bluuebunny/crossref_metadata_2025 huggingface dataset:
Reconstruction of the carbohydrate 6-O sulfotransferase gene family evolution in vertebrates reveals novel member, CHST16, lost in amniotes
Authors: Ocampo Daza Daniel , Haitina Tatjana
Published: June 2019

Glycosaminoglycans are sulfated polysaccharide molecules, essential for many biological processes. The 6-O sulfation of glycosaminoglycans is carried out by carbohydrate 6-O sulfotransferases (C6OST), previously named Gal/GalNAc/GlcNAc 6-O sulfotransferases. Here for the first time we present a detailed phylogenetic reconstruction, analysis of gene synteny conservation and propose an evolutionary scenario for the C6OST family in major vertebrate groups, including mammals, birds, non-avian reptiles, amphibians, lobe-finned fishes, ray-finned fishes, cartilaginous fishes and jawless vertebrates. The C6OST gene expansion likely occurred in the chordate lineage, after the divergence of tunicates and before the emergence of extant vertebrate lineages.

The two rounds of whole genome duplication in early vertebrate evolution (1R/2R) only contributed two additional C6OST subtype genes, increasing the vertebrate repertoire from four genes to six, divided into two branches. The first branch includesCHST1andCHST3as well as a previously unrecognized subtype,CHST16, that was lost in amniotes. The second branch includesCHST2,CHST7andCHST5. Subsequently, local duplications ofCHST5gave rise toCHST4in the ancestor of tetrapods, and toCHST6in the ancestor of primates.

The teleost specific gene duplicates were identified forCHST1,CHST2andCHST3and are result of whole genome duplication (3R) in the teleost lineage. We could also detect multiple, more recent lineage-specific duplicates. Thus, the repertoire of C6OST genes in vertebrate species has been shaped by different events at several stages during vertebrate evolution, with implications for the evolution of the skeleton, nervous system and cell-cell interactions.
Concise whole blood transcriptional signatures for incipient tuberculosis: A systematic review and patient-level pooled meta-analysis
Authors: Gupta Rishi K. , Turner Carolin T. , Venturini Cristina , Esmail Hanif , Rangaka Molebogeng X. , Copas Andrew , Lipman Marc , Abubakar Ibrahim , Noursadeghi Mahdad
Published: June 2019

Blood transcriptional signatures may predict risk of tuberculosis (TB). We compared the performance of 17 mRNA signatures in a pooled dataset comprising 1,026 samples, including 183 samples from 127 incipient TB cases, from four studies conducted in South Africa, Ethiopia, The Gambia and the UK. We show that eight signatures (comprising 1-25 transcripts) that predominantly reflect interferon inducible gene expression, have equivalent diagnostic accuracy for incipient TB over a two-year period with areas under the receiver operating characteristic curves ranging from 0.70 (95% confidence interval 0.64-0.76) to 0.77 (0.71-0.82). The sensitivity of all eight signatures declined with increasing disease-free time interval. Using a threshold derived from two standard deviations above the mean of uninfected controls giving specificities of >90%, the eight signatures achieved sensitivities ranging 24.7-39.9% over a 24 month interval, rising to 47.1-81.0% over 3 months. Based on pre-test probability of 2%, the eight signatures achieved positive predictive value ranging from 6.8-9.4% over 24 months, rising to 11.1-14.3% over 3 months. When using biomarker thresholds maximising sensitivity and specificity with equal weighting to both, no signature met the minimum World Health Organization (WHO) Target Product Profile parameters for incipient TB biomarkers over a two-year period. Blood transcriptional biomarkers reflect short-term risk of TB and only exceed WHO benchmarks if applied to 3-6 month intervals.
Oscillatory Viscoelastic Microfluidics for Efficient Focusing and Separation of Nanoscale Species
Authors: Asghari Mohammad , Cao Xiaobao , Mateescu Bogdan , van Leeuwen Daniel , Stavrakis Stavros , deMello Andrew J.
Published: June 2019

The ability to precisely control particle migration within microfluidic systems is essential for focusing, separating, counting and detecting a wide range of biological species. To date, viscoelastic microfluidic systems have primarily been applied to the focusing, separation and isolation of micron-sized species, with their use in nanoparticle manipulations being underdeveloped and underexplored, due to issues related to nanoparticle diffusivity and a need for extended channel lengths. To overcome such issues, we herein present sheathless oscillatory viscoelastic microfluidics as a method for focusing and separating both micron and sub-micron species. To highlight the efficacy of our approach, we segment our study into three size regimes, namely micron (where characteristic particle dimensions are above 1 μm), sub-micron (where characteristic dimensions are between 1 μm and 100 nm) and nano (where characteristic dimensions are below 100 nm) regimes. Based on the ability to successfully manipulate particles in all these regimes, we demonstrate the successful isolation of p-bodies from biofluids (in the micron regime), the focusing of λ-DNA (in the sub-micron regime) and the focusing of extracellular vesicles (in the nano-regime). Finally, we characterize the physics underlying viscoelastic microflows using a dimensionless number that relates the lateral velocity (due to elastic effects) to the diffusion constant of the species within the viscoelastic carrier fluid. Based on the ability to precisely manipulate species in all three regimes, we expect that sheathless oscillatory viscoelastic microfluidics will provide for significant new opportunities in a range of biological and life science applications.
Humanization of yeast genes with multiple human orthologs reveals principles of functional divergence between paralogs
Authors: Laurent Jon M. , Garge Riddhiman K. , Teufel Ashley I. , Wilke Claus O. , Kachroo Aashiq H. , Marcotte Edward M.
Published: June 2019

