bluuebunny/crossref_metadata_2025_split huggingface dataset:
A computationally tractable birth-death model that combines phylogenetic and epidemiological data
Authors: Zarebski Alexander E. , du Plessis Louis , Parag Kris V. , Pybus Oliver G. 
Published: October 2020

AbstractInferring the dynamics of pathogen transmission during an outbreak is an important problem in both infectious disease epidemiology. In mathematical epidemiology, estimates are often informed by time series of confirmed cases, while in phylodynamics genetic sequences of the pathogen, sampled through time, are the primary data source. Each data type provides different, and potentially complementary, insight; recent studies have recognised that combining data sources can improve estimates of the transmission rate and number of infected individuals. However, inference methods are typically highly specialised and field-specific and are either computationally prohibitive or require intensive simulation, limiting their real-time utility.We present a novel birth-death phylogenetic model and derive a tractable analytic approximation of its likelihood, the computational complexity of which is linear in the size of the dataset. This approach combines epidemiological and phylodynamic data to produce estimates of key parameters of transmission dynamics and the number of unreported infections. Using simulated data we show (a) that the approximation agrees well with existing methods, (b) validate the claim of linear complexity and (c) explore robustness to model misspecification. This approximation facilitates inference on large datasets, which is increasingly important as large genomic sequence datasets become commonplace.Author summaryMathematical epidemiologists typically studies time series of cases, ie theepidemic curve, to understand the spread of pathogens. Genetic epidemiologists study similar problems but do so using measurements of the genetic sequence of the pathogen which also contain information about the transmission process. There have been many attempts to unite these approaches so that both data sources can be utilised. However, striking a suitable balance between model flexibility and fidelity, in a way that is computationally tractable, has proven challenging; there are several competing methods but for large datasets they are intractable. As sequencing of pathogen genomes becomes more common, and an increasing amount of epidemiological data is collected, this situation will only be exacerbated. To bridge the gap between the time series and genomic methods we developed an approximation scheme, called TimTam, which can accurately and efficiently estimate key features of an epidemic such as the prevalence of the infection and the effective reproduction number, ie how many people are currently infected and the degree to which the infection is spreading.
Absence of postsynaptic activity on developing neurons alters gene expression profiles without preventing the refinement of inputs
Authors: Chong Yumaine , Cooper Ellis 
Published: October 2020

AbstractSynaptic activity plays several roles as developing neurons make connections with their targets. It acts locally at synapses to influence the expression of genes needed to establish and maintain synaptic contacts. And, downstream it provides the necessary activity to strengthen and refine connections. Many studies have demonstrated how synaptic activity alters synaptic strength and increases synapse numbers. Much less is known, however, about the long-term consequences when a circuit develops without synaptic activity. To address this, we developed a mosaic model of sympathetic ganglia where synaptically-active and synaptically-inactive sympathetic neurons develop side-by-sidein vivo.This model allowed us to address two issues. One is the relationship between activity and the refinement of converging inputs; the second is how synaptic activity contributes to a neuron’s gene expression profile. Our results indicate that converging presynaptic inputs to synaptically-silent neurons do not require postsynaptic activity to refine, provided these neurons share targets with synaptically-active neurons. Second, we demonstrate with single-cell RNA sequencing experiments that the expression of many genes by sympathetic neurons is independent of endogenous activity or local signals immediately downstream of excitatory postsynaptic potentials. An exception are genes required for neurotransmitter metabolism: We found that for a large sub-population of sympathetic neurons, synaptic activity increases the expression of adrenergic genes and supresses the expression of cholinergic genes. We conclude that signals generated locally at synapses do not initiate refinement of converging inputs, and that synaptic activity’s influence on a neuron’s gene expression profiles is complex and depends on context.
Multi-Level Multi-Growth Models: New opportunities for addressing developmental theory using longitudinal designs
Authors: McCormick Ethan M. 
Published: October 2020

