bluuebunny/crossref_metadata_2025_split huggingface dataset:
Telomere shortening produces an inflammatory environment that promotes tumor invasiveness in zebrafish
Authors: Lex Kirsten , Gil Mariana Maia , Figueira Margarida , Marzullo Marta , Lopes-Bastos Bruno , Giannetti Kety , Carvalho Tania , Ferreira Miguel Godinho 
Published: November 2019

AbstractCancer incidence increases exponentially with age, when human telomeres are shorter. Similarly, telomerase mutant zebrafish (tert) have premature short telomeres and anticipate cancer incidence to younger ages. However, because short telomeres constitute a road block to cell proliferation, telomere shortening is currently viewed as a tumor suppressor mechanism and should protect from cancer. This conundrum is not fully understood. In our current study, we report that telomere shortening promotes cancer in a non-cell autonomous manner. Using zebrafish chimeras, we show increased incidence of invasive melanoma when WT tumors are generated in tert mutant zebrafish. tert zebrafish show increased levels of senescence (cdkn2a and ink4a/b) and inflammation (TNF-α). In addition, we transferred second generation tert blastula cells into WT to produce embryo chimeras. Cells with very short telomeres induced senescence and increased neutrophil numbers in surrounding larval tissues in a non-cell autonomous manner, creating an inflammatory environment. Considering that inflammation is pro-tumorigenic, we transplanted melanoma-derived cells into second generation tert zebrafish embryos and observed that tissue environment with short telomeres leads to increased micrometastasis. To test if inflammation was necessary for this effect, we treated melanoma transplants with non-steroid anti-inflammatory drugs and show that higher melanoma invasiveness can be averted. Thus, apart from the cell autonomous role of short telomeres in contributing to genome instability, we propose that telomere shortening with age causes systemic chronic inflammation leading to increased tumor incidence.Significance StatementCancer incidence increases exponentially in human midlife. Even though mutation accumulation in somatic tissues results in increased tumorigenesis, it is currently not understood how aging contributes to cancer. Telomeres, the ends of eukaryotic linear chromosomes, shorten with each cell division. Here we show that telomere shortening contributes to cancer in a non-cell autonomous manner. Using embryo chimeras of telomerase deficient zebrafish generated from melanoma-prone fish, we show that tumors arise more frequently and become more invasive in animals with shorter telomeres. Telomere shortening gives rise to increased senescence and systemic inflammation. We observed increased melanoma metastasis dissemination in zebrafish larvae with very short telomeres. Thus, telomere shortening similar to human aging, generates a chronic inflammatory environment that increases cancer incidence.
A Priori Activation of Apoptosis Pathways of Tumor (AAAPT) Technology: Development of Targeted Apoptosis Initiators for Cancer Treatment
Authors: Pandurangi Raghu , Tomasetti Marco , Sekar Thillai Verapazham , Paulmurugan Ramasamy , Ma Cynthia , Sandeep  , Anjanappa Manjushree , Nakshatri Harikrishna 
Published: November 2019

AbstractCancer cells develop tactics to circumvent the interventions by desensitizing themselves to interventions. The principle routes of desensitization include a) activation of survival pathways (e.g. NF-kB, PARP) and b) downregulation of cell death pathways (e.g. CD95/CD95L). As a result, it requires high therapeutic dose to achieve tumor regression which, in turn damages normal cells through the collateral damaging effects. Methods are needed to sensitize the low and non-responsive resistant tumor cells including cancer stem cells (CSCs) in order to evoke a better response from the current treatments. Current treatments including chemotherapy can induce cell death only in bulk cancer cells sparing CSCs and cancer resistant cells (CRCs) which are shown to be responsible for high recurrence of disease and low patient survival. Here, we report several novel tumor targeted sensitizers derived from the natural Vitamin E analogue (AMP-001-003). The drug design is based on a novel concept “A priori activation of apoptosis pathways of tumor technology (AAAPT) which is designed to activate specific cell death pathways and inhibit survival pathways simultaneously. Our results indicate that AMP-001-003 sensitize various types of cancer cells including MDA-MB-231 (triple negative breast cancer), PC3 (prostate cancer) and A543 (ling cancer) cells resulting in reducing the IC-50 of doxorubicin in vitro. At higher dose, AMP-001 acts as an anti-tumor agent on its own. The synergy between AMP-001 and doxorubicin could pave a new pathway to use AMP-001 as a neoadjuvant to chemotherapy to achieve a better efficacy and reduced off-target toxicity by the current treatments.Summary StatementA Priori Activation of Apoptosis Pathways of Tumor often referred to as “AAAPT” is a novel targeted tumor sensitizing technology which synergizes with chemotherapy to enhance the treatment efficacy.
WolbachiastrainwAu efficiently blocks arbovirus transmission inAedes albopictus
Authors: Mancini Maria Vittoria , Herd Christie S. , Ant Thomas H. , Murdochy Shivan M. , Sinkins Steven P. 
Published: November 2019

