bluuebunny/crossref_metadata_2025_split huggingface dataset:
Asymmetric Gait Patterns Alter the Reactive Control of Intersegmental Coordination Patterns during Walking
Authors: Liu Chang , Finley James M. 
Published: October 2019

AbstractRecovery from perturbations during walking is primarily mediated by reactive control strategies that coordinate multiple body segments to maintain balance. Balance control is often impaired in clinical populations who walk with spatiotemporally asymmetric gait, and, as a result, rehabilitation efforts often seek to reduce asymmetries in these populations. Previous work has demonstrated that the presence of spatiotemporal asymmetries during walking does not impair the control of whole-body dynamics during perturbation recovery. However, it remains to be seen how the neuromotor system adjusts intersegmental coordination patterns to maintain invariant whole-body dynamics. Here, we determined if the neuromotor system generates stereotypical coordination patterns irrespective of the level of asymmetry or if the neuromotor system allows for variance in intersegmental coordination patterns to stabilize whole-body dynamics. Nineteen healthy participants walked on a dual-belt treadmill at a range of step length asymmetries, and they responded to unpredictable, slip-like perturbations. We used principal component analysis of segmental angular momenta to characterize intersegmental coordination patterns before, during, and after imposed perturbations. We found that two principal components were sufficient to explain ~ 95% of the variance in segmental angular momentum during both steading walking and responses to perturbations. Our results also revealed that walking with asymmetric step lengths led to changes in intersegmental coordination patterns during the perturbation and during subsequent recovery steps without affecting whole-body angular momentum. These results suggest that the nervous system allows for variance in segment-level coordination patterns to maintain invariant control of whole-body angular momentum during walking. Future studies exploring how these segmental coordination patterns change in individuals with asymmetries that result from neuromotor impairments can provide further insight into how the healthy and impaired nervous system regulates dynamic balance during walking.
Fetal liver hepcidin secures iron stores in utero
Authors: Kämmerer Lara , Mohammad Goran , Wolna Magda , Robbins Peter A. , Lakhal-Littleton Samira 
Published: October 2019

AbstractIn the adult, the liver-derived hormone hepcidin (HAMP) controls systemic iron levels by blocking the iron-exporting protein ferroportin (FPN) in the gut and spleen, the sites of iron absorption and recycling respectively. Impaired HAMP expression or FPN responsiveness to HAMP result in iron overload. HAMP is also expressed in the fetal liver but its role in controlling fetal iron stores is not understood. To address this question in a manner that safeguards against the confounding effects of altered maternal iron homeostasis, we generated fetuses harbouring a paternally-inherited ubiquitous knock-in of the HAMP-resistantfpnC326Y. Additionally, to safeguard against any confounding effects of altered placental iron homeostasis, we generated fetuses with a liver-specific knock-in offpnC326Y or knockout of thehampgene. These fetuses had reduced liver iron stores, and markedly increased FPN in the liver, but not in the placenta. Thus, in contrast to the adult, fetal liver HAMP operates cell-autonomously to increase fetal liver iron stores. Our findings also suggest that FPN in the placenta is permissive rather than regulatory of iron transport.
High-resolution micro-epidemiology of parasite spatial and temporal dynamics in a high malaria transmission setting in Kenya
Authors: Nelson Cody S. , Sumner Kelsey M. , Freedman Elizabeth , Saelens Joseph W. , Obala Andrew A. , Mangeni Judith N. , Taylor Steve M. , O’Meara Wendy P. 
Published: October 2019

ABSTRACTNovel interventions that leverage the heterogeneity of parasite transmission are needed to push malaria further towards elimination. To better understand spatial and temporal dynamics of transmission, we applied amplicon NGS of two polymorphic gene regions (csp and ama1) to a cohort identified via reactive case detection in a high-transmission setting in western Kenya. From 4/2013–6/2014, we enrolled 442 symptomatic children with malaria, 442 matched controls, and all household members of both groups. We evaluated genetic similarity between infected individuals using three novel indices: sharing of parasite haplotypes on binary and proportional scales and the L1 norm. Symptomatic children more commonly shared haplotypes with their own household members. Furthermore, we identified robust temporal structuring of parasite genetic similarity that we exploited to identify the molecular signature of an outbreak. These findings of both micro- and macro-scale organization of parasite populations might be harnessed to inform next-generation malaria control measures.
Transcriptomics at maize embryo/endosperm interfaces identify a novel transcriptionally distinct endosperm sub-domain adjacent to the embryo scutellum (EAS)
Authors: Doll Nicolas M. , Just Jeremy , Brunaud Véronique , Caïus José , Grimault Aurélie , Depège-Fargeix Nathalie , Esteban Eddi , Pasha Asher , Provart Nicholas J. , Ingram Gwyneth C. , Rogowsky Peter M. , Widiez Thomas 
Published: October 2019

