAZymes and 64 potential effectors were significantly upregulated during infection. Furthermore, 17 secondary metabolite gene clusters were also differentially expressed during infection. The clusters responsible for the production of Destruxin B, Brassicicene C, and HC-toxin were significantly upregulated during infection. Collectively, these results provide an overview of the critical pathways underlying the pathogenesis of A. brassicae and highlight the distinct gene networks that are temporally regulated, resulting in a biphasic mode of infection. The study thus provides novel insights into the transcriptional plasticity of a necrotrophic pathogen during infection of its host. Additionally, the in planta expression evidence for many potential effectors provides a theoretical basis for further investigations into the effector biology of necrotrophic pathogens such as A. brassicae.
Cross-Modal Representation of Identity in Primate Hippocampus
Authors: Tyree Timothy J , Metke Michael , Miller Cory T 
Published: September 2022

AbstractFaces and voices are the dominant social signals used to recognize individuals amongst human and nonhuman primates (1–4). Yet it is not known how these critical signals are integrated into a cross-modal representation of individual identity in the primate brain. Here we show that while, like humans (5–7), single neurons in the marmoset hippocampus exhibit selective responses when presented with the face or voice of a specific individual conspecific, a parallel mechanism for representing the cross-modal identities for multiple individuals is evident within single neurons and at a population level. Manifold projections likewise showed separability of individuals, as well as clustering for others’ families, suggesting that multiple learned social categories are encoded as related dimensions of identity in hippocampus. These findings demonstrate that neural representations of identity in hippocampus are both modality-independent and reflect the hierarchical structure of the primate social network.One-Sentence SummaryWe show that cross-modal representations of identity in primate hippocampus can be achieved by at least two distinct neural mechanisms and comprise multiple social categories that reflect different relationships.
Hourglass, a tool to mine bioimaging data, uncovers sex-disparities in the IL-6-associated T cell response in pancreatic tumors
Authors: Aliar Kazeera , Waterhouse Henry R. , Vyas Foram , Krebs Niklas , Poulton Emily , Zhang Bowen , Chan Nathan , Bronsert Peter , Fischer Sandra E. , Gallinger Steven , Grünwald Barbara T. , Khokha Rama 
Published: September 2022

SummaryRecent advances in digital pathology have led to an explosion in high-content multidimensional imaging approaches. Yet, our ability to gainfully process, visualize, integrate and mine the resulting mass of bioimaging data remains a challenge. We have developed Hourglass, an open access user-friendly software that streamlines complex biology-driven post-processing and visualization of multiparametric data. Directed at datasets derived from tissue microarrays or imaging methods that analyze multiple regions of interest per patient specimen, Hourglass systematically organizes observations across spatial and global levels as well as within patient subgroups. Application of Hourglass to our large and complex pancreatic cancer bioimaging dataset (540,617 datapoints derived from 26 bioimaging analyses applied to 596 specimens from 165 patients) consolidated a breadth of known IL-6 functions in a well-annotated human pancreatic cancer cohort and uncovered new unprecedented insights into a sex-linked Interleukin-6 (IL-6) association with immune phenotypes. Specifically, regional effects of IL-6 on the intratumoral T cell response were restricted to male patients only. In conclusion, Hourglass facilitates multi-layered knowledge extraction from complex multiparametric bioimaging datasets and provides tailored analytical means to productively harness heterogeneity at the sample and patient level.
The ribosome quality control factors Asc1 and Hel2 regulate the expression of HSP70 during heat shock and recovery
Authors: Boopathy Lokha R. Alagar , Beadle Emma , Xiao Alan , Rico Aitana Garcia-Bueno , Alecki Celia , de-Andres Irene Garcia , Vera Maria 
Published: September 2022

ABSTRACTCells rapidly adapt to survive harsh environmental conditions through the potent upregulation of molecular chaperones or heat shock proteins (HSPs). The inducible members of the HSP70 family are the fastest and most transcriptionally induced chaperone upon stress. TheHSP70mRNA life cycle regulation in the cytoplasm is unique because it is translated during stress when general translation is repressed and rapidly degraded once conditions are optimal for growth. Contrary to the role of theHSP70mRNA 5’ untranslated region in maximizing the synthesis of HSP70, we discovered that the coding sequence (CDS) represses its translation through the ribosome quality control (RQC) mechanism. The CDS of the most inducible HSP70 inSaccharomyces cerevisiae, SSA4, is uniquely biased with low-frequency codons that promote ribosome stalling during heat stress. The stalled ribosomes are recognized by RQC components Asc1p and Hel2p and two ribosome proteins, Rps28A and Rps19B, that we identified as new RQC components. Surprisingly, RQC does not signal the degradation of theSSA4mRNA by no-go-decay (NGD). Instead, Asc1p destabilizes theSSA4mRNA during recovery from heat stress by a mechanism independent of its ribosome binding andSSA4CDS codon optimality. Therefore, Asc1p operates two synergistic mechanisms that converge to regulate the life cycle ofHSP70mRNA during stress and recovery. Our research identifies Asc1p as a critical regulator of the stress response and RQC as the system tuning HSP70 synthesis.