bluuebunny/crossref_metadata_2025_split huggingface dataset:
A unique form of collective epithelial migration is crucial for tissue fusion in the secondary palate and can overcome loss of epithelial apoptosis
Authors: Teng Teng , Teng Camilla , Kaartinen Vesa , Bush Jeffrey O. 
Published: September 2021

AbstractTissue fusion is an oft-employed process in morphogenesis which often requires the removal of the epithelia intervening multiple distinct primordia to form one continuous structure. In the mammalian secondary palate, a midline epithelial seam (MES) forms between two palatal shelves and must be removed to allow mesenchymal confluence. Abundant apoptosis and cell extrusion in this epithelial seam support their importance in its removal. However, by genetically disrupting the intrinsic apoptotic regulators BAX and BAK within the MES, we find a complete loss of cell death and cell extrusion, but successful removal of the MES, indicating that developmental compensation enables fusion. Novel static and live imaging approaches reveal that the MES is removed through a unique form of collective epithelial cell migration in which epithelial trails and islands stream through the mesenchyme to reach the oral and nasal epithelial surfaces. These epithelial trails and islands begin to express periderm markers while retaining expression of the basal epithelial marker ΔNp63, suggesting their migration to the oral and nasal surface is concomitant with their differentiation to an epithelial intermediate. Live imaging reveals anisotropic actomyosin contractility within epithelial trails that drives their peristaltic movement, and genetic loss of non-muscle myosin IIA-mediated actomyosin contractility results in dispersion of epithelial collectives and dramatic failure of normal MES migration. These findings demonstrate redundancy between cellular mechanisms of morphogenesis and reveal a crucial role for a unique form of collective epithelial migration during tissue fusion.
LIFE-Seq: A universal Large Integrated DNA Fragment Enrichment Sequencing strategy for transgene integration in genetically modified organisms
Authors: Zhang Hanwen , Li Rong , Guo Yongkun , Zhang Yuchen , Zhang Dabing , Yang Litao 
Published: September 2021

AbstractMolecular characterisation of genetically modified organisms (GMOs) yields basic information on exogenous DNA integration, including integration sites, entire inserted sequences and structures, flanking sequences and copy number, providing key data for biosafety assessment. However, there are few effective methods for deciphering transgene integration, especially for large DNA fragment integration with complex rearrangement, inversion, and tandem repeats. Herein, we developed a universal Large Integrated DNA Fragments Enrichment strategy combined with PacBio Sequencing (LIFE-Seq) for deciphering transgene integration in GMOs. Universal tilling DNA probes targeting transgenic elements and exogenous genes facilitate specific enrichment of large inserted DNA fragments associated with transgenes from plant genomes, followed by PacBio sequencing. LIFE-Seq were evaluated using six GM events and four crop species. Target DNA fragments averaging ∼6275 bp were enriched and sequenced, generating ∼26,352 high fidelity reads for each sample. Transgene integration structures were determined with high repeatability and sensitivity. Compared with whole-genome sequencing, LIFE-Seq achieved better data integrity and accuracy, greater universality, and lower cost, especially for transgenic crops with complex inserted DNA structures. LIFE-Seq could be applied in molecular characterisation of transgenic crops and animals, and complex DNA structure analysis in genetics research.
Genome-wide transcriptional profiling uncovers a similar oligodendrocyte-related transcriptional response to acute and chronic alcohol drinking in the amygdala
Authors: Narendra Sharvari , Klengel Claudia , Hamzeh Bilal , Patel Drasti , Otten Joy , Lardenoije Roy , Newman Emily L. , Miczek Klaus A. , Klengel Torsten , Ressler Kerry J. , Suh Junghyup 
Published: September 2021