AbstractLongitudinal models have become increasingly popular in recent years because of their power to test theoretically derived hypotheses by modeling within-person processes with repeated measures. Growth models constitute a flexible framework for modeling a range of complex trajectories across time in outcomes of interest, including non-linearities and time-varying covariates. However, these models have not thus far been expanded to include the effects of multiple growth processes at once on a single outcome. Here, I outline such an extension, showing how multiple growth processes can be modeled as a specific case of the general ability to include time-varying covariates in growth models. I show that this extension of growth models cannot be accomplished by statistical models alone, and that study design plays a crucial role in allowing for proper parameter recovery. I demonstrate these principles through simulations to mimic important theoretical conditions where modeling the effects of multiple growth processes can address developmental theory including, disaggregating the effects of age and practice or treatment in repeated assessments and modeling age- and puberty-related effects during adolescence. I compare how these models behave in two common longitudinal designs, cohort-sequential and accelerated, and how planned missingness in observations is key to parameter recovery. I conclude with directions for future substantive research using the method outlined here.
Spontaneous depolarization-induced action potentials of ON-starburst amacrine cells during cholinergic and glutamatergic retinal waves
Authors: Yan Rong-Shan , Yang Xiong-Li , Zhong Yong-Mei , Zhang Dao-Qi 
Published: October 2020

AbstractCorrelated spontaneous activity in the developing retina (termed “retinal waves”) plays an instructive role in refining neural circuits of the visual system. Depolarizing (ON) and hyperpolarizing (OFF) starburst amacrine cells (SACs) initiate and propagate cholinergic retinal waves. Where cholinergic retinal waves stop, SACs are thought to be driven by glutamatergic retinal waves initiated by ON-bipolar cells. However, the properties and function of cholinergic and glutamatergic waves in ON- and OFF-SACs still remain poorly understood. As expected, we found that both SAC subtypes exhibited spontaneous rhythmic depolarization during cholinergic and glutamatergic waves. Interestingly, ON-SACs had wave-induced action potentials (APs) in an age-dependent manner, but OFF-SACs did not. We further found that the number of APs in ON-SACs was correlated with the amplitude of Ca2+transients of either ON- or OFF-SACs during cholinergic retinal waves. These results advance the understanding of the cellular mechanisms underlying correlated spontaneous activity in the developing retina.
Fine-mapping of Parkinson’s disease susceptibility loci identifies putative causal variants
Authors: Schilder Brian M. , Raj Towfique 
Published: October 2020

AbstractRecent genome-wide association studies have identified 78 loci associated with Parkinson’s Disease susceptibility but the underlying mechanisms remain largely unclear. To identify variants likely causal for disease risk, we fine-mapped these Parkinson’s-associated loci using four different statistical and functional fine-mapping methods. We then integrated multi-assay cell-type-specific epigenomic profiles to pinpoint the likely mechanism of action of each variant, allowing us to identify Consensus SNPs that disruptLRRK2andFCGR2Aregulatory elements in microglia,MBNL2enhancers in oligodendrocytes, andDYRK1Aenhancers in neurons. Finally, we confirmed the functional relevance of fine-mapped SNPs using a suite ofin silicovalidation approaches. Together, these results provide a robust list of likely causal variants underlying Parkinson’s Disease risk for further mechanistic studies.
Role of PIF4 and FLC in controlling flowering time under daily variable temperature profile
Authors: Jenkitkonchai Jutapak , Marriott Poppy , Yang Weibing , Sriden Napaporn , Jung Jae-Hoon , Wigge Philip A , Charoensawan Varodom 
Published: October 2020