AbstractThe global incidence of arboviral diseases transmitted byAedesmosquitoes, including dengue, chikungunya, yellow fever, and Zika, has increased dramatically in recent decades. The release ofAedes aegypticarrying the maternally inherited symbiontWolbachiaas an intervention to control arboviruses is being trialled in several countries. However, these efforts are compromised in many endemic regions due to the co-localization of the secondary vectorAedes albopictus, the Asian tiger mosquito.Ae. albopictushas an expanding global distribution following incursions into a number of new territories. To date, only thewMel andwPip strains ofWolbachiahave been reported to be transferred into and characterized in this vector. AWolbachiastrain naturally infectingDrosophila simulans,wAu, was selected for transfer into a MalaysianAe. albopictusline to create a novel triple-strain infection. The newly generated line showed self-compatibility, moderate fitness cost and complete resistance to Zika and dengue infections.Author summaryAedes albopictus, the invasive Asian tiger mosquito, is responsible for numerous outbreaks of important viruses such as dengue and Zika in various regions of the world. The need for alterative control interventions propelled the development of a novel approach that exploits a natural insect symbiont,Wolbachia; when transferred into non-native hosts, these maternally-inherited bacteria are able to interfere with the transmission of mosquito-borne viruses, and also provide reproductive advantages to the host, offering a promising tool for self-sustaining field applications. Currently, several field trials are ongoing for the primary vector of dengue and several other arboviruses,Aedes aegypti, providing encouraging results. In this study,Ae. albopictushas been targeted for a similar approach: this mosquito species naturally carries two strains ofWolbachia. The artificial introduction of a third, non-native strain made this line less able to transmit dengue and Zika viruses and had an impact on its fitness.
The adoptive transfer of BCG-induced T lymphocytes contributes to hippocampal cell proliferation and tempers anxiety-like behavior in immune deficient mice
Authors: Song Dan , Qi Fangfang , Liu ShuaiShuai , Tang Zhongsheng , Duan Jinhai , Yao Zhibin 
Published: November 2019

1.AbstractWe previously have reported that neonatal Bacillus Calmette-Guerin (BCG) vaccination improves neurogenesis and behavior in early life through affecting the neuroimmune milieu in the brain, but it is uncertain whether activation phenotypes and functional changes in T lymphocytes shape brain development. Here, we studied the effects of BCG vaccination via the adoptive transfer of T lymphocytes from the BALB/c wild-type mice into naive mice. Our results show that mice adoptive BCG-induced lymphocytes (BCG->naive mice) showed anxiolytic and antidepressant-like performance when completing an elevated plus maze (EPM) test. Meanwhile, BCG->naive mice possess more cell proliferation and newborn neurons than PBS->naive and nude mice in the hippocampus. IFN-γ and IL-4 levels in the serum of BCG->naive mice also increased, while TNF-α and IL-1β levels were reduced relative to those of PBS->naive and nude mice. We further found that BCG->naive mice showed different repartition of CD4+ and CD8+ T cell to naive (CD62L+ CD44low), effector memory (CD62L− CD44hi), central memory (CD62L+ CD44hi) and acute/activated effector (CD62L− CD44low) cells in the spleen. Importantly, the adoptive transfer of BCG-induced T lymphocytes infiltrated into the dura mater and brain parenchyma of the nude mice. Activation phenotypes and functional changes in T lymphocytes are very likely to affect the neuroimmune milieu in the brain, and alterations in ratios of splenic CD4+ and CD8+ memory T cells may affect the expression of correlative cytokines in the serum, accounting for our behavioral results. We conclude thus that the adoptive transfer of BCG-induced T lymphocytes contributes to hippocampal cell proliferation and tempers anxiety-like behavior in immune deficient mice. Our work shows that BCG vaccination improves hippocampal cell proliferation outcomes and behaviors, likely as a result of splenic effector/memory T lymphocytes regulating the neuroimmune niche in the brain.
Herpes Simplex Virus Infection, Acyclovir and IVIG Treatment All Independently Cause Gut Dysbiosis
Authors: Ramakrishna Chandran , Mendonca Stacee , Ruegger Paul M. , Kim Jane Hannah , Borneman James , Cantin Edouard 
Published: November 2019