Despite over a billion years of evolutionary divergence, several thousand human genes possess clearly identifiable orthologs in yeast, and many have undergone lineage-specific duplications in one or both lineages. The ortholog conjecture postulates that orthologous genes between species retain ancestral functions despite divergence over vast timescales, but duplicated genes will be free to diverge in function. However, the retention of ancestral functions among co-orthologs between species and within gene families has been difficult to test experimentally at scale. In order to investigate how ancestral functions are retained or lost post-duplication, we systematically replaced hundreds of essential yeast genes with their human orthologs from gene families that have undergone lineage-specific duplications, including those with single duplications (one yeast gene to two human genes, 1:2) or higher-order expansions (1:>2) in the human lineage. We observe a variable pattern of replaceability across different ortholog classes, with an obvious trend towards differential replaceability inside gene families, rarely observing replaceability by all members of a family. We quantify the ability of various properties of the orthologs to predict replaceability, showing that in the case of 1:2 orthologs, replaceability is predicted largely by the divergence and tissue-specific expression of the human co-orthologs, i.e. the human proteins that are less diverged from their yeast counterpart and more ubiquitously expressed across human tissues more often replace their single yeast ortholog. These trends were consistent with in silico simulations demonstrating that when only one ortholog is replaceable, it tends to be the least diverged of the pair. Replaceability of yeast genes having more than two human co-orthologs was marked by retention of orthologous interactions in functional or protein networks as well as by more ancestral subcellular localization. Overall, we performed >400 human gene replaceability assays revealing 56 new human-yeast complementation pairs, thus opening up avenues to further functionally characterize these human genes in a simplified organismal context.
Aerosolized TLR Agonists Suppress Acute Sendai Virus Lung Infection and Chronic Airway Disease in Mice
Authors: Goldblatt David L. , Flores Jose R. , Valverde Ha Gabriella , Jaramillo Ana M. , Tkachman Sofya , Kirkpatrick Carson T. , Wali Shradha , Hernandez Belinda , Ost David E. , Scott Brenton L. , Chen Jichao , Evans Scott E. , Tuvim Michael J. , Dickey Burton F.
Published: June 2019

Respiratory viral infections play central roles in the initiation, exacerbation and progression of asthma in humans. An acute paramyxoviral infection in mice can cause a chronic lung disease that resembles human asthma. We sought to determine whether reduction of Sendai virus lung burden in mice by stimulating innate immunity with aerosolized Toll-like receptor (TLR) agonists could attenuate the severity of chronic asthma-like lung disease. Treatment with 1 µM oligodeoxynucleotide (ODN) M362, an agonist of the TLR9 homodimer, and 4 µM Pam2CSK4 (Pam2), an agonist of the TLR2/6 heterodimer, within a few days before or after Sendai virus challenge, resulted in a ∼75% reduction in lung Sendai virus burden five days after challenge. The reduction in acute lung virus burden was associated with marked reductions 49 days after viral challenge in eosinophilic and lymphocytic lung inflammation, airway mucous metaplasia, lumenal mucus occlusion, and hyperresponsiveness to methacholine. Mechanistically, ODN/Pam2 treatment attenuated the chronic asthma phenotype by suppressing IL-33 production by type 2 pneumocytes, both by reducing the severity of acute infection and by downregulating Type 2 (allergic) inflammation. These data suggest that treatment of susceptible human hosts with aerosolized ODN and Pam2 at the time of a respiratory viral infection might attenuate the severity of the acute infection and reduce progression of asthma.

One Sentence Summary

Respiratory viral infections can induce chronic airway disease, and we find that stimulating innate immunity within the lungs of mice reduces the severity of acute infection and development of a chronic asthma phenotype.
Reinforcement learning as an intermediate phenotype in psychosis? Deficits sensitive to illness stage but not associated with polygenic risk of schizophrenia in the general population
Authors: Montagnese M , Knolle F , Haarsma J , Griffin JD , Richards A , Vertes P , Kiddle B , Fletcher PC , Jones PB , Owen MJ , Fonagy P , Bullmore ET , Dolan R , Consortium NSPN , Moutoussis M , Goodyer I , Murray GK
Published: June 2019

Background

Schizophrenia is a complex disorder in which the causal relations between risk genes and observed clinical symptoms are not well understood and the explanatory gap is too wide to be clarified without considering an intermediary level. Thus, we aimed to test the hypothesis of a pathway from molecular polygenic influence to clinical presentation occurring via deficits in reinforcement learning.

Methods

We administered a reinforcement learning task (Go/NoGo) that measures reinforcement learning and the effect of Pavlovian bias on decision making. We modelled the behavioural data with a hierarchical Bayesian approach (hBayesDM) to decompose task performance into its underlying learning mechanisms. Study 1 included controls (n= 29, F|M=0.81), At Risk Mental State for psychosis (ARMS, n= 23, F|M=0.35) and FEP (First-episode psychosis, n= 26, F|M=0.18). Study 2 included healthy adolescents (n= 735, F|M= 1.06), 390 of whom had their polygenic risk scores for schizophrenia (PRSs) calculated.

