bluuebunny/crossref_metadata_2025 huggingface dataset:
Visualizing single atom dynamics in heterogeneous catalysis using analytical
in situ
environmental scanning transmission electron microscopy
Authors: Boyes Edward D. , LaGrow Alec P. , Ward Michael R. , Martin Thomas E. , Gai Pratibha L.
Published: October 2020

Progress is reported in analytical
in situ
environmental scanning transmission electron microscopy (ESTEM) for visualizing and analysing in real-time dynamic gas–solid catalyst reactions at the single-atom level under controlled reaction conditions of gas environment and temperature. The recent development of the ESTEM advances the capability of the established ETEM with the detection of fundamental single atoms, and the associated atomic structure of selected solid-state heterogeneous catalysts, in catalytic reactions in their working state. The new data provide improved understanding of dynamic atomic processes and reaction mechanisms, in activity and deactivation, at the fundamental level; and in the chemistry underpinning important technological processes. The benefits of atomic resolution-E(S)TEM to science and technology include new knowledge leading to improved technological processes, reductions in energy requirements and better management of environmental waste.

This article is part of a discussion meeting issue ‘Dynamic
in situ
microscopy relating structure and function’.
Patterns of oncogene co-expression at single cell resolution in cancer influence survival
Authors: Hoppe Michal Marek , Jaynes Patrick , Shuangyi Fan , Peng Yanfen , Hoang Phuong Mai , Xin Liu , De Mel Sanjay , Poon Limei , Chan Esther , Lee Joanne , Ong Choon Kiat , Tang Tiffany , Lim Soon Thye , Nagarajan Chandramouli , Grigoropoulos Nicholas Francis , Tan Soo-Yong , Hue Susan Swee-Shan , Chang Sheng-Tsung , Chuang Shih-Sung , Li Shaoying , Khoury Joseph D. , Choi Hyungwon , Harris Carl , Bottos Alessia , Gay Laura J. , Runge Hendrik F. P. , Moutsopoulos Ilias , Mohorianu Irina , Hodson Daniel J. , Farinha Pedro , Mottok Anja , Scott David W. , Kumar Gayatri , Kannan Kasthuri , Chng Wee-Joo , Chee Yen Lin , Ng Siok-Bian , Tripodo Claudio , Jeyasekharan Anand D.
Published: October 2020

Background

Cancers often overexpress multiple clinically relevant oncogenes. However, it is not known if multiple oncogenes within a cancer combine uniquely in specific cellular sub-populations to influence clinical outcome. We studied this phenomenon using the prognostically relevant oncogenes MYC, BCL2 and BCL6 in Diffuse Large B-Cell Lymphoma (DLBCL).

Methods

Quantitative multispectral imaging simultaneously measured oncogene co-expression at single-cell resolution in reactive lymphoid tissue (n=12) and four independent cohorts (n=409) of DLBCL. Mathematically derived co-expression phenotypes were evaluated in DLBCLs with immunohistochemistry (n=316) and eight DLBCL cohorts with gene expression data (n=4186). Bulk and single-cell RNA sequencing was performed on patient-derived B-cells with induced co-expression of MYC, BCL2 and BCL6.

Results

Unlike in non-malignant lymphoid tissue where the co-expression of MYC, BCL2 and BCL6 in a B-cell is limited, DLBCLs show multiple permutations of oncogenic co-expression in malignant B-cells. The percentage of cells with a unique combination MYC+BCL2+BCL6-(M+2+6-) consistently predicts survival in contrast to that of other combinations (including M+2+6+). An estimated percentage of M+2+6-cells can be derived from any quantitative measurement of the component individual oncogenes, and correlates with survival in immunohistochemistry and gene expression datasets. Comparative transcriptomic analysis of DLBCLs and transformed patient-derived B-cells identifies cyclin D2 (CCND2) as a potential BCL6-repressed regulator of proliferation in the M+2+6-population.

