bluuebunny/crossref_metadata_2025_split huggingface dataset:
Negative immune regulation contributes to disease tolerance in Drosophila
Authors: Prakash Arun , Monteith Katy M. , Vale Pedro F. 
Published: September 2021

AbstractDisease tolerance is an infection phenotype where hosts show relatively high health despite harbouring elevated pathogen loads. Variation in the ability to reduce immunopathology may explain why some hosts can tolerate higher pathogen burdens with reduced pathology. Negative immune regulation would therefore appear to be a clear candidate for a mechanism underlying disease tolerance. Here, we examined how the negative regulation of the immune deficiency (IMD) pathway affects disease tolerance inDrosophila melanogasterwhen infected with four doses of the gram-negative bacterial pathogenPseudomonas entomophila. We find that while flies unable to regulate the IMD response exhibited higher expression of antimicrobial peptides and lower bacterial loads as expected, this was not accompanied by a proportional reduction in mortality. Instead, UAS-RNAi knockdown of negative regulators of IMD (pirkandcaudal) substantially increased the per-pathogen-mortality in both males and females across all tested infectious doses. Our results therefore highlight that in addition to regulating an efficient pathogen clearance response, negative regulators of IMD also contribute to disease tolerance.
Cryo-EM structures reveal high-resolution mechanism of a DNA polymerase sliding clamp loader
Authors: Gaubitz Christl , Liu Xingchen , Pajak Joshua , Stone Nicholas P. , Hayes Janelle A. , Demo Gabriel , Kelch Brian A 
Published: September 2021

SUMMARYSliding clamps are ring-shaped protein complexes that are integral to the DNA replication machinery of all life. Sliding clamps are opened and installed onto DNA by clamp loader AAA+ ATPase complexes. However, how a clamp loader opens and closes the sliding clamp around DNA is still unknown. Here, we describe structures of the S. cerevisiae clamp loader Replication Factor C (RFC) bound to its cognate sliding clamp Proliferating Cell Nuclear Antigen (PCNA) en route to successful loading. RFC first binds to PCNA in a dynamic, closed conformation that blocks both ATPase activity and DNA binding. RFC then opens the PCNA ring through a large-scale ‘crab-claw’ expansion of both RFC and PCNA that explains how RFC prefers initial binding of PCNA over DNA. Next, the open RFC:PCNA complex binds DNA and interrogates the primer-template junction using a surprising base-flipping mechanism. Our structures indicate that initial PCNA opening and subsequent closure around DNA do not require ATP hydrolysis, but are driven by binding energy. ATP hydrolysis, which is necessary for RFC release, is triggered by interactions with both PCNA and DNA, explaining RFC’s switch-like ATPase activity. Our work reveals how a AAA+ machine undergoes dramatic conformational changes for achieving binding preference and substrate remodeling.
Dysregulated coordination ofMAPTexon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD
Authors: Bowles Kathryn R. , Pugh Derian A. , Oja Laura-Maria , Jadow Benjamin M. , Farrell Kurt , Whitney Kristen , Sharma Abhijeet , Cherry Jonathan D. , Raj Towfique , Pereira Ana C. , Crary John F. , Goate Alison M. 
Published: September 2021