Results

Patients with FEP showed significant impairments in overriding Pavlovian conflict, a lower learning rate and a lower sensitivity to both reward and punishment. Less widespread deficits were observed in ARMS. PRSs did not significantly predict performance on the task in the general population, which only partially correlated with measures of psychopathology.

Conclusions

Reinforcement learning deficits are observed in first episode psychosis and, to some extent, in those at clinical risk for psychosis, and were not predicted by molecular genetic risk for schizophrenia in healthy individuals. The study does not support the role of reinforcement learning as an intermediate phenotype in psychosis.
Propagating activity in neocortex, mediated by gap-junctions and modulated by extracellular potassium
Authors: Papasavvas Christoforos A. , Parrish R. Ryley , Trevelyan Andrew J.
Published: June 2019

Parvalbumin-expressing interneurons in cortical networks are coupled by gap-junctions, forming a syncytium that supports propagating epileptiform discharges, induced by 4-aminopyridine. It remains unclear, however, whether these propagating events occur under more natural states, without pharmacological blockade. In particular, we investigated whether propagation also happens when extracellular K+ rises, as is known to occur following intense network activity, such as during seizures. We examined how increasing [K+]o affects the likelihood of propagating activity away from a site of focal (200-400µm) optogenetic activation of PV-interneurons. Activity was recorded using a linear 16-electrode array placed along layer V of primary visual cortex. At baseline levels of [K+]o (3.5mM), induced activity was recorded only within the illuminated area. However, when [K+]o was increased above a threshold level (50th percentile= 8.0mM; interquartile range= 7.5-9.5mM), time-locked, fast-spiking unit activity, indicative of parvalbumin-expressing interneuron firing, was also recorded outside the illuminated area, propagating at 59.1 mm/s. Blockade of glutamatergic synaptic transmission reduced the efficacy of propagation, but could be restored by further increasing [K+]o. Propagation was further reduced, and in most cases prevented altogether, by pharmacological blockade of gap-junctions, achieved by any of three different drugs, quinine, mefloquine or carbenoxolone. Wash-out of quinine rapidly re-established the pattern of propagating activity. Computer simulations show qualitative differences between propagating discharges in high [K+]o and 4-aminopyridine, arising from differences in the electrotonic effects of these two manipulations. These interneuronal syncytial interactions are likely to affect the complex electrographic dynamics of seizures, once [K+]o is raised above this threshold level.

Significance statement

We demonstrate the spatially extended propagation of activity through a gap-junction mediated syncytium of parvalbumin-expressing interneurons, in conditions that are known to exist at times within the brain. Previous work has only shown gap-junction coordination very locally, through directly connected cells, or induced at a distance by pharmacological means. We show that cell-class specific spread is facilitated by raised extracellular K+. This is highly pertinent to what happens at the onset of, and during, seizures, when extracellular K+ can rise rapidly to levels well in excess of the measured threshold for propagation. Our data suggests that interneuronal coupling will be enhanced at this time, and this has clear implications for the behaviour of these cells as seizures progress.
PQLC2 signals lysosomal cationic amino acid abundance to the C9orf72 complex
Authors: Amick Joseph , Tharkeshwar Arun Kumar , Talaia Gabriel , Ferguson Shawn M.
Published: June 2019

The C9orf72 protein is required for normal lysosome function. In support of such functions, C9orf72 forms a heterotrimeric complex with SMCR8 and WDR41 that is recruited to lysosomes when amino acids are scarce. These properties raise questions about the identity of the lysosomal binding partner of the C9orf72 complex and the amino acid sensing mechanism that regulates C9orf72 complex abundance on lysosomes. We now demonstrate that an interaction with the lysosomal cationic amino acid transporter PQLC2 mediates C9orf72 complex recruitment to lysosomes. This is achieved through an interaction between PQLC2 and WDR41. The interaction between PQLC2 and the C9orf72 complex is negatively regulated by arginine, lysine and histidine, amino acids that PQLC2 transports across the membrane of lysosomes. These results define a new role for PQLC2 in the regulated recruitment of the C9orf72 complex to lysosomes and reveal a novel mechanism that allows cells to sense and respond to changes in the availability of cationic amino acids within lysosomes.
Phage-centric ecological interactions in aquatic ecosystems revealed through ultra-deep metagenomics
Authors: Kavagutti Vinicius S. , Andrei Adrian-Ştefan , Mehrshad Maliheh , Salcher Michaela M. , Ghai Rohit
Published: June 2019