AbstractSeeds are complex biological systems comprising three genetically distinct tissues nested one inside another (embryo, endosperm and maternal tissues). However, the complexity of the kernel makes it difficult to understand inter compartment interactions without access to spatially accurate information. Here we took advantage of the large size of the maize kernel to characterize genome-wide expression profiles of tissues at embryo/endosperm interfaces. Our analysis identifies specific transcriptomic signatures in two interface tissues compared to whole seed compartments: The scutellar aleurone layer (SAL), and the newly named endosperm adjacent to scutellum (EAS). The EAS, which appears around 9 days after pollination and persists for around 11 days, is confined to one to three endosperm cell layers adjacent to the embryonic scutellum. Its transcriptome is enriched in genes encoding transporters. The absence of the embryo in anembryo specific(emb) mutant can alter the expression pattern of EAS marker genes. The detection of cell death in some EAS cells together with an accumulation of crushed cell walls suggests that the EAS is a dynamic zone from which cell layers in contact with the embryo are regularly eliminated, and to which additional endosperm cells are recruited as the embryo grows.
Specialization of the Chromatin Remodeler RSC to Mobilize Partially-Unwrapped Nucleosomes
Authors: Schlichter Alisha , Kasten Margaret M. , Parnell Timothy J. , Cairns Bradley R. 
Published: October 2019

AbstractSWI/SNF-family chromatin remodeling complexes, such as S. cerevisiae RSC, slide and eject nucleosomes to regulate transcription. Within nucleosomes, stiff DNA sequences confer spontaneous partial unwrapping, prompting whether and how SWI/SNF-family remodelers are specialized to remodel partially-unwrapped nucleosomes. RSC1 and RSC2 are orthologs of mammalian PBRM1 (polybromo) which define two separate RSC sub-complexes. Remarkably, in vitro the Rsc1-containing complex remodels partially-unwrapped nucleosomes much better than does the Rsc2-containing complex. Moreover, a rsc1Δ mutation, but not rsc2Δ, is lethal with histone mutations that confer partial unwrapping. Rsc1/2 isoforms both cooperate with the DNA-binding proteins Rsc3/30 and the HMG protein, Hmo1, to remodel partially-unwrapped nucleosomes, but show differential reliance on these factors. Notably, genetic impairment of these factors strongly reduces the expression of genes with wide nucleosome-deficient regions (e.g. ribosomal protein genes), known to harbor partially-unwrapped nucleosomes. Taken together, Rsc1/2 isoforms are specialized through composition and interactions to manage and remodel partially-unwrapped nucleosomes.
Shigella sonneiO-antigen inhibits internalisation, vacuole escape and inflammasome activation
Authors: Watson Jayne L , Sanchez-Garrido Julia , Goddard Philippa J , Torraca Vincenzo , Mostowy Serge , Shenoy Avinash R , Clements Abigail 
Published: October 2019

AbstractTwoShigellaspecies,flexneriandsonnei, cause approximately 90% of bacterial dysentery worldwide. WhileS. flexneriis the dominant species in low-income countries,S. sonneicauses the majority of infections in middle and high-income countries.S. flexneriis a prototypic cytosolic bacterium; once intracellular it rapidly escapes the phagocytic vacuole and causes pyroptosis of macrophages, which is important for pathogenesis and bacterial spread. By contrast little is known about the invasion, vacuole escape and induction of pyroptosis duringS. sonneiinfection of macrophages. We demonstrate thatS. sonneicauses substantially less pyroptosis in human primary monocyte-derived macrophages and THP1 cells. This is due to reduced bacterial uptake and lower relative vacuole escape, which results in fewer cytosolicS. sonneiand hence reduced activation of caspase-1 inflammasomes. Mechanistically, the O-antigen, which inS. sonneiis contained in both the lipopolysaccharide and the capsule, was responsible for reduced uptake and the T3SS was required for vacuole escape. Our findings suggest thatS. sonneihas adapted to an extracellular lifestyle by incorporating additional O-antigen into its surface structures compared to otherShigellaspecies.
Relaxed constraint and functional divergence of the progesterone receptor (PGR) in the human stem-lineage
Authors: Marinić Mirna , Lynch Vincent J. 
Published: October 2019