AbstractAlcohol intake progressively increases after prolonged consumption of alcohol, but relatively few new therapeutics targeting development of alcohol use disorder (AUD) have been validated. Here, we conducted a genome-wide RNA-sequencing (RNA-seq) analysis in mice exposed to different modes (acute vs chronic) of ethanol drinking. We focused on transcriptional profiles in the amygdala including the central and basolateral subnuclei, a brain area previously implicated in alcohol drinking and seeking, demonstrating distinct gene expression patterns and canonical pathways induced by both acute and chronic intake. Surprisingly, both drinking modes triggered similar transcriptional changes, including up-regulation of ribosome-related/translational pathways and myelination pathways, and down-regulation of chromatin binding and histone modification. Notably, multiple genes that were significantly regulated in mouse amygdala with alcohol drinking, including Atp2b1, Slc4a7, Nfkb1, Nts, and Hdac2, among others had previously been associated with human AUD via GWAS or other genomic studies. In addition, analyses of hub genes and upstream regulatory pathways predicted that voluntary ethanol consumption affects epigenetic changes via histone deacetylation pathways, oligodendrocyte and myelin function, and oligodendrocyte-related transcriptional factor, Sox17.Overall, our results suggest that the transcriptional landscape in the central and basolateral subnuclei of the amygdala is sensitive to voluntary alcohol drinking. They provide a unique resource of gene expression data for future translational studies examining transcriptional mechanisms underlying the development of AUD due to alcohol consumption.
Characterization of the Endogenous DAF-12 Ligand and Its Use as an Anthelmintic Agent inStrongyloides stercoralis
Authors: Wang Zhu , Cheong Mi Cheong , Tsien Jet , Deng Heping , Qin Tian , Stoltzfus Jonathan D. C. , Jaleta Tegegn G. , Li Xinshe , Lok James B. , Kliewer Steven A. , Mangelsdorf David J. 
Published: September 2021

ABSTRACTA prevalent feature ofStrongyloides stercoralisis a life-long and potentially lethal infection that is due to the nematode parasite’s ability to autoinfect and, thereby, self-replicate within its host. Here, we investigated the role of the parasite’s nuclear receptor,Ss-DAF-12, in governing infection. We identified Δ7-DA as the endogenousSs-DAF-12 ligand and elucidated the hormone’s biosynthetic pathway. Genetic loss of function of the ligand’s rate-limiting enzyme demonstrated that Δ7-DA synthesis is necessary for parasite reproduction, whereas its absence is required for development of infectious larvae. Availability of the ligand permitsSs-DAF-12 to function as an on/off switch governing autoinfection, making it vulnerable to therapeutic intervention. In a preclinical model of hyperinfection, pharmacologic activation of DAF-12 suppressed autoinfection and markedly reduced lethality. Moreover, when Δ7-DA was administered with ivermectin, the current but limited drug of choice for treating strongyloidiasis, the combinatorial effects of the two drugs resulted in a near cure of the disease.
The spliced leader RNA silencing (SLS) pathway in Trypanosoma brucei is induced by perturbations of endoplasmic reticulum, Golgi, or mitochondrial proteins factors and functional analysis of SLS inducing kinase, PK3
Authors: Okalang Uthman , Bar-Ner Bar Mualem , Rajan K. Shanmugha , Friedman Nehemya , Aryal Saurav , Egarmina Katarina , Hope Ronen , Khazanov Netaly , Senderowitz Hanoch , Alon Assaf , Fass Deborah , Michaeli Shulamit 
Published: September 2021

ABSTRACTIn the parasite Trypanosoma brucei, the causative agent of human African sleeping sickness, all mRNAs are trans-spliced to generate a common 5’ exon derived from the spliced leader RNA (SL RNA). Perturbations of protein translocation across the endoplasmic reticulum (ER) induce the spliced leader RNA silencing (SLS) pathway. SLS activation is mediated by a serine-threonine kinase, PK3, which translocates from the cytosolic face of the ER to the nucleus, where it phosphorylates the TATA binding protein TRF4, leading to the shut-off of SL RNA transcription, followed by induction of programmed cell death. Here, we demonstrate that SLS is also induced by depletion of the essential ER resident chaperones BiP and calreticulin, ER oxidoreductin 1 (ERO1), and the Golgi-localized quiescin sulfhydryl oxidase (QSOX1). Most strikingly, silencing of Rhomboid-like 1(TIMRHOM1) involved in mitochondrial protein import, also induces SLS. The PK3 kinase, which integrates SLS signals, is modified by phosphorylation on multiple sites. To determine which of the phosphorylation events activate PK3, several individual mutations or their combination were generated. These mutations failed to completely eliminate the phosphorylation or translocation of the kinase to the nucleus. The structure of PK3 kinase and its ATP binding domain were therefore modeled. A conserved phenylalanine at position 771 was proposed to interact with ATP, and the PK3F771L mutation completely eliminated phosphorylation under SLS, suggesting that the activation involves most if not all the phosphorylation sites. The study suggests that the SLS occurs broadly in response to failures in protein sorting, folding, or modification across multiple compartments.
Metabolic reconstitution by a gnotobiotic microbiota varies over the circadian cycle
Authors: Hoces Daniel , Lan Jiayi , Wenfei Sun , Geiser Tobias , Cappio Barazzone Elisa , Arnoldini Markus , Nowok Sven , Macpherson Andrew J , Stecher Bärbel , Zenobi Renato , Hardt Wolf-Dietrich , Wolfrum Christian , Slack Emma 
Published: September 2021