ABSTRACTUnderstanding regulation ofMAPTsplicing is important to the etiology of many nerurodegenerative diseases, including Alzheimer disease (AD) and progressive supranuclear palsy (PSP), in which different tau isoforms accumulate in pathologic inclusions.MAPT, the gene encoding the tau protein, undergoes complex alternative pre-mRNA splicing to generate six isoforms. Tauopathies can be categorized by the presence of tau aggregates containing either 3 (3R) or 4 (4R) microtubule binding domain repeats (determined by inclusion/exclusion of exon 10), but the role of the N terminal domain of the protein, determined by inclusion/exclusion of exons 2 and 3 has been less well studied. Using an unbiased correlational screen in human brain tissue, we observed coordination ofMAPTexons 2 and 10 splicing. Expression of exon 2 splicing regulators and subsequently exon 2 inclusion are differentially disrupted in PSP and AD brain, resulting in the accumulation of 1N4R isoforms in PSP and 0N isoforms in AD temporal cortex. Furthermore, we identified different N-terminal isoforms of tau present in neurofibrillary tangles, dystrophic neurites and tufted astrocytes, indicating a role for differential N-terminal splicing in the development of disparate tau neuropathologies. We conclude that N-terminal splicing and combinatorial regulation with exon 10 inclusion/exclusion is likely to be important to our understanding of tauopathies.
Unrestricted eye movements strengthen causal connectivity from hippocampal to oculomotor regions during scene construction
Authors: Ladyka-Wojcik Natalia , Liu Zhong-Xu , Ryan Jennifer D. 
Published: September 2021

AbstractScene construction is a key component of memory recall, navigation, and future imagining, and relies on the medial temporal lobes (MTL). A parallel body of work suggests that eye movements may enable the imagination and construction of scenes, even in the absence of external visual input. There are vast structural and functional connections between regions of the MTL and those of the oculomotor system. However, the directionality of connections between the MTL and oculomotor control regions, and how it relates to scene construction, has not been studied directly in human neuroimaging. In the current study, we used dynamic causal modeling (DCM) to interrogate effective connectivity between the MTL and oculomotor regions using a scene construction task in which participants’ eye movements were either restricted (fixed-viewing) or unrestricted (free-viewing). By omitting external visual input, and by contrasting free- versus fixed- viewing, the directionality of neural connectivity during scene construction could be determined. As opposed to when eye movements were restricted, allowing free viewing during construction of scenes strengthened top-down connections from the MTL to the frontal eye fields, and to lower-level cortical visual processing regions, suppressed bottom-up connections along the visual stream, and enhanced vividness of the constructed scenes. Taken together, these findings provide novel, non-invasive evidence for the causal architecture between the MTL memory system and oculomotor system associated with constructing vivid mental representations of scenes.HighlightsThe role of eye movements in mentally constructing scene imagery was investigatedRestricting eye movements impaired vividness of constructed scene imageryMaking eye movements strengthened connectivity from memory to oculomotor regions
Prioritizing candidate peptides for cancer vaccines by PEPPRMINT: a statistical model to predict peptide presentation by HLA-I proteins
Authors: Zhou Laura Y. , Zou Fei , Sun Wei 
Published: September 2021

AbstractRecent development of cancer immunotherapy has opened unprecedented avenues to eliminate tumor cells using the human immune system. Cancer vaccines composed of neoantigens, or peptides unique to tumor cells due to somatic mutations, have emerged as a promising approach to activate or strengthen the immune response against cancer. A key step to identifying neoantigens is computationally predicting which somatically mutated peptides are presented on the cell surface by a human leukocyte antigen (HLA). Computational prediction relies on large amounts of high-quality training data, such as mass spectrometry data of peptides presented by one of several HLAs in living cells. We developed a complete pipeline to prioritize neoantigens for cancer vaccines. A key step of our pipeline is PEPPRMINT (PEPtide PResentation using a MIxture model and Neural neTwork), a model designed to exploit mass spectrometry data to predict peptide presentation by HLAs. We applied our pipeline to DNA sequencing data of 60 melanoma patients and identified a group of neoantigens that were more immunogenic in tumor cells than in normal cells. Additionally, the neoantigen burden estimated by PEPPRMINT was significantly associated with activity of the immune system, suggesting these neoantigens could induce an immune response.
The genomic context for aflatoxin B1-degrading Pseudomonas strains
Authors: Tang Jiahong , Deng Dun , Song Maopeng , Liu Zhichang , Ma Sanmei , Wang Yongfei 
Published: September 2021