AbstractThe steroid hormone progesterone, acting through the progesterone receptor (PR), a ligand-activated DNA-binding transcription factor, plays an essential role in regulating nearly every aspect of female reproductive biology. While many reproductive traits regulated by PR are conserved in mammals, Catarrhine primates evolved several derived traits including spontaneous decidualization, menstruation, and a divergent (and unknown) parturition signal, suggesting that PR may also have evolved divergent functions in Catarrhines. There is conflicting evidence, however, whether the progesterone receptor gene (PGR) was positively selected in the human lineage. Here we show thatPGRevolved rapidly in the human stem-lineage (as well as other Catarrhine primates), which likely reflects an episode of relaxed selection intensity rather than positive selection. Coincident with the episode of relaxed selection intensity, ancestral sequence resurrection and functional tests indicate that the major human PR isoforms (PR-A and PR-B) evolved divergent functions in the human stem-lineage. These results suggest that the regulation of progesterone signaling by PR-A and PR-B may also have diverged in the human lineage and that non-human animal models of progesterone signaling may not faithfully recapitulate human biology.
Fatty acid oxidation impairs macrophage effector functions that controlMycobacterium tuberculosis
Authors: Chandra Pallavi , He Li , Zimmerman Matthew , Yang Guozhe , Köster Stefan , Ouimet Mireille , Wang Han , Moore Kathyrn J. , Dartois Véronique , Schilling Joel D. , Philips Jennifer A. 
Published: October 2019

SUMMARYMacrophage activation involves metabolic reprogramming to support antimicrobial cellular functions. How these metabolic shifts influence the outcome of infection by intracellular pathogens remains incompletely understood.M. tuberculosis(Mtb) modulates host metabolic pathways and utilizes host nutrients, including cholesterol and fatty acids, to survive within macrophages. We found that intracellular growth of Mtb depends on host fatty acid catabolism: when host fatty acid β-oxidation (FAO) was blocked chemically with trimetazidine, a compound in clinical use, or genetically by deletion of the mitochondrial fatty acid transporter carnitine palmitoyltransferase 2 (CPT2), Mtb failed to grow in macrophages and its growth was attenuated in mice. Global metabolic profiling and mechanistic studies support a model in which inhibition of FAO generates mitochondrial reactive oxygen species, which enhance macrophage NADPH oxidase and xenophagy activity to better control Mtb infection. Thus, FAO inhibition promotes key antimicrobial functions of macrophages and overcomes immune evasion mechanisms of Mtb.
Site Frequency Spectrum of the Bolthausen-Sznitman Coalescent
Authors: Kersting Götz , Siri-Jégousse Arno , Wences Alejandro H. 
Published: October 2019

AbstractWe derive explicit formulas for the two first moments of he site frequency spectrum (SFSn,b)1≤b≤n−1 of the Bolthausen-Sznitman coalescent along with some precise and efficient approximations, even for small sample sizes n. These results provide new L2-asymptotics for some values of b = o(n). We also study the length of internal branches carrying b > n/2 individuals. In this case we obtain the distribution function and a convergence in law. Our results rely on the random recursive tree construction of the Bolthausen-Sznitman coalescent.
Somatic mutations and genome stability maintenance in clonal coral colonies
Authors: López Elora H. , Palumbi Stephen R. 
Published: October 2019

