bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural basis of peptidoglycan endopeptidase regulation
Authors: Shin Jung-Ho , Sulpizio Alan G. , Kelley Aaron , Alvarez Laura , Murphy Shannon G. , Cava Felipe , Mao Yuxin , Saper Mark A. , Dörr Tobias 
Published: November 2019

AbstractMost bacteria surround themselves with a cell wall, a strong meshwork consisting primarily of the polymerized aminosugar peptidoglycan (PG). PG is essential for structural maintenance of bacterial cells, and thus for viability. PG is also constantly synthesized and turned over, the latter process is mediated by PG cleavage enzymes, for example the endopeptidases (EPs). EPs themselves are essential for growth, but also promote lethal cell wall degradation after exposure to antibiotics that inhibit PG synthases (e.g., β-lactams). Thus, EPs are attractive targets for novel antibiotics and their adjuvants. However, we have a poor understanding of how these enzymes are regulatedin vivo, depriving us of novel pathways for the development of such antibiotics. Here, we have solved crystal structures of the LysM/M23 family peptidase ShyA, the primary EP of the cholera pathogenVibrio cholerae.Our data suggest that ShyA assumes two drastically different conformations; a more open form that allows for substrate binding, and a closed form, which we predicted to be catalytically inactive. Mutations expected to promote the open conformation caused enhanced activityin vitroandin vivo, and these results were recapitulated in EPs from the divergent pathogensNeisseria gonorrheaeandEscherichia coli. Our results suggest that LysM/M23 EPs are regulated via release of the inhibitory Domain1 from the M23 active site, likely through conformational re-arrangementin vivo.SignificanceBacteria digest their cell wall following exposure to antibiotics like penicillin. The endopeptidases (EPs) are among the proteins that catalyze cell wall digestion processes after antibiotic exposure, but we do not understand how these enzymes are regulated during normal growth. Herein, we present the structure of the major EP from the diarrheal pathogenVibrio cholerae.Surprisingly, we find that EPs from this and other pathogens appear to be produced as a largely inactive precursor that undergoes a conformational shift exposing the active site to engage in cell wall digestion. These results enhance our understanding of how EPs are regulated and could open the door for the development of novel antibiotics that overactivate cell wall digestion processes.
Microneedle manipulation of the mammalian spindle reveals specialized, short-lived reinforcement near chromosomes
Authors: Suresh Pooja , Long Alexandra F. , Dumont Sophie 
Published: November 2019

AbstractThe spindle generates force to segregate chromosomes at cell division. In mammalian cells, kinetochore-fibers connect chromosomes to the spindle. The dynamic spindle anchors kinetochore-fibers in space and time to coordinate chromosome movement. Yet, how it does so remains poorly understood as we lack tools to directly challenge this anchorage. Here, we adapt microneedle manipulation to exert local forces on the spindle with spatiotemporal control. Pulling on kinetochore-fibers reveals that the spindle retains local architecture in its center on the seconds timescale. Upon pulling, sister, but not neighbor, kinetochore-fibers remain tightly coupled, restricting chromosome stretching. Further, pulled kinetochore-fibers freely pivot around poles but not around chromosomes, retaining their orientation within 3 µm of chromosomes. This local reinforcement has a 20 s lifetime, and requires the microtubule crosslinker PRC1. Together, these observations indicate short-lived, specialized reinforcement of the kinetochore-fiber in the spindle center. This could help the spindle protect local structure near chromosomes from transient forces while allowing its remodeling over longer timescales, thereby supporting robust chromosome attachments and movements.
Apcdd1 is a dual BMP/Wnt inhibitor in the developing nervous system and skin
Authors: Vonica Alin , Bhat Neha , Phan Keith , Guo Jinbai , Iancu Lăcrimioara , Weber Jessica A. , Karger Amir , Cain John W. , Wang Etienne C. E. , DeStefano Gina M. , O’Donnell-Luria Anne H. , Christiano Angela M. , Riley Bruce , Butler Samantha J. , Luria Victor 
Published: November 2019

