bluuebunny/crossref_metadata_2025_split huggingface dataset:
Co-infection withToxoplasma gondiileads to a loss of resistance inHeligmosomoides bakeritrickle-infected mice due to ineffective granulomas
Authors: Fougere Breton , Ariyaratne Anupama , Chege Naomi , Perera Shashini , Forrester Emma , Luzzi Mayara de Cassia , Bowron Joel , Coria Aralia Leon , Szabo Edina , Finney Constance A. M. 
Published: December 2020

ABSTRACTThe intestinal roundwormHeligmosomoides bakericauses chronic infection in susceptible (C57Bl/6) mice; however, repeat (trickle) infection confers immunity and facilitates worm clearance. We previously showed that this acquired immunity is associated with a strong Th2 response, notably the enhanced production of intestinal granulomas. Here we demonstrate that elevated proportions of IgG1-bound eosinophils and macrophages are observed around the developing tissue worms of trickle-infected female C57Bl/6 mice compared to bolus infected animals. Levels of IgG2c, IgA or IgE were not detected in the granulomas. Increased proportions of SiglecF+and CD206+cells, but not Ly6G+and/or NK1.1+cells, were also found in the granulomas of trickle-infected mice. However, in the natural world rather than the laboratory setting, immune environments are more nuanced. We examined the impact of a mixed immune environment on trickle infection-induced immunity, using a pre-infection withToxoplasma gondii. The mixed immune environment resulted in fewer and smaller granulomas with a lack of IgG -bound cells as well as reduced proportions of SiglecF+and CD206+cells, measured by immunofluorescence and flow cytometry. This was associated with a higher worm burden in the co-infected animals. Our data confirm the importance of intestinal granulomas and parasite-specific antibody for parasite clearance. They highlight why it may be more difficult to clear worms in the field than in the laboratory.AUTHOR’S SUMMARYDespite decades of research on intestinal parasitic worms, we are still unable to clearly point to why so many people (approximately 1.8 billion) and most livestock/wild animals are infected with these parasites. We have made progress in understanding how the immune system responds to parasitic worms, and how these parasites manipulate our immune system. However, identifying effective clearance mechanisms is complex and context dependent. We have used models of trickle infection (multiple low doses of parasites) and co-infection (two intestinal parasites) to simulate how people/animals get infected in the real world. Using these models, we have confirmed the host/parasite interface (the granuloma) within the intestinal tissue to be key in determining the host’s ability to clear worms. The lack of specific immune cells and antibodies within the granuloma was associated with chronic infection. Our results help explain why intestinal parasitic worms are so prevalent and why it may be difficult to clear worms in natural settings.
Behavioral gain following isolation of attention
Authors: Edwards Grace , Berestova Anna , Battelli Lorella 
Published: December 2020

AbstractStable sensory perception is achieved through balanced excitatory-inhibitory interactions of lateralized sensory processing. In real world experience, sensory processing is rarely equal across lateralized processing regions, resulting in continuous rebalancing. Using lateralized attention as a case study, we predicted rebalancing lateralized processing following prolonged spatial attention imbalance could cause a gain in attention the opposite direction. In neurotypical human adults, we isolated covert attention to one visual field with a 30-minute attention-demanding task and found anincreasein attention in the opposite visual field after manipulation. We suggest a gain in lateralized attention in the previously unattended visual field is due to an overshoot through attention rebalancing. The offline post-manipulation effect is suggestive of long-term potentiation affecting behavior. Our finding of visual field specific attention rebound could be critical for the development of clinical rehabilitation for patients with a unilateral lesion and lateralized attention deficits. This proof-of-concept study initiates the examination of overshoot following the release of imbalance in other lateralized control and sensory domains, important in our basic understanding of lateralized processing.
A cryo-EM structure of metazoan TRAPPIII, the multisubunit complex that activates the GTPase Rab1
Authors: Galindo Antonio , Planelles-Herrero Vicente J. , Degliesposti Gianluca , Munro Sean 
Published: December 2020