Conclusions

Unique patterns of oncogene co-expression at single-cell resolution affect clinical outcomes in DLBCL. Similar analyses evaluating oncogenic combinations at the cellular level may impact diagnostics and target discovery in other cancers.
Exploiting collider bias to apply two-sample summary data Mendelian randomization methods to one-sample individual level data
Authors: Barry Ciarrah , Liu Junxi , Richmond Rebecca , Rutter Martin K , Lawlor Deborah A , Dudbridge Frank , Bowden Jack
Published: October 2020

Over the last decade the availability of SNP-trait associations from genome-wide association studies data has led to an array of methods for performing Mendelian randomization studies using only summary statistics. A common feature of these methods, besides their intuitive simplicity, is the ability to combine data from several sources, incorporate multiple variants and account for biases due to weak instruments and pleiotropy. With the advent of large and accessible fully-genotyped cohorts such as UK Biobank, there is now increasing interest in understanding how best to apply these well developed summary data methods to individual level data, and to explore the use of more sophisticated causal methods allowing for non-linearity and effect modification.

In this paper we describe a general procedure for optimally applying any two sample summary data method using one sample data. Our procedure first performs a meta-analysis of summary data estimates that are intentionally contaminated by collider bias between the genetic instruments and unmeasured confounders, due to conditioning on the observed exposure. These estimates are then used to correct the standard observational association between an exposure and outcome. Simulations are conducted to demonstrate the method's performance against naive applications of two sample summary data MR. We apply the approach to the UK Biobank cohort to investigate the causal role of sleep disturbance on HbA1c levels, an important determinant of diabetes.

Our approach can be viewed as a generalization of Dudbridge et al. (Nat. Comm. 10: 1561), who developed a technique to adjust for index event bias when uncovering genetic predictors of disease progression based on case-only data. Our work serves to clarify that in any one sample MR analysis, it can be advantageous to estimate causal relationships by artificially inducing and then correcting for collider bias.
Associations between Affect, Physical Activity, and Anxiety Among US Children During COVID-19
Authors: Alves Jasmin M. , Yunker Alexandra G. , DeFendis Alexis , Xiang Anny H. , Page Kathleen A.
Published: October 2020

We investigated how emotional responses (positive and negative affect), physical activity (PA), and sedentary behaviors related to anxiety among US children during the COVID-19 pandemic. Sixty-four typically-developing children (63% girls) age 9-15 years old completed two virtual visits during height of “stay-at-home” measures between April 22 – July 29, 2020. Children completed 24-hour PA recalls, state portion of State-Trait Anxiety Inventory for Children (STAIC), and the shortened 10-item Positive and Negative Affect Schedule for Children (PANAS-C). Children reported state anxiety scores that were more than 5 standard deviations greater than values from healthy pediatric populations prior to the pandemic. Children with higher positive affect and who reported more time in PA reported less state anxiety. Sedentary and leisure screen time were positively correlated with negative affect. Our findings suggest that maintaining positive affect, engaging in PA, and limiting leisure screen time may be important for child mental health during stressful periods.

Statement of Relevance

There is increasing concern regarding how the COVID-19 pandemic may impact the psychological and physical health of children. To date, studies on mental health during the pandemic in children are limited. We investigated links between activity levels and psychological outcomes in children during the height of the “stay-at-home” measures. We found that children had anxiety scores that were more than 5 standard deviations greater than normative values from healthy pediatric populations prior to the pandemic, and 94% of children exceeded the American Academy of Pediatrics recommendations on leisure screen time. Positive affect and physical activity were associated with reduced anxiety levels in children during the pandemic. These findings highlight the important mental health benefits of maintaining positive affect, engaging in physical activity, and limiting leisure screen time for children, especially during stressful periods.
Early intervention is the key to success in COVID-19 control
Authors: Binny Rachelle N. , Baker Michael G. , Hendy Shaun C. , James Alex , Lustig Audrey , Plank Michael J. , Ridings Kannan M. , Steyn Nicholas
Published: October 2020