The persistent inertia in the ability to culture environmentally abundant microbes from aquatic ecosystems represents an obstacle in disentangling the complex web of ecological interactions spun by a diverse assortment of participants (pro- and eukaryotes and their viruses). In aquatic microbial communities, the numerically most abundant actors, the viruses, remain the most elusive, and especially in freshwaters their identities and ecology remain obscure. Here, using ultra-deep metagenomic sequencing from freshwater habitats we recovered complete genomes of >2000 phages, including small “miniphages” and large “megaphages” infecting iconic prokaryotic lineages. We also show that many phages encode genes that likely enhance survival of infected microbes during strong eukaryotic grazing pressure. For instance, we describe genes that afford protection to their host from reactive oxygen species (ROS) in the environment and from the oxidative burst in protist phagolysosomes (phage-mediated ROS defense) or those that directly effect targeted killing of the predators upon ingestion of a phage-infected microbe (Trojan horse). Spatiotemporal abundance analyses of phage genomes revealed evanescence as the primary dynamic in upper water layers, where they displayed short-lived existences. In contrast, persistence was characteristic for the deeper layers where many identical phage genomes were recovered repeatedly. Phage and host abundances corresponded closely, with distinct populations displaying preferential distributions in different seasons and depths, closely mimicking overall stratification and mixis.
Seven-year-olds recall non-adjacent dependencies after overnight retention
Authors: Schaadt Gesa , Paul Mariella , Muralikrishnan R. , Männel Claudia , Friederici Angela D.
Published: June 2019

Becoming a successful speaker depends on acquiring and learning grammatical dependencies between neighboring and non-neighboring linguistic elements (non-adjacent dependencies; NADs). Previous studies have demonstrated children’s and adults’ ability to distinguish NADs from NAD violations right after familiarization. However, demonstrating NAD recall after retention is crucial to demonstrate a lasting effect of NAD learning. We tested 7-year-olds’ NAD learning in a natural, non-native language on one day and NAD recall on the next day by means of event-related potentials (ERPs). Our results revealed ERPs with a more positive amplitude to NAD violations than correct NADs after familiarization on day one, but ERPs with a more negative amplitude to NAD violations on day two. This change from more positive to more negative ERPs to NAD violations possibly indicates that children’s representations of NADs changed during an overnight retention period, potentially associated with children’s NAD learning. Indeed, our descriptive analyses showed that both ERP patterns (i.e., day one: positive, day two: negative) were related to stronger behavioral improvement (i.e., more correct answers on day two compared to day one) in a grammaticality judgment task from day one to day two. We suggest these findings to indicate that children successfully built associative representations of NADs on day one and then strengthened these associations during overnight retention, revealing NAD recall on day two. The present results suggest that 7-year-olds readily track NADs in a natural, non-native language and are able to recall NADs after a retention period involving sleep, providing evidence of a lasting effect of NAD learning.

Highlights

7-year-olds’ non-adjacent dependency learning in a foreign language tested

Children gave grammaticality judgments while electroencephalography was recorded

Brain responses revealed children’s learning of non-adjacent dependencies

Brain responses after overnight retention showed different polarity

Children’s recall of dependencies after sleep associated with representation change
The phylogenetic range of bacterial and viral pathogens of vertebrates
Authors: Shaw Liam P. , Wang Alethea D. , Dylus David , Meier Magda , Pogacnik Grega , Dessimoz Christophe , Balloux Francois
Published: June 2019

Many major human pathogens are multi-host pathogens, able to infect other vertebrate species. Describing the general patterns of host-pathogen associations across pathogen taxa is therefore important to understand risk factors for human disease emergence. However, there is a lack of comprehensive curated databases for this purpose, with most previous efforts focusing on viruses. Here, we report the largest manually compiled host-pathogen association database, covering 2,595 bacteria and viruses infecting 2,656 vertebrate hosts. We also build a tree for host species using nine mitochondrial genes, giving a quantitative measure of the phylogenetic similarity of hosts. We find that the majority of bacteria and viruses are specialists infecting only a single host species, with bacteria having a significantly higher proportion of specialists compared to viruses. Conversely, multi-host viruses have a more restricted host range than multi-host bacteria. We perform multiple analyses of factors associated with pathogen richness per host species and the pathogen traits associated with greater host range and zoonotic potential. We show that factors previously identified as important for zoonotic potential in viruses—such as phylogenetic range, research effort, and being vector-borne—are also predictive in bacteria. We find that the fraction of pathogens shared between two hosts decreases with the phylogenetic distance between them. Our results suggest that host phylogenetic similarity is the primary factor for host-switching in pathogens.
PTY 2 As DPP-IV Inhibitor Prevents Intestinal Cell’s Apoptosis
Authors: Srivastava Shivani , Pandey Harsh , Singh Surya K , Tripathi Yamini Bhusan
Published: June 2019

Enhanced DPP-IV expression is found to get enhanced in various intestinal diseases. PTY-2 has already been known to have DPP-IV inhibitory potential. This inhibition has not yet been studied at mRNA level. Increased incretin secretion due to DPP-IV inhibition could lead to suppression of stress & intestinal cells apoptosis. Through histological analysis, we have found morphological damage of intestine after STZ injection (65 mg/kg bw) to male Charles foster rats. mRNA expressions were analyzed by PCR and apoptosis of cells was checked through tunnel assay & Bcl 2 expression. The number and length of villi get reduced in STZ induced diabetic control, but these damages have been getting reversed after the PTY-2 treatment for 10 days. The expression of SOD was found to get reduced while that of DPP-IV was enhanced in diabetic control group along with significant intestinal cell apoptosis. PTY-2 treatment reduces the stress by upregulating the expression of SOD and through downregulation of DPP-IV mRNA expression. These recoveries by PTY-2 leads to suppression of intestinal cells apoptosis. These short studies explain the protective action of PTY-2 against STZ induced intestinal damage. Hence, PTY-2 could be taken as an herbal treatment against intestinal disorders in case of chronic diabetes.
Mapping person-to-person variation in viral mutations that escape polyclonal serum targeting influenza hemagglutinin
Authors: Lee Juhye M. , Eguia Rachel , Zost Seth J. , Choudhary Saket , Wilson Patrick C. , Bedford Trevor , Stevens-Ayers Terry , Boeckh Michael , Hurt Aeron , Lakdawala Seema S. , Hensley Scott E. , Bloom Jesse D.
Published: June 2019