SUMMARYThe capacity of the intestinal microbiota to degrade otherwise indigestible diet components is known to greatly improve the recovery of energy from food. This has led to the hypothesis that increased digestive efficiency may underlie the contribution of the microbiome to obesity. OligoMM12-colonized gnotobiotic mice have a consistently higher fat-mass than germ-free or fully colonized counterparts. We therefore investigated their food intake, digestion efficiency, energy expenditure and respiratory quotient using a novel isolator-housed metabolic cage system which allows long-term measurements without contamination risk. This demonstrated that microbiota- released calories are perfectly balanced by decreased food intake in fully colonized versus gnotobiotic OligoMM12 and germ-free mice fed a standard chow diet, i.e., microbiota-released calories can in fact be well-integrated into appetite control. We also observed no significant difference in energy expenditure per gram lean mass between the different microbiota groups, suggesting that cumulative very small differences in energy balance, or altered energy storage must underlie fat accumulation in OligoMM12 mice. Consistent with altered energy storage, major differences were observed in the type of respiratory substrates used in metabolism over the circadian cycle: in germ-free mice the respiratory exchange ratio was consistently lower than that of fully colonized mice at all times of day, indicative of more reliance on fat and less on glucose metabolism. Intriguingly the RER of OligoMM12-colonized gnotobiotic mice phenocopied fully colonized mice during the dark (active/eating) phase but phenocopied germ-free mice during the light (fasting/resting) phase. Further, OligoMM12-colonized mice showed a germ-free-like drop in liver glycogen storage during the light cycle and both liver and plasma metabolomes of OligoMM12 mice clustered closely with germ-free mice. This implies the existence of microbiota functions that are required to maintain normal host metabolism during the resting/fasting phase of circadian cycle, and which are absent in the OligoMM12 consortium.
Intercellular crosstalk regulating ARRB2/RARRES1 is involved in transition from fibrosis to cancer
Authors: Schierwagen Robert , Dietrich Peter , Heinzen Judith , Klein Sabine , Uschner Frank E. , Ortiz Cristina , Tyc Olaf , Torres Sandra , Hieber Christoph , Kraus Nico , Premont Richard T. , Grünewald Leon D. , Poisson Johanne , Rautou Pierre-Emmanuel , Kristiansen Glen , Gracia-Sancho Jordi , Poglitsch Marko , Ludwig-Portugall Isis , Walther Thomas , Trautwein Christian , Abdullah Zeinab , Münch Christian , Welsch Christoph , Fernandez Mercedes , Zeuzem Stefan , Moreau Richard , Hellerbrand Claus , Rombouts Krista , Kastenmüller Wolfgang , Diehl Anna Mae , Trebicka Jonel 
Published: September 2021

AbstractProgressive fibrogenesis in chronic liver injury is often associated with cancer development. Beta-arrestin-2 (ARRB2) is a regulator of the profibrotic Angiotensin II type 1 receptor (AGTR1). The role of ARRB2 in liver fibrosis and in the transition from fibrosis to cancer is not fully understood and was investigated in this study.This study demonstrates that upregulation of the retinoic acid receptor responder 1 (RARRES1) in HSC mediated by ARRB2 leads to fibrosis. This process is driven by exosomal ARRB2 transfer to HSC, major fibrosis contributors, from injured hepatocytes, which highly express ARRB2. By contrast, downregulation of RARRES1 in hepatocytes induces malignant transformation and hepatocellular carcinoma (HCC) development. Consequently, Arrb2-deficient mice show higher number and size of liver tumors than wild-type mice in a hepatocellular carcinoma model with fibrosis. The identified relationship between ARRB2 and RARRES1 was observed in at least two species, including human cells and tissues in fibrosis and HCC and has a predictive value for survival in cancer patients. This study describes the discovery of a novel molecular pathway mediating the transition from fibrosis to cancer offering potential diagnostics and therapeutics.
Flexible Path Planning Through Vicarious Trial and Error
Authors: Krichmar Jeffrey L. , Ketz Nicholas A. , Pilly Praveen K. , Soltoggio Andrea 
Published: September 2021