SummaryThe TRAPP complexes are highly conserved nucleotide exchange factors, with TRAPPIII activating Rab1 and TRAPPII acting primarily on Rab11. The two complexes share a core of small subunits that affect nucleotide exchange, but are distinguished by additional large subunits that are essential for activity in vivo, and are mutated in a range of human disorders. Crystal structures of the core subunits have revealed the mechanism of Rab activation, but how and why the large subunits associate with the core remains unclear. We report here a cryo-EM structure of the entire TRAPPIII complex fromDrosophila. The TRAPPIII-specific subunits TRAPPC8 and TRAPPC11 hold the catalytic core like a pair of tongs, with TRAPPC12 and TRAPPC13 positioned at the joint between them. TRAPPC2 and TRAPPC2L link the core to the two large arms, with the interfaces containing residues affected by disease-causing mutations. The TRAPPC8 arm is positioned such that it would contact bound Rab1, indicating how the arms could alter the Rab specificity of the core. A lower resolution structure of TRAPPII shows a similar architecture, and suggests that the TRAPP complexes evolved from a single ur-TRAPP.
Dextran sulfate sodium salt corrupted colonic crypts declined the smooth muscle tension in mouse large intestine
Authors: Yiwei Sun , Aihua Hu , shouyan Fan , Lusi Wei , Yuechuan Shi , Lu Wen , Aden Cham Mohamed , Lingfeng Gao , Yang Wang 
Published: December 2020

AbstractUlcerative colitis is one kind of colonic mucosa damage, shows high number of inflammatory epithelial cells. Dextran sulfate sodium salt (DSS) induce a milder onset of colitis or a more aggressive response. It may damage the protective effects on intestinal barrier. In this study, we investigated the damaging of colon crypts, evaluated the smooth muscle tension beneath corrupted crypts in DSS exposed mice.Methodsfemale specific-pathogen-freeBALB/Cmice (n=16) are randomly divided as: group A: control mice (n=4); group B: DSS-mice (colitis, 5% DSS in drink water, days 1 to 7, n = 12). The DSS is replaced every 2 days. On day 8, mice colons are excised from the colon-cecal junction to the anus. The distal colon segment is longitude incision and aberrant crypt area are determined by methylene blue staining method. The smooth muscle strip is separated and prepared for passive tension tests. The rest segment is fixed with 10% formalin and embedded in paraffin. Histological scores are evaluated in hematoxylin-eosin staining section: crypt damage (none = 0, basal 1/3 damaged = 1, basal 2/3 damaged = 2, only the surface epithelium is intact = 3, and entire crypt and epithelium are lost = 4). The smooth muscle passive tension beneath the aberrant crypt area in DSS-mice are tested and compared with the preparations from control mice.ResultsIn DSS uptake mice, the inflammation in large intestine mucosa damaged crypts with architectural distortions on day 7 (n=7). In crypts damage area, the smooth muscle passive tension and relative myogenic spontaneous contraction parameters are significantly reduced under the high preload conditions. The maximum rate of change of velocity of spontaneous contraction was noticeable attenuated.ConclusionOur findings demonstrate that low dosage DSS water drink result in corrupted colonic crypts. The corrupted crypts damage the large intestinal epithelium barrier, affect the smooth muscle functions, which declined in myogenic spontaneous contraction under the preload. This further may reduce the peristalsis in large intestine.
BART Cancer: a web resource for transcriptional regulators in cancer genomes
Authors: Thomas Zachary V. , Wang Zhenjia , Zang Chongzhi 
Published: December 2020

ABSTRACTDysregulation of gene expression plays an important role in cancer development. Identifying transcriptional regulators, including transcription factors and chromatin regulators, that drive the oncogenic gene expression program is a critical task in cancer research. Genomic profiles of active transcriptional regulators from primary cancer samples are limited in the public domain. Here we present BART Cancer (bartcancer.org), an interactive web resource database to display the putative transcriptional regulators that are responsible for differentially regulated genes in 15 different cancer types in The Cancer Genome Atlas (TCGA). BART Cancer integrates over 10,000 gene expression profiling RNA-seq datasets from TCGA with over 7,000 ChIP-seq datasets from the Cistrome Data Browser database and the Gene Expression Omnibus (GEO). BART Cancer uses Binding Analysis for Regulation of Transcription (BART) for predicting the transcriptional regulators from the differentially expressed genes in cancer samples compared to normal samples. BART Cancer also displays the activities of over 900 transcriptional regulators across cancer types, by integrating computational prediction results from BART and the Cistrome Cancer database. Focusing on transcriptional regulator activities in human cancers, BART Cancer can provide unique insights into epigenetics and transcriptional regulation in cancer, and is a useful data resource for genomics and cancer research communities.
Rectal bacteria produce sex pheromones in the male oriental fruit fly
Authors: Ren Lu , Yingao Ma , Xie Mingxue , Lu Yongyue , Cheng Daifeng 
Published: December 2020