A longstanding question is how influenza evolves to escape human immunity, which is polyclonal and can target many distinct epitopes on the virus. Here we map how all amino-acid mutations to influenza’s major surface protein affect viral neutralization by polyclonal human sera. The serum of some individuals is so focused that it selects single mutations that reduce viral neutralization by over an order of magnitude. However, different viral mutations escape the sera of different individuals. This individual-to-individual variation in viral escape mutations isnotpresent among ferrets, which are frequently used as a model in influenza studies. Our results show how different single mutations help influenza escape the immunity of different members of the human population, a phenomenon that could shape viral evolution and disease susceptibility.
Inhibition of Histone deacetylase 1 (HDAC1) and HDAC2 enhances CRISPR/Cas9 genome editing
Authors: Liu Bin , Chen Siwei , Rose Anouk La , Chen Deng , Cao Fangyuan , Kiemel Dominik , Aïssi Manon , Dekker FJ , Haisma HJ
Published: June 2019

Despite the rapid development of CRISPR/Cas9-mediated gene editing technology, the gene editing potential of CRISPR/Cas9 is hampered by low efficiency, especially for clinical applications. One of the major challenges is that chromatin compaction inevitably limits the Cas9 protein access to the target DNA. However, chromatin compaction is precisely regulated by histone acetylation and deacetylation. To overcome these challenges, we have comprehensively assessed the impacts of histone modifiers such as HDAC (1-9) inhibitors and HAT (p300/CBP, Tip60 and MOZ) inhibitors, on CRISPR/Cas9 mediated gene editing efficiency. Our findings demonstrate that attenuation of HDAC1, HDAC2 activity, but not other HDACs, enhances CRISPR/Cas9-mediated gene knockout frequencies by NHEJ as well as gene knock-in by HDR. Conversely, inhibition of HDAC3 decreases gene editing frequencies. Furthermore, our study showed that attenuation of HDAC1, HDAC2 activity leads to an open chromatin state, facilitates Cas9 access and binding to the targeted DNA and increases the gene editing frequencies. This approach can be applied to other nucleases, such as ZFN and TALEN.
Tetrodotoxin-sensitive sodium channels mediate action potential firing and excitability in menthol-sensitive Vglut3-lineage sensory neurons
Authors: Griffith Theanne N. , Docter Trevor A. , Lumpkin Ellen A.
Published: June 2019

Small-diameter vesicular glutamate transporter 3-lineage (Vglut3lineage) dorsal root ganglion (DRG) neurons play an important role in mechanosensation and thermal hypersensitivity; however, little is known about their intrinsic electrical properties. We therefore set out to investigate mechanisms of excitability within this population. Calcium microfluorimetry analysis of male and female mouse DRG neurons demonstrated that the cooling compound menthol selectively activates a subset of Vglut3lineage neurons. Whole-cell recordings showed that small-diameter Vglut3lineage DRG neurons fire menthol-evoked action potentials and exhibited robust, transient receptor potential melastatin 8 (TRPM8)-dependent discharges at room temperature. This heightened excitability was confirmed by current-clamp and action potential phase-plot analyses, which showed menthol-sensitive Vglut3lineage neurons to have more depolarized membrane potentials, lower firing thresholds, and higher evoked firing frequencies compared with menthol-insensitive Vglut3lineage neurons. A biophysical analysis revealed voltage-gated sodium channel (NaV) currents in menthol-sensitive Vglut3lineage neurons were resistant to entry into slow inactivation compared with menthol-insensitive neurons. Multiplex in situ hybridization showed similar distributions of tetrodotoxin (TTX)-sensitive NaVs transcripts between TRPM8-positive and -negative Vglut3lineage neurons; however, NaV1.8 transcripts, which encode TTX-resistant channels, were more prevalent in TRPM8-negative neurons. Conversely, pharmacological analyses identified distinct functional contributions of NaV subunits, with NaV1.1 driving firing in menthol-sensitive neurons, whereas other small-diameter Vglut3lineage neurons rely primarily on TTX-resistant NaV channels. Additionally, when NaV1.1 channels were blocked, the remaining NaV currents readily entered into slow inactivation in menthol-sensitive Vglut3lineage neurons. Thus, these data demonstrate that TTX-sensitive NaVs drive action potential firing in menthol-sensitive sensory neurons and contribute to their heightened excitability.