AbstractThe whole genomes of three strains were sequenced and annotated. COG (Clusters of Orthologous Groups) and GO (Gene Ontology) annotations of the protein-coding genes from three strains show a conservation of genome-wide protein functions in genus Pseudomonas. However, the AFB1-degrading strains HAI2 and HT3 harbor much more genes belonged to the pathway of xenobiotics biodegradation and metabolism than non-degrading strain 48. Besides, the enzyme families potentially involved in the AFB1 degradation of bacteria are more abundant in the two AFB1-degrading strains. A pan-genome profile was then formed by comparing the genomes against other reference genomes of the corresponding Pseudomonas species. Accordingly, a total of 1,528 genes were found to be specific in AFB1-degrading strains, and 65 genes of them are related to oxidoreductase activity.
Genetic studies of human-chimpanzee divergence using stem cell fusions
Authors: Song Janet H.T. , Grant Rachel L. , Behrens Veronica C. , Kucka Marek , Roberts Kingman Garrett A. , Soltys Volker , Chan Yingguang Frank , Kingsley David M. 
Published: September 2021

AbstractComplete genome sequencing has identified millions of DNA changes that differ between humans and chimpanzees. Although a subset of these changes likely underlies important phenotypic differences between humans and chimpanzees, it is currently difficult to distinguish causal from incidental changes and to map specific phenotypes to particular genome locations. To facilitate further genetic study of human-chimpanzee divergence, we have generated human and chimpanzee auto-tetraploids and allo-tetraploids by fusing induced pluripotent stem cells (iPSCs) of each species. The resulting tetraploid iPSCs can be stably maintained and retain the ability to differentiate along ectoderm, mesoderm, and endoderm lineages. RNA sequencing identifies thousands of genes whose expression differs between humans and chimpanzees when assessed in single-species diploid or auto-tetraploid iPSCs. Analysis of gene expression patterns in inter-specific allo-tetraploid iPSCs shows that human-chimpanzee expression differences arise from substantial contributions of both cis-acting changes linked to the genes themselves, and trans-acting changes elsewhere in the genome. To enable further genetic mapping of species differences, we tested chemical treatments for stimulating genome-wide mitotic recombination between human and chimpanzee chromosomes, and CRISPR methods for inducing species-specific changes on particular chromosomes in allo-tetraploid cells. We successfully generated derivative cells with nested deletions or inter-specific recombination on the X chromosome. These studies identify a long distance cis-regulatory domain of the Fragile X-associated gene (FMR1), confirm an important role for the X chromosome in trans-regulation of other expression differences, and illustrate the potential of this system for more detailed mapping of the molecular basis of human and chimpanzee evolution.Significance StatementComparative studies of humans and chimpanzees have revealed many anatomical, physiological, behavioral, and molecular differences. However, it has been challenging to map these differences to particular chromosome regions. Here, we develop a genetic approach in fused stem cell lines that makes it possible to map human-chimpanzee molecular and cellular differences to specific regions of the genome. We illustrate this approach by mapping chromosome regions responsible for species-specific gene expression differences in fused tetraploid cells. This approach is general, and could be used in the future to map the genomic changes that control many other humanchimpanzee differences in various cell types or organoids in vitro.
Rapamycin attenuated zinc-induced tau phosphorylation and oxidative stress in animal model: Involvement of dual mTOR/p70S6K and Nrf2/HO-1 pathways
Authors: Lai Chencen , Ding Yuanting , Chen Qian , Su Songbai , Liu Heng , Ni Ruiqing , Tang Zhi 
Published: September 2021