AbstractHerpes simplex virus 1 (HSV) is a ubiquitous human virus resident in a majority of the global population as a latent infection. Acyclovir (ACV), is the standard of care drug used to treat primary and recurrent infections, supplemented in some patients with intravenous immunoglobulin (IVIG) treatment to suppress deleterious inflammatory responses. We found that HSV, ACV and IVIG can all independently disrupt the gut bacterial community in a sex biased manner when given to uninfected mice. Treatment of HSV infected mice with ACV or IVIG alone or together revealed complex interactions between these drugs and infection that caused pronounced sex biased dysbiosis. ACV reducedBacteroideteslevels in male but not female mice, while levels of the Anti-inflammatory Clostridia (AIC) were reduced in female but not male mice, which is significant as these taxa are associated with protection against the development of GVHD in hematopoietic stem cell transplant (HSCT) patients. Gut barrier dysfunction is associated with GVHD in HSCT patients and ACV also decreasedAkkermansia muciniphila,which is important for maintaining gut barrier functionality. Cumulatively, our data suggest that long-term prophylactic ACV treatment of HSCT patients may contribute to GVHD and potentially impact immune reconstitution. These data have important implications for other clinical settings, including HSV eye disease and genital infections, where ACV is given long-term.Author SummaryPrimary and reactivated HSV and VZV infections are treated with Acyclovir (ACV), an antiviral drug that blocks viral DNA synthesis. In some patients IVIG is used as adjunctive therapy to block deleterious inflammation. Long term preventative treatment of patients who receive stem transplants for various blood cancers has been successful in preventing life threatening reactivated HSV and VZV infections, but GVHD remains a major factor limiting transplant success. Studies reported here reveal that HSV infection, ACV and IVIG given alone can all disrupt the gut microbiota and that complex interactions between these drugs and infection results in even more pronounced sex biased changes in the gut bacteria community structure. Importantly, ACV treatment decreased the levels of specific bacterial taxa, including the anti-inflammatoryClostriodiaandBacteroidetesthat have been shown to protect against development of GVHD in stem cell transplant patients. These data suggest that long term preventative treatment of patients with ACV may contribute to GVHD in transplant patients and have negative consequences in other HSV induced diseases treated long term with ACV. The health effects of long term ACV and IVIG treatments warrant further clinical studies.
Noncoding regions underpin avian bill shape diversification at macroevolutionary scales
Authors: Yusuf Leeban , Heatley Matthew C. , Palmer Joseph P.G. , Barton Henry J. , Cooney Christopher R. , Gossmann Toni I. 
Published: November 2019

