bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computationally guided high-throughput design of self-assembling drug nanoparticles
Authors: Reker Daniel , Rybakova Yulia , Kirtane Ameya R. , Cao Ruonan , Yang Jee Won , Navamajiti Natsuda , Gardner Apolonia , Zhang Rosanna M. , Esfandiary Tina , L’Heureux Johanna , von Erlach Thomas , Smekalova Elena M. , Leboeuf Dominique , Hess Kaitlyn , Lopes Aaron , Rogner Jaimie , Collins Joy , Tamang Siddartha M. , Ishida Keiko , Chamberlain Paul , Yun DongSoo , Lytoon-Jean Abigail , Soule Christian K. , Cheah Jaime H. , Hayward Alison M. , Langer Robert , Traverso Giovanni 
Published: October 2019

AbstractNanoformulations are transforming our capacity to effectively deliver and treat a myriad of conditions. However, many nanoformulation approaches still suffer from high production complexity and low drug loading. One potential solution relies on harnessing co-assembly of drugs and small molecular excipients to facilitate nanoparticle formation through solvent exchange without the need for chemical synthesis, generating nanoparticles with up to 95% drug loading. However, there is currently no understanding which of the millions of possible combinations of small molecules can result in the formation of these nanoparticles. Here we report the development of a high-throughput screening platform coupled to machine learning to enable the rapid evaluation of such nanoformulations. Our platform identified 101 novel self-assembling drug nanoparticles from 2.1 million pairings derived from 788 candidate drugs with one of 2686 excipients, spanning treatments for multiple diseases and often harnessing well-known food additives, vitamins, or approved drugs as carrier materials – with potential for accelerated approval and translation. Given their long-term stability and potential for clinical impact, we further characterize novel sorafenib-glycyrrhizin and terbinafine-taurocholic acid nanoparticlesex vivoandin vivo. We anticipate that this platform could accelerate the development of safer and more efficacious nanoformulations with high drug loadings for a wide range of therapeutics.
Success of Escherichia coli O25b:H4 ST131 clade C associated with a decrease in virulence
Authors: Duprilot Marion , Baron Alexandra , Blanquart François , Dion Sara , Lettéron Philippe , Flament-Simon Saskia-Camille , Clermont Olivier , Denamur Erick , Nicolas-Chanoine Marie-Hélène 
Published: October 2019

AbstractEscherichia coli of sequence type (ST) 131 resistant to fluoroquinolones and producer of CTX-M-15 is globally one of the major extraintestinal pathogenic E. coli (ExPEC). ST131 phylogenesis showed that multidrug-resistant ST131 strains belong to a clade called C, descending from an ancestral clade called B, comprising mostly antibiotic-susceptible strains. Antibiotic resistance could appear as one of the keys of the clade C global success. We hypothesized that other features of ST131 clade C could contribute to this success since other major global ExPEC clones (ST73, ST95) are mostly antibiotic-susceptible. To test this hypothesis, we measured the growth abilities, early biofilm formation and virulence-factor content of a collection of clade B and clade C strains. Moreover, using competition assays, we measured the capacity of selected representative strains of clades B and C to colonize the mouse intestine and urinary tract, and to kill mice in a septicemia model. Clade B and C strains had similar growth ability. However, clade B strains were more frequently early biofilm producers, expressed mostly faster their type 1 fimbriae and displayed more virulence factor-encoding genes than clade C strains. Clade B outcompeted clade C in the gut and/or urinary tract colonization models and in the septicemia model. These results strongly suggest that clade C strain evolution includes a loss of virulence, i.e. a process that could enhance micro-organism persistence in a given host and thus optimize transmission. This process, associated with acquired antibiotic-resistance, could ensure clade C strain survival in environments under antibiotic pressure.ImportanceExtraintestinal pathogen Escherichia coli (ExPEC) are virulent but mostly antibiotic-susceptible. One worrying exception is ST131, a major multidrug resistant ExPEC clone that has spread worldwide since the 2000s. To contain the emergence of this threatening clone, we need to understand what factors favored its emergence and dissemination. Here, we investigated whether multidrug-resistant ST131 had advantageous phenotypic properties beyond multidrug resistance. To this end, we competed the emergent multidrug-resistant ST131 with its antibiotic-susceptible ancestor in different conditions: biofilm production, in vivo colonization and virulence experiments. In all in vivo competitions, we found that multidrug-resistant ST131 was losing to its ancestor, suggesting a lesser virulence of multidrug-resistant ST131. It was previously described that losing virulence can increase micro-organism persistence in some populations and subsequently its level of transmissibility. Thus, a decreased level of virulence, associated with multidrug resistance, could explain the global success of ST131.
Subordinate effect of −21M HLA-B dimorphism on NK cell repertoire diversity and function in HIV-1 infected individuals of African origin
Authors: Cubero Elia Moreno , Ogbe Ane , Cohen Myron S. , Haynes Barton F. , Borrow Persephone , Peppa Dimitra 
Published: October 2019