AbstractAlzheimer’s disease is pathologically featured by abnormal accumulation of amyloid-beta plaque, neurofibrillary tangles, oxidative stress, neuroinflammation, and neurodegeneration. Metal dysregulation including excessive zinc released by presynaptic neurons plays an important role in tau pathology and oxidase activation. The activities of mammalian target of rapamycin (mTOR)/ ribosomal S6 protein kinase (p70S6K) are elevated in the brains of patients with Alzheimer’s disease. Zinc induces tau hyperphosphorylation via mTOR/P70S6K activation in vitro. However, the involvement of mTOR/P70S6K pathway in zinc-induced oxidative stress, tau degeneration, synaptic and cognitive impairment, has not been fully elucidated in vivo. Here we assessed in the effect of pathological concentration of zinc in SH-SY5Y cells by using biochemical assays and immunofluorescence staining. Rats (n = 18, male) were lateral ventricularly-injected with zinc and treated with rapamycin (intraperitoneal injection) for one week and assessed using Morris water maze. Evaluation of the oxidative stress, tau phorsphylation and synaptic impairment were performed using the hippocampus tissue of the rats by biochemical assays and immunofluorescence staining. Results from Morris water maze showed that the capacity of spatial memory is impaired in zinc-treated rats. Zinc sulfate significantly increased the levels of P-mTOR Ser2448, P-p70S6K Thr389, and P-tau Ser356, and decreased levels of Nrf2 and HO□1 in SH-SY5Y cells and in zinc-treated rats compared with control groups. Increased expressions of reactive oxygen species were observed in zinc sulfate-induced SH-SY5Y cells as well as in the hippocampus of zinc-injected rats. Rapamycin, an inhibitor of mTOR, rescued the zinc-induced increases in mTOR/p70S6K activations, tau phosphorylation and oxidative stress, as well as Nrf2/HO□1 inactivation, cognitive impairment and synaptic impairment reduced the expression of synapse-related proteins in zinc-injected rats. In conclusion, our findings imply that rapamycin prevents zinc-induced cognitive impairment and protects neurons from tau pathology, oxidative stress and synaptic impairment, by decreasing mTOR/p70S6K hyperactivity and increasing Nrf2/HO □ 1 activity.
Local adaptation to novel habitats and climatic changes in a wild tomato species via selective sweeps
Authors: Wei Kai , Silva-Arias Gustavo A , Tellier Aurélien 
Published: September 2021

SummaryPositive selection is the driving force underpinning local adaptation, and leaves footprints of selective sweeps at the underlying major genes. Quantifying the timing of selection and revealing the genetic bases of adaptation in plants species occurring in steep and varying environmental gradients is crucial to predict a species’ ability colonize new niches.We use whole genome sequence data from six populations across three different habitats of the wild tomato species Solanum chilense to infer the past demographic history and search for genes under strong positive selection. We then correlate current and past climatic projections with the demographic history, allele frequencies, the age of selection events, and distribution shifts.We find evidence for several selective sweeps targeting regulatory networks involved in root hair development in low altitude, and response to photoperiod and vernalization in high altitude populations. These sweeps occur in a concerted fashion in a given regulatory gene network at particular periods of substantial climatic change.We decipher the genetic bases and the timing of local adaptation during plant colonization of semi-arid habitats using a unique combination of genome scans for selection and modelling of past climatic data.
Single EV analysis (sEVA) of mutated proteins allows detection of stage 1 pancreatic cancer
Authors: Ferguson Scott , Yang Katherine S. , Zelga Piotr , Liss Andrew S. , Carlson Jonathan , del Castillo Carlos Fernandez , Weissleder Ralph 
Published: September 2021