ABSTRACTInitiation of flowering is a crucial developmental event that requires both internal and environmental signals to determine when floral transition should occur to maximize reproductive success. Ambient temperature is one of the key environmental signals that highly influence flowering time, not only seasonally but also in the context of drastic temperature fluctuation due to global warming. Molecular mechanisms of how high or low constant temperatures affect the flowering time have been largely characterized in the model plantArabidopsis thaliana; however, the effect of natural daily variable temperature outside laboratories is only partly explored. Several groups of flowering genes have been shown to play important roles in temperature responses, including two temperature-responsive transcription factors (TFs), namely PHYTOCHROME INTERACTING FACTOR 4 (PIF4) and FLOWERING LOCUS C (FLC), that act antagonistically to regulate flowering time by activating or repressing floral integratorFLOWERING LOCUS T (FT). In this study, we have demonstrated that the daily variable temperature (VAR) causes early flowering in both natural accessions Col-0, C24 and their late flowering hybrid C24xCol, which carries both functional floral repressor FLC and its activator FRIGIDA (FRI), as compared to a constant temperature (CON). The loss-of-function mutation ofPIF4exhibits later flowering in VAR, suggesting that PIF4 at least in part, contributes to acceleration of flowering in response to the daily variable temperature. We find that VAR increasesPIF4transcription at the end of the day when temperature peaks at 32 °C. TheFTtranscription is also elevated in VAR, as compared to CON, in agreement with earlier flowering observed in VAR. In addition, VAR causes a decrease inFLCtranscription in 4-week-old plants, and we further show that overexpression ofPIF4can reduceFLCtranscription, suggesting that PIF4 might also regulateFTindirectly through the repression ofFLC. To further conceptualize an overall model of gene regulatory mechanisms involvingPIF4andFLCin controlling flowering in response to temperature changes, we construct a co-expression – transcriptional regulatory network by combining publicly available transcriptomic data and gene regulatory interactions of our flowering genes of interest and their partners. The network model reveals the conserved and tissue-specific regulatory functions of 62 flowering-time-relating genes, namelyPIF4,PIF5,FLC,ELF3and their immediate neighboring genes, which can be useful for confirming and predicting the functions and regulatory interactions between the key flowering genes.
PTBP1 Regulates Injury Responses and Sensory Pathways in Adult Peripheral Neurons
Authors: Alber Stefanie , Di-Matteo Pierluigi , Zdradzinski Matthew D. , Marvaldi Letizia , Kawaguchi Riki , Medzihradszky Katalin F. , Doron-Mandel Ella , Okladnikov Nataliya , Rishal Ida , Nevo Reinat , Lee Seung Joon , Sahoo Pabitra K. , Burlingame Alma L. , Coppola Giovanni , Twiss Jeffery L. , Fainzilber Mike 
Published: October 2020

SummaryPolypyrimidine Tract Binding Protein 1 (PTBP1) is expressed only at embryonic stages in central neurons. Its downregulation triggers neuronal differentiation in precursor and non-neuronal cells, an approach recently used to generate neuronsde novofor amelioration of neurodegenerative disorders. Moreover, PTBP1 is replaced by its paralog PTBP2 in mature central neurons. Surprisingly, we found both proteins co-expressed in adult sensory and motor neurons, with PTBP2 restricted mainly to the nucleus, while PTBP1 shows strong axonal localization. Levels of axonal PTBP1 increased markedly after peripheral nerve injury, and its cargos include mRNAs involved in axonal growth and regeneration, such as importin β1 and RhoA. Perturbation of PTBP1 affects neuronal injury responses, axon outgrowth and sensationin vivo. Thus, PTBP1 has roles in sensory function and regenerative capacity of adult sensory neurons. These findings suggest that caution may be required before considering targeting PTBP1 for therapeutic purposes.
The auxin transporter PIN1 and the cytokinin transporter AZG1 interact to regulate the root stress response
Authors: Tessi TM , Shahriari M , Maurino VG , Meissner E , Novak O , Pasternak T , Schumacher BS , Flubacher NS , Nautscher M , Williams A , Kazimierczak Z , Strnad M , Thumfart JO , Palme K , Desimone M , Teale WD 
Published: October 2020

AbstractRoot system development is crucial for optimal growth and yield in plants, especially in sub-optimal soil conditions. The architecture of a root system is environmentally responsive, enabling the plant to exploit regions of high nutrient density whilst simultaneously minimizing abiotic stress. Despite the vital contribution of root systems to the growth of both model and crop species, we know little of the mechanisms which regulate their architecture. One factor which is relatively well understood is the transport of auxin, a plant growth regulator which defines the frequency of lateral root (LR) initiation and the rate of LR outgrowth. Here we describe a search for proteins which regulate RSA by interacting directly with a key auxin transporter, PIN1. The native separation of PIN1 identified several co-purifying proteins. Among them, AZG1 was subsequently confirmed as a PIN1 interactor. AZG1-GFP fusions co-localized with PIN1 in procambium cells of the root meristem. Roots ofazg1plants contained less PIN1 and blocking proteolysis restored PIN1 levels, observations which are consistent with PIN1 being stabilized by AZG1 in the plasma membrane. Furthermore, we show that AZG1 is a cytokinin import protein; accordingly,azg1plants are insensitive to exogenously applied cytokinin. In wild-type plants, the frequency of LRs falls with increasing salt concentration, a response which is not observed inazg1 x azg2plants, although their drought response is unimpaired. This report therefore identifies a potential point for auxin:cytokinin crosstalk in the environmentally-responsive determination of root system architecture.
Neural structure of a sensory decoder for motor control
Authors: Egger Seth W. , Lisberger Stephen G. 
Published: October 2020