AbstractIn recent decades, a growing body of literature has indicated that microbial symbionts of insects can modulate their hosts’ chemical profiles and mate choice decisions. However, there is currently little direct evidence indicate that insect pheromones can be produced by symbionts. UsingBactrocera dorsalisas a model system, we demonstrate thatBacillus sp.in the rectum of maleB. dorsalisplays a pivotal role in sex pheromones production. We demonstrate that 2,3,5-trimethylpyrazine (TMP) and 2,3,5,6-tetramethylpyrazine (TTMP) are sex pheromones produced in the male rectums. Mature virgin females can be strongly attracted by TMP and TTMP. TMP and TTMP contents in male rectums can be decreased when rectal bacteria are inhibited with antibiotics. Moreover,Bacillussp. isolated from male rectum can produce TMP and TTMP when providing with substrates-glucose and threonine, for which the contents are significantly higher in rectums of mature males. These findings highlight the influence of microbial symbionts on insect pheromones and provide an example of direct bacterial production of pheromones in insects.
SARS-CoV-2-Specific Antibody Profiles Distinguish Patients with Moderate from Severe COVID-19
Authors: de Campos Mata Leire , Piñero Janet , Vaquero Sonia Tejedor , Tachó-Piñot Roser , Kuksin Maria , Aldea Itziar Arrieta , Melero Natalia Rodrigo , Carolis Carlo , Furlong Laura , Cerutti Andrea , Villar-García Judit , Magri Giuliana 
Published: December 2020

SummaryThe production of SARS-CoV-2-specific neutralizing antibodies is widely considered as a key mechanism for COVID-19 resolution and protection. However, beyond their protective function, antibodies to SARS-CoV-2 may also participate in disease pathogenesis. To explore the potential relationship between virus-specific humoral responses and COVID-19 immunopathology, we measured serum antibody classes and subclasses to the receptor-binding domain of the SARS-CoV-2 spike protein and the nucleoprotein in a cohort of hospitalized COVID-19 patients with moderate to severe disease. We found that RBD-specific IgG1 and IgG3 dominated the humoral response to SARS-CoV-2, were more abundant in severe patients, and positively correlated with several clinical parameters of inflammation. In contrast, a virus-specific IgA2 response skewed toward RBD rather than NP associated with a more favorable clinical course. Interestingly, RBD-dominant IgA2 responses were mostly detected in patients with gastrointestinal symptoms, suggesting the possible involvement of intrinsically tolerogenic gut immune pathways in the attenuation of virus-induced inflammation and disease resolution.
Let the DOCTOR Decide Whom to Test: Adaptive Testing Strategies to Tackle the COVID-19 Pandemic
Authors: Liang Yu , Yadav Amulya 
Published: December 2020