Significance Statement

Somatosensensory neurons encode various sensory modalities including thermoreception, mechanoreception, nociception and itch. This report identifies a previously unknown requirement for tetrodotoxin-sensitive sodium channels in action potential firing in a discrete subpopulation of small-diameter sensory neurons that are activated by the cooling agent menthol. Together, our results provide a mechanistic understanding of factors that control intrinsic excitability in functionally distinct subsets of peripheral neurons. Furthermore, as menthol has been used for centuries as an analgesic and anti-pruritic, these findings support the viability of NaV1.1 as a therapeutic target for sensory disorders.
Carbohydrate and PepO control bimodality in competence development byStreptococcus mutans
Authors: Underhill Simon A.M. , Shields Robert C. , Burne Robert A. , Hagen Stephen J.
Published: June 2019

InStreptococcus mutans, the alternative sigma factor ComX controls entry into genetic competence. Competence signaling peptide (CSP) induces bimodal expression ofcomX, with only a fraction of cells in the population becoming transformable. Curiously, bimodalcomXactivation in response to CSP is affected by peptides in the growth medium and by carbohydrate source. CSP elicits bimodal expression ofcomXin media rich in small peptides, but in defined media lacking small peptides CSP induces no response incomX. In addition, growth on certain sugars other than glucose increases the proportion of the population that activatescomXin response to CSP, relative to growth on glucose. By investigating the connection between media and bimodalcomXexpression, we find evidence for two mechanisms that modulate transcriptional positive feedback in the ComRS system, which is the origin ofcomXbimodality. We find that the endopeptidase PepO suppresses the ComRS feedback loop, most likely by degrading the intracellular XIP/ComS signal. Deletion ofpepOeliminates bimodality incomX, leading to a unimodalcomXresponse to CSP in defined and complex media. We also find that CSP upregulatescomRin a carbohydrate source-dependent fashion, providing an additional stimulus to the ComRS feedback system. Our data provide mechanistic insight into how CSP regulates the bistable competence circuit and explain the puzzle of growth medium-dependence inS. mutanscompetence regulation.
DREAM Interrupted: Severing LIN-35-MuvB association in Caenorhabditis elegans impairs DREAM function but not its chromatin localization
Authors: Goetsch Paul D. , Strome Susan
Published: June 2019

The mammalian pocket protein family, which includes the Retinoblastoma protein (pRb) and Rb-like pocket proteins p107 and p130, regulates entry into and exit from the cell cycle by repressing cell cycle gene expression. Although pRb plays a dominant role in mammalian systems, p107 and p130 are the ancestral pocket proteins. The Rb-like pocket proteins interact with the highly conserved 5-subunit MuvB complex and an E2F-DP transcription factor heterodimer, forming the DREAM (for Dp, Rb-like, E2F, and MuvB) complex. DREAM complex assembly on chromatin culminates in repression of target genes mediated by the MuvB subcomplex. Here, we examined how the Rb-like pocket protein contributes to DREAM formation and function by disrupting the interaction between the sole Caenorhabditis elegans pocket protein LIN-35 and the MuvB subunit LIN-52 using CRISPR/Cas9 targeted mutagenesis. A triple alanine substitution of LIN-52’s LxCxE motif severed LIN-35-MuvB association and caused classical DREAM mutant phenotypes, including synthetic multiple vulvae, high-temperature arrest, and ectopic expression of germline genes in the soma. However, RNA-seq revealed limited upregulation of DREAM target genes when LIN-35-MuvB association was severed, as compared to gene upregulation following LIN-35 loss. Based on chromatin immunoprecipitation, disrupting LIN-35-MuvB association did not affect the chromatin localization of E2F-DP, LIN-35, or MuvB components. In a previous study we showed that in worms lacking LIN-35, E2F-DP and MuvB chromatin occupancy was reduced genome-wide. With LIN-35 present but unable to associate with MuvB, our present study suggests that the E2F-DP-LIN-35 interaction promotes E2F-DP’s chromatin localization, which we hypothesize supports MuvB chromatin occupancy indirectly through DNA. Altogether, this study highlights how the pocket protein’s association with MuvB supports DREAM function but is not required for DREAM’s chromatin occupancy.
Surface protein imputation from single cell transcriptomes by deep neural networks
Authors: Zhou Zilu , Ye Chengzhong , Wang Jingshu , Zhang Nancy R.
Published: June 2019

While single cell RNA sequencing (scRNA-seq) is invaluable for studying cell populations, cell-surface proteins are often integral markers of cellular function and serve as primary targets for therapeutic intervention. Here we propose a transfer learning framework, single cell Transcriptome to Protein prediction with deep neural network (cTP-net), to impute surface protein abundances from scRNA-seq data by learning from existing single-cell multi-omic resources.
Single-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4/6 inhibitor resistant HER2-positive breast cancer
Authors: Wang Qingfei , Guldner Ian H. , Golomb Samantha M. , Sun Longhua , Harris Jack , Lu Xin , Zhang Siyuan
Published: June 2019