AbstractFlexible planning is necessary for reaching goals and adapting when conditions change. We introduce a biologically plausible path planning model that learns its environment, rapidly adapts to change, and plans efficient routes to goals. Unlike prior models of hippocampal replay, our model addresses the decision-making process when faced with uncertainty. We tested the model in simulations of human and rodent navigation in mazes. Like the human and rat, the model was able to generate novel shortcuts, and take detours when familiar routes were blocked. Similar to rodent hippocampus recordings, the neural activity of the model resembles neural correlates of Vicarious Trial and Error (VTE) during early learning or during uncertain conditions. Similar to rodent studies, after learning, the neural activity resembles forward replay or preplay predicting a future route, and VTE activity decreases. We suggest that VTE, in addition to weighing possible outcomes, is a way in which an organism may gather information for future use.
Host- and age-dependent transcriptional changes in Mycobacterium tuberculosis cell envelope biosynthesis genes after exposure to human alveolar lining fluid
Authors: Allué-Guardia Anna , Garcia-Vilanova Andreu , M. Olmo-Fontánez Angélica , Peters Jay , Maselli Diego J. , Wang Yufeng , Turner Joanne , Schlesinger Larry S. , Torrelles Jordi B. 
Published: September 2021

AbstractTuberculosis (TB) infection, caused by the airborne pathogen Mycobacterium tuberculosis (M.tb), resulted in almost 1.4 million deaths in 2019 and the number of deaths is predicted to increase by 20% over the next 5 years due to the COVID-19 pandemic. Upon reaching the alveolar space, M.tb comes in close contact with the lung mucosa before and after its encounter with host alveolar compartment cells. Our previous studies show that homeostatic innate soluble components of the alveolar lining fluid (ALF) can quickly alter the cell envelope surface of M.tb upon contact, defining subsequent M.tb-host cell interactions and infection outcomes in vitro and in vivo. We also demonstrated that ALF from 60+ year old elders (E-ALF) vs. healthy 18- to 45-year-old adults (A-ALF) is dysfunctional with loss of homeostatic capacity and impaired innate soluble responses linked to high local oxidative stress. In this study, a targeted transcriptional assay demonstrates that M.tb exposure to human ALF alters the expression of its cell envelope genes. Specifically, our results indicate that A-ALF-exposed M.tb upregulates cell envelope genes associated with lipid, carbohydrate, and amino acid metabolism, as well as genes associated with redox homeostasis and transcriptional regulators. Conversely, M.tb exposure to E-ALF shows lesser transcriptional response, with most of the M.tb genes unchanged or downregulated. Overall, this study indicates that M.tb responds and adapts to the lung alveolar environment upon contact, and that the host ALF status determined by factors such as age might play an important role in determining infection outcome.
Riparian forest restoration as sources of biodiversity and ecosystem functions in anthropogenic landscapes
Authors: Antonini Y , Beirão MV , Costa FV , Azevedo CSv , Wojakowski MM , Kozovits AR , Pires MRS , Sousa HC de , Messias MCTB , Fujaco MA , Leite MGP , Vidigal JP , Monteiro GF , Dirzo R 
Published: September 2021