AbstractNatural Killer (NK) cells play an important role in antiviral defence and their potent effector function identifies them as key candidates for immunotherapeutic interventions in chronic viral infections. Their remarkable functional agility is achieved by virtue of a wide array of germline encoded inhibitory and activating receptors ensuring a self-tolerant and tunable repertoire. NK cell diversity is generated by a combination of factors including genetic determinants and infections/environmental factors, which together shape the NK cell pool and functional potential. Recently a genetic polymorphism at position −21 of HLA-B, which influences the supply of HLA-E binding peptides and availability of HLA-E for recognition by the inhibitory NK cell receptor NKG2A, was shown to have a marked influence on NK cell functionality in healthy human cytomegalovirus (HCMV) seronegative Caucasian individuals. In this study, −21 methionine (M)-expressing alleles supplying HLA-E binding peptides were largely poor ligands for inhibitory killer immunoglobulin-like receptors (KIRs), and a bias to NKG2A-mediated education of functionally-potent NK cells was observed. Here, we investigated the effect of this polymorphism on the phenotype and functional capacity of NK cells in a cohort of African individuals with human immunodeficiency virus type 1 (HIV-1)/HCMV co-infection. A similarly profound influence of dimorphism at position −21 of HLA-B on NK cells was not evident in these subjects. They predominantly expressed African specific HLA-B and −C alleles that contribute a distinct supply of NKG2A and KIR ligands, and these genetic differences were compounded by the marked effect of HIV/HCMV coinfection on NK cell differentiation. Together, these factors resulted in a lack of correlation of the HLA-B −21 polymorphism with surface abundance of HLA-E and loss of the NK cell functional advantage in subjects with −21M HLA-B alleles. Instead our data suggest that during HIV/HCMV co-infection exposure of NK cells to an environment that displays altered HLA-E ligands drives adaptive NKG2C+ NK cell expansions influencing effector responses. Increased efforts to understand how NK cells are functionally calibrated to self-HLA during chronic viral infections will pave the way to developing targeted therapeutic interventions to overcome the current barriers to enhancing immune-based antiviral control.
Regulation of Bud Emergence by a MAPK Pathway
Authors: Prabhakar Aditi , Chow Jacky , Siegel Alan J. , Cullen Paul J. 
Published: October 2019

ABSTRACTAll cells establish and maintain an axis of polarity that is critical for cell shape and progression through the cell cycle. A well-studied example of polarity establishment is bud emergence in yeast, where the Rho GTPase Cdc42p regulates symmetry breaking at bud sites and the establishment of polarity by interacting with effector proteins. The prevailing view of bud emergence does not account for regulation by extrinsic cues or signal transduction pathways. Here, we show that the MAPK pathway that controls filamentous growth (fMAPK pathway), which also requires Cdc42p and the effector p21 activated kinase (PAK) Ste20p, regulates bud emergence under nutrient-limiting conditions that favor filamentous/invasive growth. The fMAPK pathway regulated the expression of polarity targets that included the gene encoding a direct effector of Cdc42p, Gic2p. The fMAPK pathway also stimulated GTP-Cdc42p levels, which is a critical determinant of polarity establishment. The fMAPK pathway activity was spatially restricted to bud sites and highest at a period in the cell cycle that coincided with bud emergence. Time-lapse fluorescence microscopy showed that the fMAPK pathway stimulated the rate of bud emergence during filamentous growth. Unregulated activation of the fMAPK pathway induced growth at multiple sites that resulted from multiple rounds of symmetry breaking inside the growing bud. Collectively, our findings identify a new regulatory aspect of bud emergence that sensitizes this essential cellular process to external cues.
Revisiting biogeography of livestock animal domestication
Authors: Žliobaitė Indrė 
Published: October 2019