Development of acquired resistance to targeted cancer therapy is one of the most significant clinical challenges. Acquiring resistance under drug selection pressure is a result of evolutionary adaptation to a complex and dynamic tumor microenvironment (TME). New therapy regimens combining CDK4/6 inhibitor are under active investigation in clinical trials to treat HER2+ breast cancer patients. In parallel with clinical trial settings, in this study, we sought to prospectively model the tumor evolution in response to a targeted therapy regimen in vivo and identify a clinically actionable strategy to combat potential acquired resistance. Notably, despite a promising initial response, acquired resistance emerged rapidly to the anti-Her2/Neu antibody plus CDK4/6 inhibitor Palbociclib combination treatment. By leveraging high-throughput single-cell analyses of the evolving tumors over the course of treatments, we revealed a distinct immunosuppressive immature myeloid cell (IMC) population infiltrated in the resistant TME. Guided by single-cell transcriptome analysis, we demonstrated a combinatorial immunotherapy of IMC-targeting tyrosine kinase inhibitor cabozantinib and immune checkpoint blockades enhanced anti-tumor immunity, and overcame the resistance. Further, sequential combinatorial immunotherapy enabled a sustained control of the rapidly evolving CDK4/6 inhibitor-resistant tumors. Our study demonstrates a translational framework for treating rapidly evolving tumors through preclinical modeling and single-cell analyses. Our findings provide a rationale for an immediate clinical proposition of combinatorial immunotherapy for HER2+ breast cancer as a strategy to mitigate the emergence of resistance.
Interpretable Multimodality Embedding Of Cerebral Cortex Using Attention Graph Network For Identifying Bipolar Disorder
Authors: Yang Huzheng , Li Xiaoxiao , Wu Yifan , Li Siyi , Lu Su , Duncan James S. , Gee James C. , Gu Shi
Published: June 2019

Bipolar Disorder (BP) is a mental disorder that affects 1 ∼ 2% of the population. Early diagnosis and targeted treatment can benefit from associated biological markers. The existing methods typically utilize biomarkers from anatomical MRI or functional BOLD imaging, but lack the ability of revealing the relationship between integrated modalities and disease. In this paper, we developed an Edge-weighted Graph Attention Network (EGAT) with Dense Hierarchical Pooling (DHP), to better understand the underlying roots of the disorder from the view of structure-function integration. For the input, the underlying graphs are constructed from functional connectivity matrices and the nodal features consist of both the anatomical features and the statistics of the connectivity. We investigated the potential benefits of using EGAT to classify BP vs. Healthy Control (HC). Compared with traditional machine learning classifiers, our proposed EGAT embedding increased improved 10 ∼ 20% in the accuracy and F1-score, compared with alternative classifiers. More specifically, by examining the attention map and gradient sensitivity of nodal features, we indicated that associated with the abnormality of anatomical geometric properties, multiple interactive patterns among Default Mode, Fronto-parietal and Cingulo-opercular networks contribute to identifying BP.
Embracing curiosity eliminates the exploration-exploitation dilemma
Authors: Peterson Erik J , Verstynen Timothy D
Published: June 2019

Balancing exploration with exploitation is seen as a mathematically intractable dilemma that all animals face. In this paper, we provide an alternative view of this classic problem that does not depend on exploring to optimize for reward. We argue that the goal of exploration should be pure curiosity, or learning for learning’s sake. Through theory and simulations we prove that explore-exploit problems based on this can be solved by a simple rule that yields optimal solutions: when information is more valuable than rewards, be curious, otherwise seek rewards. We show that this rule performs well and robustly under naturalistic constraints. We suggest three criteria can be used to distinguish our approach from other theories.
Base-rate neglect and neural computations for subjective weight in probabilistic inference
Authors: Yang Yun-Yen , Wu Shih-Wei
Published: June 2019

Abstract

Humans show systematic biases when estimating probability of uncertain events. Base-rate neglect is a well-known bias that describes the tendency to underweight information from the past relative to the present. In this study, we characterized base-rate neglect at the computational and neural implementation levels. At the computational level, we established that base-rate neglect arises from insufficient adjustment to weighting prior information in response to changes in prior variability. At the neural implementation level, we found that orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) represent subjective weighting of information that reflects base-rate neglect. Critically, both subjective-weight and subjective-value signals that guide choice were found in mPFC. However, subjective-weight signals preceded subjective-value signals. These results indicate that when facing multiple sources of information, estimation bias such as base-rate neglect arises from information weighting computed in OFC and mPFC, which directly contributes to subjective-value computations that guide decisions under uncertainty.

Significance Statement

Facing uncertainty, estimating the probability of different potential outcomes carries significant weight in affecting how we act and decide. Decades of research show that humans are prone to giving biased estimation but it remains elusive how these biases arise in the brain. We focus on base-rate neglect, a well-known bias in probability estimation and find that it is tightly associated with activity in the medial prefrontal cortex and orbitofrontal cortex. These regions represent the degree to which human participants weigh different sources of information, suggesting that base-rate neglect arises from information-weighting computations in the brain. As technology provides us the opportunity to seek and gather information at an ever-increasing pace, understanding information-weighting and its biases also carry important policy implications.
Exploring novel probiotic mechanisms ofStreptococcusA12 with functional genomics
Authors: Lee K , Walker AR , Chakraborty B , Kaspar JR , Nascimento MM , Burne RA
Published: June 2019

Health-associated biofilms in the oral cavity are composed of a diverse group of microbial species that can foster an environment that is less favorable for the outgrowth of dental caries pathogens, likeStreptococcus mutans.A novel oral bacterium, designatedStreptococcusA12, was previously isolated from supragingival dental plaque of a caries-free individual, and was shown to interfere potently with the growth and virulence properties ofS. mutans. Here, we apply functional genomics to begin to identify molecular mechanisms used by A12 to antagonize, and to resist the antagonistic factors of,S. mutans.Using bioinformatics, genes that could encode factors that enhance the ability of A12 to compete withS. mutanswere identified. Selected genes, designated aspotentialcompetitive factors (pcf), were deleted. Certain mutant derivatives showed a reduced capacity to compete withS. mutanscompared to the parental strain. The A12pcfOmutant lost the ability to inhibitcomX-inducingpeptide (XIP) signaling byS. mutans, while mutants in thepcfFEGlocus were impaired in sensing of, and were more sensitive to, the lantibiotic nisin. Loss of PcfV, annotated as a colicin V biosynthetic protein, resulted in diminished antagonism ofS. mutans.Collectively, the data provide new insights into the complexities and variety of factors that affect biofilm ecology and virulence. Continued exploration of the genomic and physiologic factors that distinguish commensals from truly beneficial members of the oral microbiota will lead to a better understanding of the microbiome and new approaches to promote oral health.