AbstractOne challenge for multicellular organisms is maintaining genome stability in the face of mutagens across long life spans. Imperfect genome maintenance leads to mutation accumulation in somatic cells, which is associated with tumors and senescence in vertebrates. Colonial reef-building corals are often large, can live for hundreds of years, rarely develop recognizable tumors, and are thought to convert somatic cells into gamete producers, so they are a pivotal group in which to understand long-term genome maintenance. To measure rates and patterns of somatic mutations, we analyzed transcriptomes from 17-22 branches from each of fourAcropora hyacinthuscolonies, determined putative single nucleotide variants, and verified them with Sanger resequencing. Unlike for human skin carcinomas, there is no signature of mutations caused by UV damage, indicating either higher efficiency of repair than in vertebrates, or strong sunscreen protection in these shallow water tropical animals. The somatic mutation frequency per nucleotide inA. hyacinthusis on the same order of magnitude (10−7) as noncancerous human somatic cells, and accumulation of mutations with age is similar. Unlike mammals, loss of heterozygosity variants outnumber gain of heterozygosity mutations about 2:1. Although the mutation frequency is similar in mammals and corals, the preponderance of loss of heterozygosity changes and potential selection may reduce the frequency of deleterious mutations in colonial animals like corals. This may limit the deleterious effects of somatic mutations on the coral organism as well as potential offspring.
Early Polycomb-target deregulations in Hutchinson-Gilford Progeria Syndrome revealed by heterochromatin analysis
Authors: Sebestyén Endre , Marullo Fabrizia , Lucini Federica , Bianchi Andrea , Petrini Cristiano , Valsoni Sara , Olivieri Ilaria , Antonelli Laura , Gregoretti Francesco , Oliva Gennaro , Ferrari Francesco , Lanzuolo Chiara 
Published: October 2019

AbstractHutchinson-Gilford progeria syndrome (HGPS) is characterized by the progressive accumulation of progerin, an aberrant form of Lamin A. This leads to chromatin structure disruption, in particular by interfering with Lamina Associated Domains. Although several cellular and molecular alterations have been characterized, it is still unclear how chromatin structural changes translate into premature senescence in HGPS. Moreover, early events in chromatin remodeling have not been detected so far. We developed a new high-throughput sequencing-based method, named SAMMY-seq, for genome-wide characterization of heterochromatin accessibility changes. Using SAMMY-seq, we detected early stage alterations of chromatin structure in HGPS primary fibroblasts. Of note, these structural changes do not disrupt the distribution of H3K9me3 but are associated with site-specific H3K27me3 variations and transcriptional dysregulation of Polycomb target genes. Our results show that SAMMY-seq represents a novel and sensitive tool to characterize heterochromatin alterations. Moreover, we found that the assembly of lamin associated domains is strictly connected to the correct Polycomb repression, rapidly lost in early HGPS pathogenesis.
Temporal analyses of CRISPR-directed gene editing on NRF2, a clinically relevant human gene involved in chemoresistance
Authors: Banas Kelly , Rivera-Torres Natalia , Bialk Pawel , Yoo Byung-Chun , Kmiec Eric B. 
Published: October 2019

AbstractRecent data suggest that a time lag exists between nuclear penetration and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-directed gene editing activity in human cells. As CRISPR/Cas approaches clinical implementation, it is critical to establish a biological time frame in which the complex enters the cell and nucleus and executes its gene editing function. We are developing CRISPR-directed gene editing for the treatment of non-small cell lung carcinoma focusing Nuclear Factor Erythroid 2-Related Factor-Like (NRF2), a transcription factor which regulates chemoresistance. In this report, we define cellular events that surround the initialization of CRISPR-directed gene editing as a function of time. We analyze the efficiency of cellular transfection of both components of the RNP particle and assess the emergence of indels. For the first time, we image the nuclear positioning of the tracrRNA and Cas9 as a complex and as individual gene editing components. Our results indicate that while the nuclear localization of the CRISPR/Cas complex is efficient and rapid, disruption of the NRF2 gene appears four to eight hours later. We reveal an initial snapshot of the schedule and processing of CRISPR/Cas in a lung cancer cell; information that will be useful as cell-based protocols are designed and advanced.
Response of neuroglia to hypoxia-induced oxidative stress using enzymatically crosslinked hydrogels
Authors: Zambuto Samantha G. , Serrano Julio F. , Vilbert Avery C. , Lu Yi , Harley Brendan A.C. , Pedron Sara 
Published: October 2019