ABSTRACTA robust testing program is necessary for containing the spread of COVID-19 infections before a vaccine becomes available. However, due to an acute shortage of testing kits (especially in low-resource developing countries), designing an optimal testing program/strategy is a challenging problem to solve. Prior literature on testing strategies suffers from two major limitations: (i) it does not account for the trade-off between testing of symptomatic and asymptomatic individuals, and (ii) it primarily focuses on static testing strategies, which leads to significant shortcomings in the testing program’s effectiveness. In this paper, we address these limitations by making five novel contributions. (i) We formally define the optimal testing problem and propose the DOCTOR POMDP model to tackle it. (ii) We solve the DOCTOR POMDP using a scalable Monte Carlo tree search based algorithm. (iii) We provide a rigorous experimental analysis of DOCTOR’s testing strategies against static baselines - our results show that when applied to the city of Santiago in Panama, DOCTOR’s strategies result in ∼40% fewer COVID-19 infections (over one month) as compared to state-of-the-art static baselines. (iv) In addition, we analyze DOCTOR’s testing policy to derive insights about the reasons behind the optimality of DOCTOR’s testing policy. (v) Finally, we characterize conditions (of the real world) under which DOCTOR’s optimization would be of most benefit to government policy makers, and thus requires significant attention from researchers in this area. Our work complements the growing body of research on COVID-19, and serves as a proof-of-concept that illustrates the benefit of having an AI-driven adaptive testing strategy for COVID-19.
Biomimetic, smart and multivalent ligands for G-quadruplex isolation and bioorthogonal imaging
Authors: Sperti Francesco Rota , Charbonnier Thibaut , Lejault Pauline , Zell Joanna , Bernhard Claire , Valverde Ibai E. , Monchaud David 
Published: December 2020

AbstractG-quadruplexes (G4s) continue to gather wide attention in the field of chemical biology as their prevalence in the human genome and transcriptome strongly suggests that they may play key regulatory roles in cell biology. G4-specific, cell-permeable small molecules (G4-ligands) innovately permit the interrogation of cellular circuitries in order to assess to what extent G4s influence cell fate and functions. Here, we report on multivalent, biomimetic G4-ligands referred to as TASQs that enable both the isolation and visualization of G4s in human cells. Two biotinylated TASQs,BioTASQandBioCyTASQ, are indeed efficient molecular tools to fish out G4s of mixtures of nucleic acids through simple affinity capture protocols and to image G4s in cellsviaa biotin/avidin pretargeted imaging system first applied here to G4s, found to be a reliable alternative toin situclick chemistry.Abstract Figure
Combinations of Indole based alkaloids fromMitragyna speciosa(Kratom) and cisplatin inhibit cell proliferation and migration of Nasopharyngeal carcinoma cell lines
Authors: Domnic Gregory , Chear Nelson Jeng-Yeou , Rahman Siti Fairus Abdul , Ramanathan Surash , Lo Kwok-Wai , Singh Darshan , Mohana-Kumaran Nethia 
Published: December 2020

AbstractEthnopharmacological relevanceMitragyna speciosa(Korth.) or kratom is a medicinal plant indigenous to Southeast Asia. The leaves ofM. speciosais used as a medication in pain management including cancer related pain, in a similar way as opioids and cannabis. Despite its well-known analgesic effect, there is a scarce of information on the cancer-suppressing potential ofM. speciosaand its active constituents.Aim of the studyTo assess the potential applicability ofM. speciosaalkaloids (mitragynine, speciociliatine or paynantheine) as chemosensitizers for cisplatin in Nasopharyngeal carcinoma (NPC) cell lines.Materials and MethodsThe cytotoxic effects of the extracts, fractions and compounds were determined by conductingin vitrocytotoxicity assays. Based on the cytotoxic screening, the alkaloid extract ofM. speciosaexhibited potent inhibitory effect on the NPC cell line HK-1, and therefore, was chosen for further fractionation and purification. NPC cell lines HK-1 and C666-1 were treated with combinations of cisplatin andM. speciosaalkaloids in 2D monolayer culture. The effect of the drug combination on cell migration was tested usingin vitrowound healing and spheroid invasion assays.ResultsIn our bioassay guided isolation, both methanolic and alkaloid extracts showed mild to moderate cytotoxic effect against the HK-1 cell line. Both NPC cell lines were insensitive to single agent and combination treatments of theM. speciosaalkaloids. However, mitragynine and speciociliatine sensitised the HK-1 and C666-1 to cisplatin ~4- and >5-fold, respectively in 2D monolayer culture. The combination of mitragynine and cisplatin also significantly inhibited cell migration of the NPC cell lines. Similarly, combination of mitragynine and cisplatin inhibited growth and invasion of HK-1 spheroids in a dose-dependent manner. Moreover, the spheroids did not rapidly develop resistance to the drug combinations at high concentrations over 10 days.ConclusionCollectively, data shows that both mitragynine and speciociliatine could be potential chemosensitizers for cisplatin. Further extensive drug mechanistic studies and investigations in animal models are necessary to delineate the applicability ofM. speciosaalkaloids for NPC therapy.
Designing an irreversible metabolic switch for scalable induction of microbial chemical production
Authors: Mannan Ahmad A. , Bates Declan G. 
Published: December 2020