Importance

Advances in defining the composition of health-associated biofilms have highlighted the important role for beneficial species in maintaining health. Comparatively little, however, has been done to address the genomic and physiological basis underlying the probiotic mechanisms of beneficial commensals. In this study, we explored the ability of a novel oral bacterial isolate,StreptococcusA12, to compete with the dental pathogenStreptococcus mutans, using various gene products with diverse functions. A12 displayed enhanced competitiveness by: i) disrupting intercellular communication pathways ofS. mutans, ii) sensing and resisting antimicrobial peptides, and iii) producing factors involved in the production of a putative antimicrobial compound. Research on the probiotic mechanisms employed byStreptococcusA12 is providing essential insights into how beneficial bacteria may help maintain oral health, which will aid in the development of biomarkers and therapeutics that can improve the practice of clinical dentistry.
Systematic analysis of Plasmodium myosins reveals differential expression, localization and function in invasive and proliferative parasite stages
Authors: Wall Richard J. , Zeeshan Mohammad , Katris Nicholas J. , Limenitakis Rebecca , Rea Edward , Stock Jessica , Brady Declan , Waller Ross F. , Holder Anthony A. , Tewari Rita
Published: June 2019

The myosin superfamily comprises of actin-dependent eukaryotic molecular motors important in a variety of cellular functions. Although well studied in many systems, knowledge of their functions in Plasmodium, the causative agent of malaria, is restricted. Previously, six myosins were identified in this genus, including three Class XIV myosins found only in Apicomplexa and some Ciliates. The well characterised MyoA, is a class XIV myosin essential for gliding motility and invasion. Here, we characterize all other Plasmodium myosins throughout the parasite life cycle and show that they have very diverse patterns of expression and cellular location. MyoB and MyoE, the other two Class XIV myosins, are expressed in all invasive stages, with apical and basal locations, respectively. Gene deletion revealed that MyoE is involved in sporozoite motility, MyoF and MyoK are likely essential in the asexual blood stages, and MyoJ and MyoB are not essential. Both MyoB and its essential light chain (MCL-B) are localised at the apical end of ookinetes but expressed at completely different time points. This work provides a better understanding of the role of actomyosin motors in Apicomplexan parasites, particularly in the motile and invasive stages of Plasmodium during sexual and asexual development within the mosquito.
Synaptic mitochondria are critical for hair-cell synapse formation and function
Authors: Wong Hiu-tung C. , Zhang Qiuxiang , Beirl Alisha J. , Petralia Ronald S. , Wang Ya-Xian , Kindt Katie S.
Published: June 2019

Sensory hair cells in the ear utilize specialized ribbon synapses. These synapses are defined by electron-dense presynaptic structures called ribbons, composed primarily of the structural protein Ribeye. Previous work has shown that voltage-gated influx of Ca2+through CaV1.3 channels is critical for hair-cell synapse function and can impede ribbon formation. We show that in mature zebrafish hair cells, evoked presynaptic-Ca2+influx through CaV1.3 channels initiates mitochondrial-Ca2+(mito-Ca2+) uptake adjacent to ribbons. Block of mito-Ca2+uptake in mature cells depresses presynaptic Ca2+influx and impacts synapse integrity. In developing zebrafish hair cells, mito-Ca2+uptake coincides with spontaneous rises in presynaptic Ca2+influx. Spontaneous mito-Ca2+loading lowers cellular NAD+/NADH redox and downregulates ribbon formation. Direct application of NAD+or NADH increases or decreases ribbon formation respectively, possibly acting through the NAD(H)-binding domain on Ribeye. Our results present a mechanism where presynaptic- and mito-Ca2+couple to confer proper presynaptic function and formation.
Radiation damage studies in cardiac muscle cells and tissue using microfocused X-ray beams: experiment and simulation
Authors: Nicolas Jan-David , Aeffner Sebastian , Salditt Tim
Published: June 2019

Soft materials are easily affected by radiation damage from intense, focused synchrotron beams, often limiting the use of scanning diffraction experiments to radiation-resistant samples. To minimize radiation damage in experiments on soft tissue and thus to improve data quality, radiation damage needs to be studied as a function of the experimental parameters. Here, the impact of radiation damage in scanning X-ray diffraction experiments on hydrated cardiac muscle cells and tissue is investigated. It is shown how the small-angle diffraction signal is affected by radiation damage upon variation of scan parameters and dose. The experimental study was complemented by simulations of dose distributions for microfocused X-ray beams in soft muscle tissue. As a simulation tool, the Monte Carlo software package EGSnrc was used that is widely used in radiation dosimetry research. Simulations also give additional guidance for a more careful planning of dose distribution in tissue.