ABSTRACTThree-dimensional cultures have exciting potential to mimic aspects of healthy and diseased brain tissue to examine the role of physiological conditions on neural biomarkers as well as disease onset and progression. Hypoxia is associated with oxidative stress, mitochondrial damage, and inflammation, key processes potentially involved in Alzheimer’s and multiple sclerosis. We describe the use of an enzymatically-crosslinkable gelatin hydrogel system within a microfluidic device to explore the effects of hypoxia-induced oxidative stress on neuroglia, astrocyte reactivity, and myelin production. This versatile platform offers new possibilities for drug discovery and modeling disease progression.
Palmitate induces apoptotic cell death and inflammasome activation in human placental macrophages
Authors: Rogers Lisa M. , Serezani Carlos H. , Eastman Alison J. , Hasty Alyssa H. , Englund-Ögge Linda , Jacobsson Bo , Vickers Kasey C. , Aronoff David M. 
Published: October 2019

AbstractIntroductionThere is an increasing prevalence of non-communicable diseases worldwide. Metabolic diseases such as obesity and gestational diabetes mellitus (GDM) increasingly affect women during pregnancy, which can harm pregnancy outcomes and the long-term health and wellbeing of exposed offspring. Both obesity and GDM have been associated with proinflammatory effects within the placenta, the critical organ governing fetal development.MethodsThe purpose of these studies was to model, in vitro, the effects of metabolic stress (high levels of glucose, insulin and saturated lipids) on placental macrophage biology, since these cells are the primary innate immune phagocyte within the placenta with roles in governing maternofetal immune tolerance and antimicrobial host defense. Macrophages were isolated from the villous core of term, human placentae delivered through nonlaboring, elective Cesarean sections and exposed to combinations of elevated glucose (30 mM), insulin (10 nM) and the saturated lipid palmitic acid (palmitate, 0.4 mM).ResultsWe found that palmitate alone induced the activation of the nucleotide-binding oligomerization domain-like receptor (NLR) Family Pyrin Domain Containing 3 (NLRP3) inflammasome in placental macrophages, which was associated with increased interleukin 1 beta release and an increase in apoptotic cell death. Glucose and insulin neither provoked these effects nor augmented the impact of palmitate itself.DiscussionOur findings confirm an impact of saturated fat on placental macrophage immune activation and could be relevant to the impact of metabolic stress in vivo.
Differential effects of commensal bacteria on progenitor cell adhesion, division symmetry and tumorigenesis in the Drosophila intestine
Authors: Ferguson Meghan , Petkau Kristina , Shin Minjeong , Galenza Anthony , Fast David , Foley Edan 
Published: October 2019

ABSTRACTMicrobial factors influence homeostatic and oncogenic growth in the intestinal epithelium. However, we know little about immediate effects of commensal bacteria on stem cell division programs. In this study, we examined effects of commensal Lactobacillus species on homeostatic, and tumorigenic stem cell growth in the Drosophila intestine. We identified Lactobacillus brevis as a potent stimulator of stem cell growth. In a wildtype midgut, Lactobacillus brevis activates growth regulatory pathways that drive stem cell divisions. In a Notch-deficient background, Lactobacillus brevis-mediated growth causes rapid expansion of mutant progenitors, leading to accumulation of large, multi-layered tumors throughout the midgut. Mechanistically, we showed that Lactobacillus brevis disrupts expression and subcellular distribution of progenitor cell integrins, supporting symmetric divisions that expand intestinal stem cell populations. Collectively, our data emphasize the impact of commensal microbes on growth and maintenance of the intestinal progenitor compartment.
Litmus-Body: a Molecularly Targeted Sensor for Cell-Surface pH Measurements
Authors: Goudge Marc C. , Kuo Joe Chin-Hun , Metzloff Ann E. , Huang Ling-Ting , Colville Marshall J. , Zipfel Warren R. , Paszek Matthew J. 
Published: October 2019

ABSTRACTPrecise pH measurements in the immediate environment of receptors is essential for elucidating the mechanisms through which local pH changes associated with diseased phenotypes manifest into aberrant receptor function. However, current pH sensors lack the molecular specificity required to make these measurements. Herein we present the Litmus-body, our recombinant protein-based pH sensor, which through fusion to an anti-mouse IgG nanobody is capable of molecular targeting to specific proteins on the cell surface. By normalizing a pH-dependent green fluorescent protein to a long-Stokes shift red fluorophore or fluorescent protein, we readily report pH independent of sensor concentration using a single 488-nm excitation. Our Litmus-body showed excellent responsiveness in solution, with a greater than 50-fold change across the physiological regime of pH. The sensor was further validated for use on live cells, shown to be specific to the protein of interest, and was able to successfully recapitulate the numerous pH changes along the endocytic pathway.