AbstractAnimal development and homeostasis depend on precise temporal and spatial intercellular signaling. Components shared between signaling pathways, generally thought to decrease specificity, paradoxically can also provide a solution to pathway coordination. Here we show that the Bone Morphogenetic Protein (BMP) and Wnt signaling pathways share Apcdd1 as a common inhibitor and that Apcdd1 is a taxon-restricted gene with novel domains and signaling functions. Previously, we showed that Apcdd1 inhibits Wnt signaling, here we find that Apcdd1 potently inhibits BMP signaling in body axis formation and neural differentiation in chicken, frog, zebrafish, and humans. Our results from experiments and modeling suggest that Apcdd1 may coordinate the outputs of two signaling pathways central to animal development and human disease.Significance StatementApcdd1is a taxon-restricted gene that inhibits both BMP and Wnt intercellular signaling pathways in multiple organisms including mice, frog, zebrafish, and chicken. It encodes a bi-functional protein with a novel protein domain that can bind to Wnt and BMP receptors and block downstream signaling.
Phosphate transporter PstSCAB of Campylobacter jejuni is essential for lactate-dependent growth and colonization in chickens
Authors: Sinha Ritam , LeVeque Rhiannon M. , Bowlin Marvin Q. , Gray Michael J. , DiRita Victor J. 
Published: November 2019

AbstractCampylobacter jejuni causes acute gastroenteritis world-wide and is transmitted primarily through poultry, in which it is often a commensal member of the intestinal microbiota. Previous RNASeq experiments showed that transcripts from an operon encoding a high affinity phosphate transporter (PstSCAB) of C. jejuni were among the most abundant when grown in chickens. Elevated levels of the pstSCAB mRNA were also identified in an RNASeq experiment from human infection studies. In this study, we explore the role of PstSCAB in the biology and colonization potential of C. jejuni. Our experimental results demonstrate that cells lacking PstSCAB survive poorly in stationary phase, nutrient-limiting media, and under osmotic conditions reflective of those in the chicken. Polyphosphate levels in the mutant cells were elevated at stationary phase, consistent with alterations in expression of polyphosphate metabolism genes. C. jejuni were highly attenuated in colonization of newly hatched chicks, recovered at levels several orders of magnitude below wild type. Mutant and wild type grew similarly in complex media but the pstSCAB mutant exhibited a significant growth defect in minimal media supplemented with L-lactate, postulated as a carbon source in vivo. Poor growth in lactate correlated with diminished expression of acetogenesis pathway genes previously demonstrated as important for colonizing chickens. The phosphate transport system is thus essential for diverse aspects of C. jejuni physiology and in vivo fitness and survival.ImportanceC. jejuni causes millions of gastrointestinal infections annually worldwide. Poultry and poultry products are major sources of C. jejuni infection to human as the microbe is a commensal colonizer of the chicken gastrointestinal tract. Due to the emergence of multi-drug resistance in C. jejuni, there is need to identify alternative ways to control this pathogen. Genes encoding the high-affinity phosphate transporter PstSCAB were highly expressed during colonization of C. jejuni in chicken and human. In this study, we address the role this high-affinity phosphate transporter PstSCAB of C. jejuni on chicken colonization and for its general physiology. PstSCAB is required for colonization in chicken, metabolism and survival under different stress responses and during growth on lactate, a potential substrate for growth of C. jejuni in chickens. Our study highlights that PstSCAB may be an effective target to develop mechanisms to control the bacterial burden in both chicken and human.
Zika virus infection during pregnancy and induced brain pathology in beclin1-deficient mouse model
Authors: Muthu Karuppan Mohan Kumar , Ojha Chet Raj , Rodriguez Myosotys , Lapierre Jessica , Javad Aman M. , Kashanchi Fatah , Toborek Michal , Nair Madhavan , El-Hage Nazira 
Published: November 2019