ABSTRACTWe seek to understand the neural mechanisms that perform sensory decoding for motor behavior, advancing the field by designing decoders based on neural circuits. A simple experiment produced a surprising result that shapes our approach. Changing the size of a target for smooth pursuit eye movements changes the relationship between the variance and mean of the evoked behavior in a way that contradicts the regime of “signal-dependent noise” and defies traditional decoding approaches. A theoretical analysis leads us to conclude that sensory decoding circuits for pursuit include multiple parallel pathways and multiple sources of variation. Behavioral and neural responses with biomimetic statistics emerge from a biologically-motivated circuit model with noise in the pathway that is dedicated to flexibly adjusting the strength of visual-motor transmission. Flexible adjustment of transmission strength applies much more broadly to issues in sensory-motor control such as Bayesian integration and control strategies to optimize motor behavior.
Agency improves working memory and accelerates visual and attentional processing
Authors: Loyola-Navarro Rocio , Moënne-Loccoz Cristóbal , Vergara Rodrigo C. , Hyafil Alexandre , Aboitiz Francisco , Maldonado Pedro E. 
Published: October 2020

ABSTRACTAgency, understood as the ability of an organism to control stimuli onset, modulates perceptual and attentional functions. Since stimulus encoding is an essential component of working memory (WM), we conjectured that the perceptual process’s agency would positively modulate WM. To corroborate this proposition, we tested twenty-five healthy subjects in a modified-Sternberg WM task under three stimuli presentation conditions: an unpredictable presentation of encoding stimulus, self-initiated presentation of the stimulus, and self-initiation presentation with random-delay stimulus onset. Concurrently, we recorded the subjects’ electroencephalographic signals during WM encoding. We found that the self-initiation condition was associated with better WM accuracy, and earlier latencies of N100 and P200 evoked potential components representing visual and attentional processes, respectively. Our work demonstrates that agency enhances WM performance and accelerates early visual and attentional processes deployed during WM encoding. We also found that self-initiation presentation correlates with an increased attentional state compared to the other two conditions, suggesting a role for temporal stimuli predictability. Our study remarks on the relevance of agency in sensory and attentional processing for WM.
The Histone Chaperone CAF-1 Sustains Myeloid Lineage Identity
Authors: Guo Yiming , Ji Fei , Murn Jernej , Frankhouser David , Blanco M Andres , Chiem Carmen , Jang MiHyun , Sadreyev Ruslan , Rockne Russel C. , Sykes David B. , Hochedlinger Konrad , Cheloufi Sihem 
Published: October 2020

AbstractDuring hematopoiesis, stem and progenitor cells become progressively restricted in their differentiation potential. This process is driven by lineage-specific transcription factors and is accompanied by dynamic changes in chromatin structure. The chromatin assembly factor complex CAF-1 is a key regulator of cellular plasticity in various cell lineages in different organisms. However, whether CAF-1 sustains lineage identity during normal homeostasis is unclear. To address this question, we investigated the role of CAF-1 in myeloid progenitor cells. CAF-1 suppression in myeloid progenitors triggered their rapid commitment but incomplete differentiation toward granulocyte, megakaryocyte, and erythrocyte lineages, resulting in a mixed cellular state. Through comparison with a canonical paradigm of directed terminal myeloid differentiation, we define changes in chromatin accessibility that underlie a unique transcriptome of the aberrantly matured CAF-1 deficient cells. We further identify C/EBPα and ELF1 as key transcription factors whose control of myeloid lineage commitment is kept in check by CAF-1. These findings shed new light on molecular underpinnings of hematopoiesis and suggest that manipulation of chromatin accessibility through modulating CAF-1 levels may provide a powerful strategy for controlled differentiation of blood cells.
How many gamebirds are released in the UK each year?
Authors: Madden Joah Robert 
Published: October 2020