AbstractRestoration of tropical riparian forests is challenging, since these ecosystems are the most diverse, dynamic, and complex physical and biological terrestrial habitats. This study tested whether biodiversity can predict ecosystem functions in a human-impacted tropical riparian forest.We explored the effects of several biodiversity components (taxonomic or functional groups) on different ecosystem functions associated with restored riparian forestsOverall, 49% of the biodiversity components showed positive effects on ecosystem functions, each component to a different degree. In general, our results showed that both taxonomic and functional biodiversity had strong effects on ecosystem functions indicating that floral and faunal biodiversity enhanced the multifunctionality of these restored riparian tropical forests.These findings indicate that in restored riparian forests, recovery of biodiversity is followed by improvement in important ecosystem functions that are the basis for successful restoration. Future research and policy for restoration programs must focus on restoring elementary faunal and floral components of biodiversity in order to promote ecosystem multifunctionality.
Foot-and-mouth disease virus localisation on follicular dendritic cells and sustained induction of neutralising antibodies is dependent on binding to complement receptors (CR2/CR1)
Authors: Gordon Lucy , Mabbott Neil , Wells Joanna , Kulik Liudmila , Juleff Nick , Charleston Bryan , Perez-Martin Eva 
Published: September 2021

AbstractPrevious studies have shown after the resolution of acute infection and viraemia, foot- and-mouth disease virus (FMDV) capsid proteins and/or genome are localised in the light zone of germinal centres of lymphoid tissue in cattle and African buffalo. The pattern of staining for FMDV proteins was consistent with the virus binding to follicular dendritic cells (FDCs). We have now demonstrated a similar pattern of FMDV protein staining in mouse spleens after acute infection and showed FMDV proteins are colocalised with FDCs. Blocking antigen binding to complement receptor type 2 and 1 (CR2/CR1) prior to infection with FMDV significantly reduced the detection of viral proteins on FDCs and FMDV genomic RNA in spleen samples. Blocking the receptors prior to infection also significantly reduced neutralising antibody titres. Therefore, the binding of FMDV to FDCs and sustained induction of neutralising antibody responses are dependent on FMDV binding to CR2/CR1 in mice.Author SummaryFoot and mouth disease virus causes a highly contagious acute vesicular disease, resulting in more than 50% of cattle, regardless of vaccination status, and almost 100% of African buffalo becoming persistently infected for long periods (months) of time. Yet, the mechanisms associated with establishment of persistent infections are still poorly understood. Infected animals are characterised by the presence of long-lived neutralising antibody titres, which contrast with the short-lived response induced by vaccination. We have used a mouse model to understand how foot and mouth disease virus is trapped and retained in the spleen for up to 28 days post infection and how the absence of antigen in the germinal centre prevents a sustainable neutralising antibody response, in the mouse. Our results highlight the importance of targeting antigen to FDCs to stimulate potent neutralising antibody responses after vaccination.
Structural origins of Escherichia coli RNA polymerase open promoter complex stability
Authors: Saecker Ruth M. , Chen James , Chiu Courtney E. , Malone Brandon , Sotiris Johanna , Ebrahim Mark , Yen Laura Y. , Eng Edward T. , Darst Seth A. 
Published: September 2021

AbstractThe first step of gene expression in all organisms requires opening the DNA duplex to expose one strand for templated RNA synthesis. In Escherichia coli, promoter DNA sequence fundamentally determines how fast the RNA polymerase (RNAP) forms “open” complexes (RPo), whether RPo persists for seconds or hours, and how quickly RNAP transitions from initiation to elongation. These rates control promoter strength in vivo but their structural origins remain largely unknown. Here we use cryo-electron microscopy to determine structures of RPo formed de novo at three promoters with widely differing lifetimes at 37°C: λPR (t1/2 ∼ 10 hours), T7A1 (t1/2 ∼ 4 minutes), and a point mutant in λPR (λPR-5C) (t1/2 ∼ 2 hours). Two distinct RPo conformers are populated at λPR, likely representing productive and unproductive forms of RPo observed in solution studies. We find that changes in the sequence and length of DNA in the transcription bubble just upstream of the start site (+1) globally alter the network of DNA-RNAP interactions, base stacking, and strand order in the single-stranded DNA of the transcription bubble; these differences propagate beyond the bubble to upstream and downstream DNA. After expanding the transcription bubble by one base (T7A1), the nontemplate-strand “scrunches” inside the active site cleft; the template-strand bulges outside the cleft at the upstream edge of the bubble. The structures illustrate how limited sequence changes trigger global alterations in the transcription bubble that modulate RPo lifetime and affect the subsequent steps of the transcription cycle.