AbstractTumor cell derived extracellular vesicles (EV) are being explored as circulating biomarkers for cancer detection. Up to now however, clinical results have been mixed for a number of reasons including the predominant use of bulk measurements, the inability to differentiate tumor from host cell derived vesicles, the general absence of uniquely identifying biomarkers and the unknown frequency of stochastically distributed biomarkers into single circulating vesicles. We hypothesized that a single EV analysis (sEVA) technique could potentially improve diagnostic accuracy necessary to detect early cancers but the actual biomarker frequency and practical detection limits are currently unknown. Using pancreatic cancer, we carefully analyzed the composition of putative cancer markers in 11 established and new patient derived models. In parental PDAC cells positive for KRASmutand/or P53mutproteins only ∼40% of EVs were also positive (range: 30-64%). This rate of positivity increased to 57% when additional PDAC biomarkers were considered (MUC1, EGFR, ⍺FG-P4OH) in cell lines. In a blinded study involving 16 patients with surgically proven stage 1 PDAC, KRASmutand P53mutprotein was detectable at much lower levels, generally in < 0.1% of vesicles. With the analytical capabilities of sEVA however, 15 of the 16 patients with stage 1 PDAC expressed low levels of biomarker positive EV. Using a modeling approach, we estimate that the current PDAC detection limit is at ∼0.1 cm3tumor volume, below clinical imaging capabilities. These findings establish the potential for single-EV analysis for early cancer detection.
Amino Acid Composition and Charge Based Prediction of Antisepsis Peptides by Random Forest Machine Learning Algorithm
Authors: Rathore Aayushi , Saini Anu , Kaur Navjot , Singh Aparna , Dutta Ojasvi , Bamhotra Mrinal , Saini Avneet , Saini Sandeep 
Published: September 2021

ABSTRACTSepsis is a severe infectious disease with high mortality, and it occurs when chemicals released in the bloodstream to fight an infection trigger inflammation throughout the body and it can cause a cascade of changes that damage multiple organ systems, leading them to fail, even resulting in death. In order to reduce the possibility of sepsis or infection antiseptics are used and process is known as antisepsis. Antiseptic peptides (ASPs) show properties similar to antigram-negative peptides, antigram-positive peptides and many more. Machine learning algorithms are useful in screening and identification of therapeutic peptides and thus provide initial filters or built confidence before using time consuming and laborious experimental approaches. In this study, various machine learning algorithms like Support Vector Machine (SVM), Random Forest (RF), K-Nearest Neighbour (KNN) and Logistic Regression (LR) were evaluated for prediction of ASPs. Moreover, the characteristics physicochemical features of ASPs were also explored to use them in machine learning. Both manual and automatic feature selection methodology was employed to achieve best performance of machine learning algorithms. A 5-fold cross validation and independent data set validation proved RF as the best model for prediction of ASPs. Our RF model showed an accuracy of 97%, Matthew’s Correlation Coefficient (MCC) of 0.93, which are indication of a robust and good model. To our knowledge this is the first attempt to build a machine learning classifier for prediction of ASPs.
Ecological and social pressures interfere with homeostatic sleep regulation in the wild
Authors: Loftus JC , Harel R , Nuñez CL , Crofoot MC 
Published: September 2021

AbstractSleep is fundamental to the health and fitness of all animals. The physiological importance of sleep is underscored by the central role of homeostasis in determining sleep investment – following periods of sleep deprivation, individuals experience longer and more intense sleep bouts. Yet, most studies of sleep have been conducted in highly controlled settings, disconnected from the ecological and social context that may exert pressures on sleep patterns in conflict with homeostatic regulation. Using tri-axial accelerometry and GPS to track the sleep patterns of a group of wild baboons (Papio anubis) at multiple temporal and spatial scales, we found that ecological and social pressures indeed interfere with homeostatic sleep regulation. Baboons sacrificed time spent sleeping when in less familiar locations and when sleeping in proximity to more group-mates, regardless of how much they had slept the prior night or how much they had physically exerted themselves the preceding day. Moreover, we found that the collective dynamics characteristic of social animal groups persist into the sleep period, as baboons exhibited synchronized patterns of waking throughout the night, particularly with nearby group-mates. Thus, for animals whose fitness depends critically on avoiding predation and developing social relationships, maintaining sleep homeostasis may be only secondary to remaining vigilant when sleeping in risky habitats and interacting with group-mates during the night. Our results highlight the importance of studying sleep in ecologically relevant contexts, where the adaptive function of sleep patterns directly reflect the complex trade-offs that have guided its evolution.