AbstractRecent progress has been made in identifying genomic regions implicated in trait evolution on a microevolutionary scale in many species, but whether these are relevant over macroevolutionary time remains unclear. Here, we directly address this fundamental question using bird beak shape, a key evolutionary innovation linked to patterns of resource use, divergence and speciation, as a model trait. We integrate class-wide geometric-morphometric analyses with evolutionary sequence analyses of 10,322 protein coding genes as well as 229,001 genomic regions spanning 72 species. We identify 1,434 protein coding genes and 39,806 noncoding regions for which molecular rates were significantly related to rates of bill shape evolution. We show that homologs of the identified protein coding genes as well as genes in close proximity to the identified noncoding regions are involved in craniofacial embryo development in mammals. They are associated with embryonic stem cells pathways, including BMP and Wnt signalling, both of which have repeatedly been implicated in the morphological development of avian beaks. This suggests that identifying genotype-phenotype association on a genome wide scale over macroevolutionary time is feasible. While the coding and noncoding gene sets are associated with similar pathways, the actual genes are highly distinct, with significantly reduced overlap between them and bill-related phenotype associations specific to noncoding loci. Evidence for signatures of recent diversifying selection on our identified noncoding loci in Darwin finch populations further suggests that regulatory rather than coding changes are major drivers of morphological diversification over macroevolutionary times.
Impact of different amino acid substitutions in penicillin-binding protein 3 on beta-lactam susceptibility in Haemophilus influenzae
Authors: Reist Josiane , Linnik Janina , Schibli Urs , Egli Adrian , Hinić Vladimira 
Published: November 2019

AbstractPurposeBeta-lactam antibiotics in combination with a beta-lactamase inhibitor are the first-line treatment option for Haemophilus influenzae infections. However, beta-lactamase-independent resistance to beta-lactams is increasing. This resistance mechanism has been linked to amino acid substitutions in the penicillin-binding protein 3 (PBP3), but how these substitutions lead to decreased binding affinities to certain beta-lactam antimicrobials remains unknown.MethodsWe investigated beta-lactam resistance and amino acid substitutions in PBP3 from fifty-three clinical isolates of H. influenzae collected in Switzerland from January to April 2016. Identification of key polymorphisms and classification of strains into PBP3 amino acid substitution groups I, II, and M was done as previously described. Based on published PBP3 crystal structures, we investigated how the group-specific amino acid substitutions impact the beta-lactam binding site.ResultsWe found that both group I and group II substitutions disrupt the Asn526-Arg517-Glu324 interaction, which might affect the configuration of the beta-lactam binding site. Amino acid substitutions in group M strains are distant from the active site and have most likely no impact on beta-lactam binding. In accordance with this observation, all group M strains showed minimal inhibitory concentrations (MICs) within the susceptible range for all tested antimicrobials and were not significantly different to the wild type (beta-lactamase producers excluded), while group I and group II strains showed significantly higher MICs for beta-lactam antimicrobials.ConclusionGroup M strains are phenotypically equal to the wild type, while amino acid substitutions of group I and group II might affect the beta-lactam binding through a common mechanism by disrupting the Asn526-Arg517-Glu324 interaction.
Inferring phylogenetic trees from mutational distance of transposable elements
Authors: Bermúdez Juanjo 
Published: November 2019

AbstractThere are many methods for establishing a phylogeny available to researchers. Some of these are based on the mutational distance between ortholog sequences of DNA, and, from these, some are based on the analysis (presence/absence) of transposable elements in specific loci of ortholog sequences. We present a new approach: a method for inferring a phylogeny based on the mutational distance of transposable elements distributed along any segment of DNA. Our method doesn’t require previously having ortholog segments of DNA from every organism. The method can be fully automated, not requiring any previous or posterior data analysis nor data preparation.
qKW9encodes a pentatricopeptide repeat protein affecting photosynthesis and grain filling in maize
Authors: Huang Juan , Lu Gang , Liu Lei , Raihan Mohammad Sharif , Xu Jieting , Jian Liumei , Zhao Lingxiao , Tran Thu M. , Zhang Qinghua , Liu Jie , Li Wenqiang , Wei Cunxu , Braun David M. , Li Qing , Fernie Alisdair R. , Jackson David , Yan Jianbing 
Published: November 2019

AbstractKernel weight is an important yield component in maize that was selected during domestication. Many kernel weight genes have been identified through mutant analysis, and are mostly involved in the biogenesis and functional maintenance of organelles or other fundamental cellular activities. However, only a limited number of loci underlying quantitative variation in kernel weight have been cloned. Here we characterize a maize kernel weight QTL,qKW9and find that it encodes a DYW motif pentatricopeptide repeat protein involved in C-to-U editing of NdhB, a subunit of the chloroplast NADH dehydrogenase-like complex. In a nullqKW9background, C-to-U editing of NdhB was abolished, and photosynthesis was reduced, suggesting thatqKW9regulates kernel weight by controling the maternal source of photosynthate for grain filling. Characterization ofqKW9highlights the importance of optimizing photosynthesis on maize grain yield production.
Measurements of the timescale and conformational space of AMPA receptor desensitization
Authors: Salazar Hector , Mischke Sabrina , Plested Andrew J. R. 
Published: November 2019