AbstractHuman society relies on four main livestock animals – sheep, goat, pig and cattle, which all were domesticated at nearly the same time and place. Many arguments have been put forward to explain why these animals, place and time were suitable for domestication, but the question – why only these, but not other animals, still does not have a clear answer. Here we offer a biogeographical perspective: we survey global occurrence of large mammalian herbivore genera around 15 000 – 5 000 years before present and compile a dataset characterising their ecology, habitats and dental traits. Using predictive modelling we extract patterns from this data to highlight ecological differences between domesticated and nondomesticated genera. The most suitable for domestication appear to be generalists adapted to persistence in marginal environments of low productivity, largely corresponding to cold semi-arid climate zones. Our biogeographic analysis shows that even though domestication rates varied across continents, potentially suitable candidate animals were rather uniformly distributed across continents. We interpret this pattern as a result of an interface between cold semi-arid and hot semi-arid climatic zones. We argue that hot Semi-arid climate was most suitable for plant domestication, cold Semi-arid climate selected for animals most suitable for domestication as livestock. We propose that the rates of domestication across biogeographic realms largely reflect how much intersection between hot and cold Semi-arid climatic zones was available at each continent.
The sensory representation of causally controlled objects
Authors: Clancy Kelly B. , Mrsic-Flogel Thomas D. 
Published: October 2019

SummaryIntentional control over external objects is informed by our sensory experience of them. To study how causal relationships are learned and effected, we devised a brain machine interface (BMI) task utilising wide-field calcium signals. Mice learned to entrain activity patterns in arbitrary pairs of cortical regions to guide a visual cursor to a target location for reward. Brain areas that were normally correlated could be rapidly reconfigured to exert control over the cursor in a sensory feedback-dependent manner. Higher visual cortex was more engaged when expert but not naïve animals controlled the cursor. Individual neurons in higher visual cortex responded more strongly to the cursor when mice controlled it than when they passively viewed it, with the greatest response boosting as the cursor approached target location. Thus, representations of causally-controlled objects are sensitive to intention and proximity to the subject’s goal, potentially strengthening sensory feedback to allow more fluent control.
Light-Inducible Recombinases for Bacterial Optogenetics
Authors: Sheets Michael B. , Wong Wilson W. , Dunlop Mary J. 
Published: October 2019

AbstractOptogenetic tools can provide direct and programmable control of gene expression. Light-inducible recombinases, in particular, offer a powerful method for achieving precise spatiotemporal control of DNA modification. However, to-date this technology has been largely limited to eukaryotic systems. Here, we develop optogenetic recombinases for Escherichia coli which activate in response to blue light. Our approach uses a split recombinase coupled with photodimers, where blue light brings the split protein together to form a functional recombinase. We tested both Cre and Flp recombinases, Vivid and Magnet photodimers, and alternative protein split sites in our analysis. The optimal configuration, Opto-Cre-Vvd, exhibits strong blue light-responsive excision and low ambient light sensitivity. For this system we characterize the effect of light intensity and the temporal dynamics of light-induced recombination. These tools expand the microbial optogenetic toolbox, offering the potential for precise control of DNA excision with light-inducible recombinases in bacteria.
Decomposing neural responses to melodic surprise in musicians and non-musicians: evidence for a hierarchy of predictions in the auditory system
Authors: Quiroga-Martinez D.R. , Hansen N.C. , Højlund A. , Pearce M. , Brattico E. , Vuust P. 
Published: October 2019