New Zealand responded to the COVID-19 pandemic with a combination of border restrictions and an Alert Level system that included strict stay-at-home orders. These interventions were successful in containing the outbreak and ultimately eliminating community transmission of COVID-19. The timing of interventions is crucial to their success. Delaying interventions may both reduce their effectiveness and mean that they need to be maintained for a longer period. Here, we use a stochastic branching process model of COVID-19 transmission and control to simulate the epidemic trajectory in New Zealand and the effect of its interventions during its COVID-19 outbreak in March-April 2020. We use the model to calculate key measures, including the peak load on the contact tracing system, the total number of reported COVID-19 cases and deaths, and the probability of elimination within a specified time frame. We investigate the sensitivity of these measures to variations in the timing of interventions and show that changing the timing of Alert Level 4 (the strictest level of restrictions) has a far greater impact than the timing of border measures. Delaying Alert Level 4 restrictions results in considerably worse outcomes and implementing border measures alone, without Alert Level 4 restrictions, is insufficient to control the outbreak. We conclude that the rapid response in introducing stay-at-home orders was crucial in reducing the number of cases and deaths and increasing the probability of elimination.
Phenome-wide screening of GWAS data reveals the complex causal architecture of obesity
Authors: García-Marín Luis M. , Campos Adrián I. , Kho Pik-Fang , Martin Nicholas G. , Cuéllar-Partida Gabriel , Rentería Miguel E.
Published: October 2020

Objective

In the present study, we sought to identify causal relationships between obesity and other complex traits and conditions using a data-driven hypothesis-free approach that uses genetic data to infer causal associations.

Methods

We leveraged available summary-based genetic data from genome-wide association studies on 1,498 phenotypes and applied the latent causal variable method (LCV) between obesity and all traits.

Results

We identified 110 traits with significant causal associations with obesity. Notably, obesity influenced 26 phenotypes associated with cardiovascular diseases, 22 anthropometric measurements, nine with the musculoskeletal system, nine with behavioural or lifestyle factors includingloneliness or isolation, six with respiratory diseases, five with body bioelectric impedances, four with psychiatric phenotypes, four related to the nervous system, four with disabilities or long-standing illness, three with the gastrointestinal system, three with use of analgesics, two with metabolic diseases, one with inflammatory response and one with the neurodevelopmental disorderADHD, among others.

Conclusions

Our results indicate that obesity causally affects a wide range of traits and comorbid diseases, thus providing an overview of the metabolic, physiological, and neuropsychiatric impact of obesity on human health.
Characterizing the Modern Light Environment and its Influence on Circadian Rhythms
Authors: Khodasevich Dennis , Tsui Susan , Keung Darwin , Skene Debra J. , Revell Victoria , Martinez Micaela E.
Published: October 2020

Humans have largely supplanted natural light cycles with a variety of artificial light sources and schedules misaligned with day-night cycles. Circadian disruption has been linked to a number of disease processes, but the extent of circadian disruption among the population is unknown. We measured light exposure and wrist temperature among residents of an urban area for a full week during each of the four seasons, as well as light illuminance in nearby outdoor locations. Daily light exposure was significantly lower for individuals, compared to outdoor light sensors, for all four seasons. There was also little seasonal variation in the realized photoperiod experienced by individuals, with the only significant difference between winter and summer. We tested the hypothesis that differential light exposure impacts circadian phase timing, detected via the wrist temperature rhythm. To determine the influence of light exposure on circadian rhythms, we modeled the impact of morning, afternoon, and nighttime light exposure on the timing of the midline-estimating statistic of rhythm (MESOR). We found that morning light exposure and nighttime light exposure had a significant but opposing impact on MESOR timing. Our results demonstrate that nighttime light can shift/alter circadian rhythms to delay the morning transition from nighttime to daytime physiology, while morning light can lead to earlier onset. Our results demonstrate that circadian shifts and disruptions may be a more regular occurrence in the general population than is currently recognized.

Significance Statement

Disruption of circadian rhythms has been linked to various diseases, but the prevalence of circadian disruption among the general population is unknown. Light plays a pivotal role in entraining circadian rhythms to the 24-hour day. Humans have largely supplanted natural light cycles with electrical lighting and through time spent indoors. We have shown that individuals experience a disconnect from natural light cycles, with low daytime light exposure, high levels of light-at-night, and minimal seasonal variation in light exposure. We identified measurable changes in the timing of wrist temperature rhythms as a function of differential light exposure during the morning and nighttime hours. Our findings suggest that circadian shifts, and potentially disruption, may be common in the general population.
Differences in outcomes following an intensive upper-limb rehabilitation programme for patients with common CNS-acting drug prescriptions
Authors: Johnstone Ainslie , Brander Fran , Kelly Kate , Bestmann Sven , Ward Nick
Published: October 2020

Difficulty using the upper-limb is a major barrier to independence for many patients post-stroke or brain injury. High dose rehabilitation can result in clinically significant improvements in function even years after the incident, however there is still high variability in patient responsiveness to such interventions that cannot be explained by age, sex or time since stroke.