AbstractBacteria can be harnessed to synthesise high-value chemicals. A promising strategy for increasing productivity uses inducible control systems to switch metabolism from growth to chemical synthesis once a large population of cell factories are generated. However, use of expensive chemical inducers limits scalability of this approach for biotechnological applications. Switching using cheap nutrients is an appealing alternative, but their tightly regulated uptake and consumption again limits scalability. Here, using mathematical models of fatty acid uptake inE. colias an exemplary case study, we unravel how the cell’s native regulation and program of induction can be engineered to minimise inducer usage. We show that integrating positive feedback loops into the circuitry creates an irreversible metabolic switch, which, requiring only temporary induction, drastically reduces inducer usage. Our proposed switch should be widely applicable, irrespective of the product of interest, and brings closer the realization of scalable and sustainable microbial chemical production.
The first insight into the genetic structure of the population of modern Serbia
Authors: Drljaca Tamara , Zukic Branka , Kovacevic Vladimir , Gemovic Branislava , Klaassen-Ljubicic Kristel , Perovic Vladimir , Lazarevic Mladen , Pavlovic Sonja , Veljkovic Nevena 
Published: December 2020

ABSTRACTThe complete understanding of the genomic contribution to complex traits, diseases, and response to treatments, as well as genomic medicine application to the well-being of all humans will be achieved through the global variome that encompasses fine-scale genetic diversity. Despite significant efforts in recent years, uneven representation still characterizes genomic resources and among the underrepresented European populations are the Western Balkans including the Serbian population. Our research addresses this gap and presents the first ever dataset of variants in clinically relevant genes in the population sample of contemporary Serbia. A few variants significantly more frequent in the analyzed sample population compared to the European population as a whole are distinguished as its unique genetic determinants. We explored thoroughly their potential functional impact and its correlation with the health burden of the population of Serbia. Our variant’s catalogue improves the understanding of genetics of modern Serbia, contributes to application of precision medicine and health equity. In addition, this resource may also be applicable in neighboring regions and in worldwide functional analyses of genetic variants in individuals of European descent.
Helium as anIn VitroFurin Inhibitor
Authors: Beihl David 
Published: December 2020

AbstractAimsCertain cancers, pathogenic infections, and other diseases are facilitated by the host enzyme furin, a calcium-dependent serine protease that is the most prominent member of the family of proprotein convertases. Furin and the other proprotein convertases modify certain other proteins to change them from their inactive to active forms. Previous attempts to find an effective, non-toxic furin inhibitor to treat diseases facilitated by furin have had only limited success, due to toxicity or large molecular size that impedes absorption of the molecule. This has placed increased importance on the development of small-molecule furin inhibitors. The object of this study was to consider the effect of the noble gas helium as a furin inhibitor.MethodsThis study uses a fluorometric furin inhibition assay to compare the enzymatic activity of recombinant human furin after exposure to balloon-grade helium gas, compared to the enzymatic activity of untreated recombinant human furin.ResultsHelium exposure was found to decrease thein vitroenzymatic activity of recombinant human furin by as much as 55%; this inhibition lasted for up to 16 hours. Fluorescence measurements of enzymatic activity were taken for 24 hours.ConclusionsThese findings appear to be the first to report helium as a partial furin inhibitor. The observed partial inhibition was consistent throughout the experiment. The effectiveness of helium as a partial furin inhibitor, its favorable side-effect profile, and its long history of safe use in respiratory therapy,when mixed with 20% oxygen or more and administered under direct medical supervision, make it a promising treatment for diseases facilitated by furin or its substrates. Further studies in cell culture or clinical trials may expand its clinical role for such diseases.