AbstractNeural responses to auditory surprise are typically studied with highly unexpected, disruptive sounds. Consequently, little is known about auditory prediction in everyday contexts that are characterized by fine-grained, non-disruptive fluctuations of auditory surprise. To address this issue, we used IDyOM, a computational model of auditory expectation, to obtain continuous surprise estimates for a set of newly composed melodies. Our main goal was to assess whether the neural correlates of non-disruptive surprising sounds in a musical context are affected by musical expertise. Using magnetoencephalography (MEG), auditory responses were recorded from musicians and non-musicians while they listened to the melodies. Consistent with a previous study, the amplitude of the N1m component increased with higher levels of computationally estimated surprise. This effect, however, was not different between the two groups. Further analyses offered an explanation for this finding: Pitch interval size itself, rather than probabilistic prediction, was responsible for the modulation of the N1m, thus pointing to low-level sensory adaptation as the underlying mechanism. In turn, the formation of auditory regularities and proper probabilistic prediction were reflected in later components: the mismatch negativity (MMNm) and the P3am, respectively. Overall, our findings reveal a hierarchy of expectations in the auditory system and highlight the need to properly account for sensory adaptation in research addressing statistical learning.Highlights- In melodies, sound expectedness (modeled with IDyOM) is associated with the amplitude of the N1m.- This effect is not different between musicians and non-musicians.- Sensory adaptation related to melodic pitch intervals explains better the N1m effect.- Auditory regularities and the expectations captured by IDyOM are reflected in the MMNm and P3am.- Evidence for a hierarchy of auditory predictions during melodic listening.
Evolution and development of male-specific leg brushes in Drosophilidae
Authors: Tanaka Kohtaro , Barmina Olga , Thompson Ammon , Massey Jonathan H. , Kim Bernard Y. , Suvorov Anton , Kopp Artyom 
Published: October 2019

AbstractThe origin, diversification, and secondary loss of sexually dimorphic characters are common in animal evolution. In some cases, structurally and functionally similar traits have evolved independently in multiple lineages. Prominent examples of such traits include the male-specific grasping structures that develop on the front legs of many dipteran insects. In this report, we describe the evolution and development of one of these structures, the male-specific “sex brush”. The sex brush is composed of densely packed, irregularly arranged modified bristles and is found in several distantly related lineages in the family Drosophilidae. Phylogenetic analysis using 250 genes from over 200 species provides modest support for a single origin of the sex brush followed by many secondary losses; however, independent origins of the sex brush cannot be ruled out completely. We show that sex brushes develop in very similar ways in all brush-bearing lineages. The dense packing of brush hairs is explained by the specification of bristle precursor cells at a near-maximum density permitted by the lateral inhibition mechanism, as well as by the reduced size of the surrounding epithelial cells. In contrast to the female and the ancestral male condition, where bristles are arranged in stereotypical, precisely spaced rows, cell migration does not contribute appreciably to the formation of the sex brush. The complex phylogenetic history of the sex brush can make it a valuable model for investigating coevolution of sex-specific morphology and mating behavior.
Motor training improves coordination and anxiety in symptomaticMecp2-null mice despite impaired functional connectivity within the motor circuit
Authors: Yue Yuanlei , Xu Pan , Liu Zhichao , Sun Xiaoqian , Su Juntao , Du Hongfei , Chen Lingling , Ash Ryan T. , Smirnakis Stelios , Simha Rahul , Kusner Linda , Zeng Chen , Lu Hui 
Published: October 2019

AbstractRett Syndrome (RTT) is a severe neurodevelopmental disorder caused by loss of function of the X-linked Methyl-CpG-binding protein 2 (MECP2). Several case studies report that gross motor function can be improved in children with RTT through treadmill walking, but whether the MeCP2-deficient motor circuit can support actual motor learning remains unclear. We used two-photon calcium imaging to simultaneously observe layer (L) 2/3 and L5a excitatory neuronal activity in the motor cortex (M1) while mice adapted to changing speeds on a computerized running wheel. Despite circuit hypoactivity and weakened functional connectivity across L2/3 and L5a, theMecp2-null circuit’s firing pattern evolved with improved performance over two weeks. Moreover, trained mice became less anxious and lived 20% longer than untrained mice. Since motor deficits and anxiety are core symptoms of Rett, which is not diagnosed until well after symptom onset, these results underscore the benefit of motor learning.
Dynamic evolution of de novo DNA methyltransferases in rodent and primate genomes
Authors: Molaro Antoine , Malik Harmit S. , Bourc’his Deborah 
Published: October 2019