ABSTRACTWe investigated the role of the autophagy protein, Beclin1, in the replication and disease of Zika virus (ZIKV) in pregnant dams and their offspring using Beclin1-deficient (Atg6+/−) and wild-type (Atg6+/+) mouse model infected with the Honduran (R103451), Puerto Rican (PRVABC59), and the Uganda (MR766) strains of ZIKV. Pregnant dams infected subcutaneously at embryonic stage (E)9 showed viral RNA in serum harvested at E13 and in various organs removed postmortem at E17. Subcutaneous infections with ZIKV also showed the vertical transmission of ZIKV from the placenta to embryos removed postmortem at E17. From the three isolates, R103451-infected Atg6+/− dams had the lowest mortality rate while 30 % of their offspring containing the hemizygous beclin1 allele (Atg6+/−) were smaller in size and had smaller and underdeveloped brain. Growth impairment in the pups became noticeable after two weeks post-birth. After 21-days, pups were sacrificed and brain tissues removed postmortem showed expression of the envelope (E) and the non-structural (NS)-1 proteins, along with signs of neuronal injury, despite an absence in viral RNA detection. A significant decrease in the mRNA expression levels of the insulin-like growth factor-1 (IGF-1) by 8-fold and a decrease in the mRNA expression levels of several microcephaly related genes along with an increase in the secretion of several inflammatory molecules may have contributed to the observed phenotype. Since autophagy regulates cytokines and chemokines production, a dysregulation in this pathway may have further exacerbated the pathology of ZIKV.IMPORTANCEPups delivered from ZIKV-infected dams showed significant growth impairments in the body and the brain. We believe that the reduction in insulin growth factor together with the increase secretion of inflammatory molecules may have triggered neuronal injury and the downregulation of the microcephalic genes, while reduced expression of the autophagy protein, Beclin1 further exacerbated the pathology. Although the mechanism is still unknown, the autophagy pathway seems to play a key role in ZIKV pathology. It is therefore of great significance to study the role of autophagy during viral infection with the goal to identify potential targets for anti-ZIKV therapeutic intervention.
aCPSF1 controlled archaeal transcription termination: a prototypical eukaryotic model
Authors: Yue Lei , Li Jie , Zhang Bing , Qi Lei , Zhao Fangqing , Li Lingyan , Dong Xiuzhu 
Published: November 2019

AbstractTranscription termination defines RNA 3′-ends and guarantees programmed transcriptomes, thus is an essential biological process for life. However, transcription termination mechanisms remain almost unknown in Archaea. Here reported the first general transcription termination factor of Archaea, the conserved ribonuclease aCPSF1, and elucidated its 3′-end cleavage dependent termination mechanism. Depletion of Mmp-aCPSF1 in a methanoarchaeon Methanococcus maripaludis caused a genome-wide transcription termination defect and overall transcriptome chaos, and cold-sensitive growth. Transcript-3′end-sequencing (Term-seq) revealed transcriptions mostly terminated downstream of a uridine-rich terminator motif, where Mmp-aCPSF1 performed cleavage. The endoribonuclease activity was determined essential to terminate transcription in vivo as well. Through super-resolution photoactivated localization microscopy imaging, co-immunoprecipitation, and chromatin immunoprecipitation, we demonstrated that Mmp-aCPSF1 localizes within nucleoid and associates with RNAP and chromosomes. aCPSF1 appears to co-evolve with archaeal RNAPs, and two distant orthologs each from Lokiarchaeota and Thaumarchaeota could replace Mmp-aCPSF1 to termination transcription. Thus, aCPSF1 dependent termination mechanism could be universally employed in Archaea, including Lokiarchaeota, one supposed archaeal ancestor of Eukaryotes. Therefore, the reported aCPSF1 cleavage-dependent termination mode not only hints an archetype of Eukaryotic 3′-end processing/cleavage triggered RNAP II termination, but also would shed lights on understanding the complex eukaryotic termination based on the simplified archaeal model.
Quantifying individual influence in leading-following behavior of Bechstein’s bats
Authors: Mavrodiev Pavlin , Fleischmann Daniela , Kerth Gerald , Schweitzer Frank 
Published: November 2019