This retrospective study investigated whether patients prescribed certain classes of CNS-acting drugs - GABA agonists, antiepileptics and antidepressants-differed in their outcomes on the 3 week intensive Queen Square Upper-Limb (QSUL) programme.

For 277 stroke or brain injury patients (167 male, median age 52 years (IQR 21), median time since incident 20 months (IQR 26)) upper-limb impairment and activity was assessed at admission to the programme and at 6 months post-discharge, using the upper limb component of the Fugl-Meyer (FM), Action Research Arm Test (ARAT), and Chedoke Arm and Hand Activity Inventory (CAHAI). Drug prescriptions were obtained from primary care physicians at referral. Specification curve analysis (SCA) was used to protect against selective reporting results and add robustness to the conclusions of this retrospective study.

Patients with GABA agonist prescriptions had significantly worse upper-limb scores at admission but no evidence for a significant difference in programme-induced improvements was found. Additionally, no evidence of significant differences in patients with or without antiepileptic drug prescriptions on either admission to, or improvement on, the programme was found in this study. Whereas, though no evidence was found for differences in admission scores, patients with antidepressant prescriptions experienced reduced improvement in upper-limb function, even when accounting for anxiety and depression scores.

These results demonstrate that, when prescribed typically, there was no evidence that patients prescribed GABA agonists performed worse on this high-intensity rehabilitation programme. Patients prescribed antidepressants, however, performed poorer than expected on the QSUL rehabilitation programme. While the reasons for these differences are unclear, identifying these patients prior to admission may allow for better accommodation of differences in their rehabilitation needs.
Noninvasive Ultrasonic Glymphatic Induction Enhances Intrathecal Drug Delivery
Authors: Aryal Muna , Zhou Quan , Rosenthal Eben L. , Airan Raag D.
Published: October 2020

Intrathecal drug delivery is routinely used to bypass the blood-brain barrier in treating varied central nervous system conditions. However, the utility of intrathecal delivery is limited by poor parenchymal uptake of agents from the cerebrospinal fluid. We demonstrate that a simple noninvasive transcranial ultrasound protocol significantly increases the brain parenchymal uptake of intrathecally administered drugs and antibodies. Essentially, we show that our protocol of transcranial ultrasound can accelerate glymphatic fluid transport from the cisternal space into the parenchymal compartment. Specifically, we administered small (∼1kDa) and large (∼150 kDa) molecule agents into the cisterna magna of rats and then applied low, diagnostic-intensity focused ultrasound in a scanning protocol throughout the brain. Using both real-time magnetic resonance imaging and ex vivo histologic analyses, we observed significantly increased uptake of each agent into the brain parenchyma from the cisternal cerebrospinal fluid, notably with no brain parenchymal damage. The low intensity of the ultrasound and its noninvasiveness underscores the ready path to clinical translation of this technique for whole-brain delivery of a variety of agents. Furthermore, this technique can be used as a means to probe the causal role of the glymphatic system in the variety of disease and physiologic processes to which it has been correlated.

eTOC Summary

A translation-ready ultrasound technique enhances the brain penetration of intrathecally delivered agents via upregulating the glymphatic pathway.
One tree, many colonies: colony structure, breeding system and colonization events of host trees in tunnelingMelissotarsusants
Authors: Eyer Pierre-André , Vargo Edward L. , Peeters Christian
Published: October 2020

Ants exhibit a striking variety of lifestyles, including highly specialist or mutualist species. The minute blind workers of the African genusMelissotarsuschew tunnels in live trees to accommodate their obligate partner scale insects. Their modified legs are adapted for tunneling, but are unsuited for walking outside, confining these ants to their initial host tree. Here, we investigated whether this unique lifestyle results in complex patterns of genetic diversity at different scales, from the same tree to different populations. Using 19 microsatellite markers, we assessed their mating strategy and colony structure among and across populations in South Africa. We showed that only one queen reproduces within a colony, mated with up to three males. Yet, several inseminated dealate queens are present in colonies; one probably replaces the older queen as colonies age. The reproduction of a single queen per colony at a given time results in genetic differentiation between colonies, even those located on the same tree. Overall, we discussed how the slow process of colony digging under the bark and the lack of worker patrolling above the bark might result in reduced competition between colonies and allow severalsecludedcolonies to cohabit in a cramped space on a tree.
High dimensionality of the stability of a marine benthic ecosystem
Authors: Valdivia Nelson , Aguilera Moisés A. , Broitman Bernardo R.
Published: October 2020