AbstractTranscriptional silencing of retrotransposons via DNA methylation is paramount for mammalian fertility and reproductive fitness. During germ cell development, most mammalian species utilize the de novo DNA methyltransferases DNMT3A and DNMT3B to establish DNA methylation patterns. However, many rodent species deploy a third enzyme, DNMT3C, to selectively methylate the promoters of young retrotransposon insertions in their germline. The evolutionary forces that shaped DNMT3C’s unique function are unknown. Using a phylogenomic approach, we confirm here that Dnmt3C arose through a single duplication of Dnmt3B that occurred between 45-71Mya in the last common ancestor of muroid rodents. Most importantly, we reveal that DNMT3C is composed of two independently evolving segments: the latter two-thirds has undergone recurrent gene conversion with Dnmt3B, whereas the N-terminus has not undergone gene conversion and has evolved under strong diversifying selection. We hypothesize that positive selection of Dnmt3C is the result on an ongoing evolutionary arms race with young retrotransposon lineages in muroid genomes. Interestingly, although primates lack DNMT3C, we find that the N-terminus of DNMT3A has also evolved under diversifying selection. Thus, the N-termini of two independent de novo DNMT enzymes have evolved under diversifying selection in rodents and primates. We hypothesize that repression of young retrotransposons might be driving the recurrent innovation of a functional domain in the N-termini on germline DNMTs in mammals.
Human neutrophil response to Pseudomonas bacteriophages
Authors: Roach Dwayne R. , Chollet-Martin Sylvie , Noël Benoît , Granger Vanessa , Debarbieux Laurent , de Chaisemartin Luc 
Published: October 2019

AbstractThe immune system offers several mechanisms of response to remove harmful microbes that invade the human body. As a first line of defense, neutrophils can remove pathogens by phagocytosis, inactivate them by the release of reactive oxygen species (ROS) or immobilize them by neutrophil extracellular traps (NETs). Although, recent studies have shown that bacteriophages (phages) make up a large portion of human microbiomes and are currently being explored as human antibacterial therapeutics, neutrophilic responses to phages are still elusive. Here, we show that exposure of isolated human resting neutrophils to high concentration of thePseudomonasphage PAK_P1 led to a 2.8 fold increase in interleukin-8 (IL-8) secretion. Importantly, phage exposure did not further affect resting neutrophil apoptosis or induce necrosis, CD11 expression, oxidative burst, and NETs. Similarly, inflammatory stimuli activated neutrophil effector responses were unaffected by phage exposure. Our work suggest that phages are unlikely to inadvertently cause excessive neutrophil responses that could damage tissues and worsen disease. Because IL-8 functions as a chemoattractant directing immune cells to sites of infection and inflammation, phage-stimulated IL-8 production may boost host immune responses.
Donor monocyte-derived macrophages promote human acute graft versus host disease
Authors: Jardine Laura , Cytlak Urszula , Gunawan Merry , Reynolds Gary , Green Kile , Wang Xiao-Nong , Pagan Sarah , Pradnya Maharani , Lamb Christopher A , Long Anna K , Hurst Erin , Nair Smeera , Jackson Graham , Publicover Amy , Bigley Venetia , Haniffa Muzlifah , Simpson A. John , Collin Matthew 
Published: October 2019

AbstractMyelopoiesis is invariably present, and contributes to pathology, in animal models of graft versus host disease (GVHD). In humans, a rich inflammatory infiltrate bearing macrophage markers has also been described in histological studies. In order to determine the origin, functional properties and role in pathogenesis of these cells, we isolated single cell suspensions from acute cutaneous GVHD and subjected them to genotype, transcriptome andin vitrofunctional analysis. A donor-derived population of CD11c+CD14+ cells was the dominant population of all leukocytes in GVHD. Surface phenotype and nanostring gene expression profiling indicated the closest steady-state counterpart of these cells to be monocyte-derived macrophages. In GVHD, however, there was upregulation of monocyte antigens SIRPα and S100A8/9, and transcripts associated with leukocyte trafficking, pattern recognition, antigen presentation, and co-stimulation. Isolated GVHD macrophages stimulated greater proliferation and activation of allogeneic T cells, and secreted higher levels of inflammatory cytokines than their steady-state counterparts. In HLA-matched mixed leukocyte reactions, we also observed differentiation of activated macrophages with a similar phenotype. These exhibited cytopathicity to a cell line and mediated pathological damage to skin explants, independently of T cells. Together, these results define the origin, functional properties and potential pathogenic roles of human GVHD macrophages.