AbstractLeading-following behavior as a way of transferring information about the location of resources is widespread in different animal societies. However, it cannot always be observed directly. Here, we develop a general method to infer leading-following events from observational data if only the discrete appearance of individuals is recorded. Our method further allows to distinguish such events from local enhancement at the resource, such as swarming behavior in case of bats, which is another widespread way of transferring information among animals. To test our methodology, we analyze longitudinal data about the roosting behavior of Bechstein’s bats from two different colonies and different years. The detection of leading-following events allows us, in a second step, to construct social networks in which nodes represent individual bats and directed and weighted links the leading-following events. We analyze the topology of these networks on the level of the colony, to see whether all individuals participate in leading-following behavior. Further, based on the leading-following network we measure the importance of individuals in this leading-following behavior by calculating different centrality measures. We find that individuals can be consistently ranked regarding their influence on others. Moreover, we identify a small set of individuals that play a central role in leading other bats to roosts. Our methodology can be used to understand the leading-following behavior and the individual impact of group members on the spread of information in animal groups in general.
Data-driven modeling of leading-following behavior in Bechstein’s bats
Authors: Mavrodiev Pavlin , Fleischmann Daniela , Kerth Gerald , Schweitzer Frank 
Published: November 2019

AbstractLeading-following behaviour in Bechstein’s bats transfers information about suitable roost sites from experienced to inexperienced individuals, and thus ensures communal roosting. We analyze 9 empirical data sets about individualized leading-following (L/F) events, to infer rules that likely determine the formation of L/F pairs. To test these rules, we propose five models that differ regarding the empirical information taken into account to form L/F pairs: activity of a bat in exploring possible roosts, tendency to lead and to follow. The comparison with empirical data was done by constructing social networks from the observed L/F events, on which centralities were calculated to quantify the importance of individuals in these L/F networks. The centralities from the empirical network are then compared for statistical differences with the model-generated centralities obtained from 105model realizations. We find that two models perform well in comparison with the empirical data: One model assumes an individual tendency to lead, but chooses followers at random. The other model assumes an individual tendency to follow and chooses leaders according to their overall activity. We note that neither individual preferences for specific individuals, nor other influences such as kinship or reciprocity, are taken into account to reproduce the empirical findings.
CXCR4 intracellular protein regulates drug resistance and tumorigenic potential via modulating the expression of Death Receptor 5
Authors: Nengroo Mushtaq Ahmed , Maheshwari Shrankhla , Singh Akhilesh , Singh Anup Kumar , Arya Rakesh Kumar , Chaturvedi Priyank , Verma Ayushi , Saini Krishan Kumar , Gupta Annapurna , Mishra Anjali , Datta Dipak 
Published: November 2019

AbstractCXCR4 overexpression in solid tumors has been strongly associated with poor prognosis and adverse clinical outcome. However, CXCR4 signaling inhibitor drug Plerixafor has shown limited clinical success in cancer treatment. Therefore, CXCR4 signaling may not be the exclusive contributor to its pro-tumorigenic functions. In our continuous effort to understand the chemokine receptor signaling inhibition as cancer therapy, here we unexpectedly discovered that instead of its signaling, intracellular CXCR4 protein augments therapy resistance and pro-tumorigenic functions. Unbiased proteome profiler apoptosis array followed by immunoblot, FACS, real-time PCR and ChIP analyses demonstrate that CXCR4 promotes DR5 downregulation via modulating differential recruitment of transcription factors p53 and YY1 to its promoter. Surprisingly, inhibiting CXCR4 mediated signals failed to block the above phenotype. Irrespective of CXCR4 surface expression, its loss compromised colon tumor growthin vivo. Finally, TCGA data mining and human patient sample data analysis showed CXCR4 and DR5 are inversely regulated in human cancers. Together, we showed evidence for the first time that targeting CXCR4 intracellular protein may be critical to dampen the pro-tumorigenic functions of CXCR4.
Characterization of Mollivirus kamchatka, the first modern representative of the proposed Molliviridae family of giant viruses
Authors: Christo-Foroux Eugene , Alempic Jean-Marie , Lartigue Audrey , Santini Sebastien , Labadie Karine , Legendre Matthieu , Abergel Chantal , Claverie Jean-Michel 
Published: November 2019