Ionotropic glutamate receptors (iGluRs) are ligand gated ion channels that mediate excitatory synaptic transmission in the central nervous system (CNS). Desensitization of the AMPA-subtype following glutamate binding appears critical for brain function, and involves rearrangement of the ligand binding domains (LBDs). Recently, several full-length structures of iGluRs in putative desensitized states were published. These structures indicate movements of the LBDs that might be trapped by cysteine crosslinks and metal bridges. We found that cysteine mutants at the interface between subunits A and C, and lateral zinc bridges (between subunits C & D or A & B) can trap freely-desensitizing receptors in a spectrum of states with different stabilities. Consistent with close approach of subunits during desensitization processes, introduction of bulky amino acids at the A-C interface produced a receptor with slow recovery from desensitization. Further, in wild-type GluA2 receptors, we detected population of stable desensitized state with a lifetime around 1 second. Using mutations that progressively stabilise deep desensitize states (E713T & Y768R), we were able to selectively protect receptors from crosslinks at both the diagonal and lateral interfaces. Ultrafast perfusion enabled us to perform chemical modification in less than 10 ms, reporting movements associated to desensitization on this timescale within LBD dimers in resting receptors. These observations suggest small disruptions of quaternary structure are sufficient for fast desensitization, and that substantial rearrangements likely correspond to stable desensitized states that are adopted relatively slowly, on a timescale much longer than physiological receptor activation.Significance statementiGluRs are central components of fast synaptic transmission in the brain. iGluR desensitization occurs as a natural consequence of receptor activation and can reduce the response of an excitatory synapse. AMPA receptor desensitization also appears necessary for proper brain development. Molecular structures of iGluRs in putative desensitized states predict a range of movements during desensitization. In the present study, we performed a series of crosslinking experiments on mutant receptors that we subjected to similar desensitizing conditions over time periods from milliseconds to minutes. These experiments allowed us to count desensitized configurations and rank them according to their stabilities. These data show that large-scale rearrangements occur during long glutamate exposures that are probably not seen in healthy brain tissue, whereas smaller changes in structure probably suffice for desensitization at synapses.
Integration of Odor-Induced Activity of Kenyon Cells in an Electrotonically CompactDrosophilaMushroom Body Output Neuron (MBON)
Authors: Hafez Omar A. , Escribano Benjamin , Pielage Jan , Niebur Ernst 
Published: November 2019

AbstractThe formation of an ecologically useful lasting memory requires that the brain has an accurate internal representation of the surrounding environment. In addition, it must have the ability to integrate a variety of different sensory stimuli and associate them with rewarding and aversive behavioral outcomes. Over the previous years, a number of studies have dissected the anatomy and elucidated some of the working principles of theDrosophilamushroom body (MB), the fly’s center for learning and memory. As a consequence, we now have a functional understanding of where and how in the MB sensory stimuli converge and are associated. However, the molecular and cellular dynamics at the critical synaptic intersection for this process, the Kenyon cell-mushroom body output neuron (KC-MBON) synapse, are largely unknown. Here, we introduce a first approach to understand this integration process and the physiological changes occurring at the KC-MBON synapse during Kenyon cell (KC) activation. We use the published connectome of theDrosophilaMB to construct a functional computational model of the MBON-α3 dendritic structure. We simulate synaptic input by individual KC-MBON synapses by current injections into precisely (μm) identified local dendritic sections, and the input from a model population of KCs representing an odor by a spatially distributed cluster of current injections. By recording the effect of the simulated current injections on the membrane potential of the neuron, we show that the MBON-α3 is electrotonically compact. This suggests that odor-induced MBON activity is likely governed by input strength while the positions of KC input synapses are largely irrelevant.