Stability is a central property of complex systems and encompasses multiple dimensions such as resistance, resilience, recovery, and invariability. How these dimensions correlate among them is focus of recent ecological research, but empirical evidence at regional scales, at which conservation decisions are usually made, remains absent. Using a field-based manipulative experiment conducted in two marine intertidal regions, we analyse the correlations among different aspects of stability in functioning (community cover) and composition of local communities facing a press disturbance. The experiment involved the removal of the local space-dominant species for 35 months in eight sites under different environmental regimes in northern- and southern-central Chile (ca. 30°S and 40°S, respectively). After the disturbance, the magnitude of the initial responses and the recovery patterns were similar among communities dominated by different species, but varied between the functional and compositional response variables, and among four dimensions of stability. The recovery trajectories in function and composition remained mostly uncorrelated across the system. Yet, larger initial functional responses were associated with faster recovery trajectories—high functional resilience, in turn, was associated with both, high and low variability in the pattern of recovery. Finally, the compositional stability dimensions were independent from each other. The results suggest that varying community compositions can perform similar levels of functioning, which might be the result of strong compensatory dynamics among species competing for space in these communities. Knowledge of several, and sometimes independent, aspects of stability is mandatory to fully describe the stability of complex ecological systems.
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

Inferring 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 summary

Mathematical 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

Synaptic 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

Longitudinal 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

Correlated 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

Recent 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

Initiation 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

Polypyrimidine 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

Root 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

We 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

Agency, 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

During 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

Large 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

PHB (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

Limited 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.
Attention reinforces human corticofugal system to aid speech perception in noise
Authors: Price Caitlin N. , Bidelman Gavin M.
Published: October 2020

Perceiving speech-in-noise (SIN) demands precise neural coding between brainstem and cortical levels of the hearing system. Attentional processes can then select and prioritize task-relevant cues over competing background noise for successful speech perception. In animal models, brainstem-cortical interplay is achieved via descending corticofugal projections from cortex that shape midbrain responses to behaviorally-relevant sounds. Attentional engagement of corticofugal feedback may assist SIN understanding but has never been confirmed and remains highly controversial in humans. To resolve these issues, we recorded source-level, anatomically constrained brainstem frequency-following responses (FFRs) and cortical event-related potentials (ERPs) to speech via high-density EEG while listeners performed rapid SIN identification tasks. We varied attention with active vs. passive listening scenarios whereas task difficulty was manipulated with additive noise interference. Active listening (but not arousal-control tasks) exaggerated both ERPs and FFRs, confirming attentional gain extends to lower subcortical levels of speech processing. We used functional connectivity to measure the directed strength of coupling between levels and characterize “bottom-up” vs. “top-down” (corticofugal) signaling within the auditory brainstem-cortical pathway. While attention strengthened connectivity bidirectionally, corticofugal transmission disengaged under passive (but not active) SIN listening. Our findings (i) show attention enhances the brain’s transcription of speech even prior to cortex and (ii) establish a direct role of the human corticofugal feedback system as an aid to cocktail party speech perception.

Ethics statement

All participants provided written informed consent prior in accordance with protocols approved by the University of Memphis IRB.

Declaration of interest

none
Crystal structure and Hirshfeld surface analysis of dichlorido(methanol-κO)bis(2-methylpyridine-κN)copper(II)
Authors: Reddy J. Prakasha
Published: October 2020

In the title complex, [CuCl2(C6H7N)2(CH3OH)], the copper atom is five-coordinated by two nitrogen atoms of 2-methylpyridine ligands, two chloro ligands and an oxygen atom of the methanol molecule, being in a tetragonal–pyramidal environment with N and Cl atoms forming the basal plane. In the crystal, complex molecules related by the twofold rotation axis are joined into dimeric units by pairs of O—H...Cl hydrogen bonds. These dimeric units are assembled through C—H...Cl interactions into layers parallel to (001).