AbstractMicrobes trapped in permanently frozen paleosoils (permafrost) are the focus of increasing researches in the context of global warming. Our previous investigations led to the discovery and reactivation of two Acanthamoeba-infecting giant viruses, Mollivirus sibericum and Pithovirus sibericum from a 30,000-year old permafrost layer. While several modern pithovirus strains have since been isolated, no contemporary mollivirus relative was found. We now describe Mollivirus kamchatka, a close relative to M. sibericum, isolated from surface soil sampled on the bank of the Kronotsky river in Kamchatka. This discovery confirms that molliviruses have not gone extinct and are at least present in a distant subarctic continental location. This modern isolate exhibits a nucleo-cytoplasmic replication cycle identical to that of M. sibericum. Its spherical particle (0.6-μm in diameter) encloses a 648-kb GC-rich double stranded DNA genome coding for 480 proteins of which 61 % are unique to these two molliviruses. The 461 homologous proteins are highly conserved (92 % identical residues in average) despite the presumed stasis of M. sibericum for the last 30,000 years. Selection pressure analyses show that most of these proteins contribute to the virus fitness. The comparison of these first two molliviruses clarify their evolutionary relationship with the pandoraviruses, supporting their provisional classification in a distinct family, the Molliviridae, pending the eventual discovery of intermediary missing links better demonstrating their common ancestry.ImportanceVirology has long been viewed through the prism of human, cattle or plant diseases leading to a largely incomplete picture of the viral world. The serendipitous discovery of the first giant virus visible under light microscopy (i.e., >0.3μm in diameter), mimivirus, opened a new era of environmental virology, now incorporating protozoan-infecting viruses. Planet-wide isolation studies and metagenomes analyses have shown the presence of giant viruses in most terrestrial and aquatic environments including upper Pleistocene frozen soils. Those systematic surveys have led authors to propose several new distinct families, including the Mimiviridae, Marseilleviridae, Faustoviridae, Pandoraviridae, and Pithoviridae. We now propose to introduce one additional family, the Molliviridae, following the description of M. kamchatka, the first modern relative of M. sibericum, previously isolated from 30,000-year old arctic permafrost.
Comparative effectiveness of probiotic-based formulations on cecal microbiota modulation in broilers
Authors: Rodrigues D.R. , Briggs W. , Duff A. , Chasser K. , Murugesan R. , Pender C. , Ramirez S. , Petri D. , Bielke L.R. 
Published: November 2019

AbstractThe potential of probiotics to manipulate the intestinal microbial ecosystem toward commensal bacteria growth offers great hope for enhancing health and performance in poultry. This study aimed to evaluate the efficacy of five probiotic-based formulations in modulating cecal microbiota in broilers at 21 and 42 days of age. Probiotics investigated included a synbiotic (SYNBIO), a yeast-based probiotic (YEAST), and three single-strain formulations of spore-formingBacillus amyloliquefaciens(SINGLE1),B. subtilis(SINGLE2) andB. licheniformis(SINGLE3). Metagenomics analyses showed that the cecal microbiota of SINGLE, YEAST, and MULTI supplemented birds had low diversity compared to the control diet without probiotics (CON) at 21d. At the same age, birds fed SYNBIO had a high population ofLactobacillus salivarusandLachnospiraceae, which was reflected in a singular microbial community illustrated by beta-diversity analyses. By 42d, there were no differences in alpha or beta-diversity in the microbiota of probiotic-treated broilers compared to CON. Birds treated with SINGLE2 had a lower abundance of lactic acid bacteria, while a higher (p<0.05) population of unidentifiedLachnospiraceaeandRuminococcaceae. Although the investigated probiotic formulations shared similar taxonomy, modulation of microbiota was not a core outcome for all probiotic-treated broilers indicating the success of microbiota-based intervention may ultimately be dependent on probiotic mixture and broiler’s age.