ABSTRACTLarge numbers of gamebirds (pheasantsPhasianus colchicus, red-legged partridgesAlectoris rufaand mallardAnus platyrhynchos) are released annually in the UK to support recreational shooting. It is important to know how many of these birds are being released because their release and management has ecological effects on the wildlife and habitats of the UK. There is little regulation governing their release and consequently the numbers being released are unknown. I made 71 estimates of the numbers released based on numbers being reported formally via import controls and the Poultry Register, or extrapolated based on the breeding outputs of reared birds, or extrapolated based on the likely numbers and behaviour of shoots, or extrapolated based on observations of surviving birds. Based on the set of these estimates that fall within credible boundaries (ranging from 14.3 to 70.1 million birds), I estimate a mean of 34.5 million birds (95%CI 30.9-38.1 million) and a median value of 32.1 million (IQR 22.0-44.9 million) being released. This suggests that 24.3-25.3 million pheasants, 4.2-9.4 million partridges and 1.0-4.9 million mallard are released annually in the UK. These figures are markedly lower than previous published estimates and I discuss why such differences may occur. I set these figures in the context of the number and behaviour of shoots operating in the UK.
Maximizing PHB content inSynechocystis sp.PCC 6803: development of a new photosynthetic overproduction strain
Authors: Koch Moritz , Bruckmoser Jonas , Scholl Jörg , Hauf Waldemar , Rieger Bernhard , Forchhammer Karl 
Published: October 2020

AbstractPHB (poly-hydroxy-butyrate) represents a promising bioplastic variety with good biodegradation properties. Furthermore, PHB can be produced completely carbon-neutral when synthesized in the natural producer cyanobacteriumSynechocystis sp.PCC 6803. This model strain has a long history of various attempts to further boost its low amounts of produced intracellular PHB of ~15 % per cell-dry-weight (CDW).We have created a new strain that lacks the regulatory protein PirC (gene product ofsll0944), which causes a rapid conversion of the intracellular glycogen pools to PHB under nutrient limiting conditions. To further improve the intracellular PHB content, two genes from the PHB metabolism, phaA and phaB from the known production strainCupriavidus necator, were introduced under the regime of the strong promotor PpsbA2. The created strain, termed PPT1 (Δsll0944-REphaAB), produced high amounts of PHB under continuous light as well under day-night rhythm. When grown in nitrogen and phosphor depleted medium, the cells produced up to 63 % / CDW. Upon the addition of acetate, the content was further increased to 81 % / CDW. The produced polymer consists of pure PHB, which is highly isotactic.The achieved amounts were the highest ever reported in any known cyanobacterium and demonstrate the potential of cyanobacteria for a sustainable, industrial production of PHB.
Cannabis sativaTerpenes are Cannabimimetic and Provide Support for the Entourage Effect Hypothesis
Authors: LaVigne Justin E. , Hecksel Ryan , Keresztes Attila , Streicher John M. 
Published: October 2020

AbstractLimited evidence has suggested that terpenes found inCannabis sativaare analgesic, and could produce an “entourage effect” whereby they modulate cannabinoids to result in improved outcomes. However this hypothesis is controversial, with limited evidence. We thus investigatedCannabis sativaterpenes alone and with the cannabinoid agonist WIN55,212 usingin vitroandin vivoapproaches. We found that the terpenes α-humulene, geraniol, linalool, and β-pinene produced cannabinoid tetrad behaviors in mice, suggesting cannabimimetic activity. Some behaviors could be blocked by cannabinoid or adenosine receptor antagonists, suggesting a mixed mechanism of action. These behavioral effects were additive with WIN55,212, providing support for a terpene “entourage effect.”In vitroexperiments showed that all terpenes activated the CB1R, while some activated other targets. Our findings suggest that theseCannabisterpenes are multifunctional cannabimimetic ligands that provide support for the entourage effect hypothesis and could be used to enhance the therapeutic properties of cannabinoids.