bluuebunny/crossref_metadata_2025 huggingface dataset:
Awareness-dependent normalization framework of visual bottom-up attention
Authors: Wang Shiyu , Huang Ling , Chen Qinglin , Wang Jingyi , Xu Siting , Zhang Xilin
Published: April 2021

Although bottom-up attention can improve visual performance with and without awareness, whether they are governed by a common neural computation remains unclear. Using a modified Posner paradigm with backward masking, we found that both the attention-triggered cueing effect with and without awareness displayed a monotonic gradient profile (Gaussian-like). The scope of this profile, however, was significantly wider with than without awareness. Subsequently, for each subject, the stimulus size was manipulated as their respective mean scopes with and without awareness while stimulus contrast was varied in a spatial cueing task. By measuring the gain pattern of contrast-response functions, we observed changes in the cueing effect consonant with changes in contrast gain for bottom-up attention with awareness and response gain for bottom-up attention without awareness. Our findings indicate an awareness-dependent normalization framework of visual bottom-up attention, placing a necessary constraint, namely, awareness, on our understanding of the neural computations underlying visual attention.
Identification of clinical features associated with mortality in COVID-19 patients
Authors: Eskandarian Rahimeh , Sani Zahra Alizadeh , Behjati Mohaddeseh , Zahmatkesh Mehrdad , Haddadi Azadeh , Kakhi Kourosh , Roshanzamir Mohamad , Shoeibi Afshin , Alizadehsani Roohallah , Hussain Sadiq , Khozeimeh Fahime , Keyvani Vahideh , Khosravi Abbas , Nahavandi Saeid , Shariful Islam Sheikh Mohammed
Published: April 2021

Background

To prevent infectious diseases, it is necessary to understand how they are spread and their clinical features. Early identification of risk factors and clinical features is needed to identify critically ill patients, provide suitable treatments, and prevent mortality.

Methods

We conducted a prospective study on COVID-19 patients referred to a tertiary hospital in Iran between March and November 2020. Of the 3008 patients (mean age 59.3±18.7 years, range 1 to 100 years), 1324 were women. We investigated COVID-19 related mortality and its association with clinical features including headache, chest pain, symptoms on CT, hospitalization, time to infection, history of neurological disorders, having a single or multiple risk factors, fever, myalgia, dizziness, seizure, abdominal pain, nausea, vomiting, diarrhoea and anorexia.

Findings

There was a significant association between COVID-19 mortality and old age, headache, chest pain, respiratory distress, low respiratory rate, oxygen saturation less than 93%, need for a mechanical ventilator, having symptoms on CT, hospitalization, time to infection, history of hypertension, neurological disorders, cardiovascular diseases and having a risk factor or multiple risk factors. In contrast, there was no significant association between mortality and gender, fever, myalgia, dizziness, seizure, abdominal pain, nausea, vomiting, diarrhoea and anorexia.

Interpretation

Our results might help identify early symptoms related to COVID-19 and better manage patients clinically.
Post-COVID-19 syndrome in outpatients: a cohort study
Authors: Desgranges Florian , Tadini Eliana , Munting Aline , Regina Jean , Filippidis Paraskevas , Viala Benjamin , Karachalias Eleftherios , Suttels Véronique , Haefliger David , Kampouri Eleftheria , Van Singer Mathias , Tschopp Jonathan , Stettler Laurence Rochat , Schaad Siméon , Brahier Thomas , Hugli Olivier , Chabloz Yolanda Mueller , Gouveia Alexandre , Opota Onya , Carron Pierre-Nicolas , Guery Benoît , Papadimitriou-Olivgeris Matthaios , Boillat-Blanco Noémie ,   the RegCOVID research group
Published: April 2021

Background

After mild COVID-19, some outpatients experience persistent symptoms. However, data are scarce and prospective studies are urgently needed.

Objectives

To characterize the post-COVID-19 syndrome after mild COVID-19 and identify predictors.

Participants

Outpatients with symptoms suggestive of COVID-19 with (1) PCR-confirmed COVID-19 (COVID-positive) or (2) SARS-CoV-2 negative PCR (COVID-negative).

Design

Monocentric cohort study with prospective phone interview between more than three months to ten months after initial visit to the emergency department and outpatient clinics.

Main Measures

Data of the initial visits were extracted from the electronic medical file. Predefined persistent symptoms were assessed through a structured phone interview. Associations between long-term symptoms and PCR results, as well as predictors of persistent symptoms among COVID-positive, were evaluated by multivariate logistic regression adjusted for age, gender, smoking, comorbidities, and timing of the survey.

Key results

The study population consisted of 418 COVID-positive and 89 COVID-negative patients, mostly young adults (median age of 41 versus 36 years in COVID-positive and COVID-negative, respectively; p=0.020) and health care workers (67% versus 82%; p=0.006). Median time between the initial visit and the phone survey was 150 days in COVID-positive and 242 days in COVID-negative patients. Persistent symptoms were reported by 223 (53%) COVID-positive and 33 (37%) COVID-negative patients (p=0.006). Overall, 21% COVID-positive and 15% COVID-negative patients (p=0.182) attended care for this purpose. Four surveyed symptoms were independently associated with COVID-19: fatigue (adjusted odds ratio [or] 2.14, 95%CI 1.04-4.41), smell/taste disorder (26.5, 3.46-202), dyspnea (2.81, 1.10-7.16) and memory impairment (5.71, 1.53-21.3). Among COVID-positive, female gender (1.67, 1.09-2.56) and overweight/obesity (1.67, 1.10-2.56) were predictors of persistent symptoms.

Conclusions

More than half of COVID-positive outpatients report persistent symptoms up to ten months after a mild disease. Only 4 of 14 symptoms were associated with COVID-19 status. The symptoms and predictors of the post-COVID-19 syndrome need further characterization as this condition places a significant burden on society.
CSF infusion of TrkB agonist, 7,8-dihydroxyflavone, is ineffective in promoting remyelination in cuprizone and EAE models of multiple sclerosis
Authors: Fletcher Jessica L , Wood Rhiannon J , Prawdiuk Alexa R , O’Rafferty Ryan , Ehrlich Ophelia , Gonsalvez David G , Murray Simon S
Published: April 2021

Small molecular weight functional mimetics of brain-derived neurotrophic factor (BDNF) which act via the TrkB receptor have been developed to overcome the pharmacokinetic limitations of BDNF as a therapeutic for neurological disease. Activation of TrkB on oligodendrocytes has been identified as a potential strategy for myelin repair in demyelinating conditions. Here, we tested the efficacy of intracerebroventricular infusion of TrkB agonist 7,8-dihydroxyflavone (DHF) to promote myelin repair in the cuprizone model and alter the course of experimental autoimmune encephalomyelitis (EAE). In these two distinct mouse models used for the preclinical testing of remyelinating therapeutics, we found that DHF infusion increased the percentage of myelin basic protein and density of oligodendrocyte progenitor cells (OPCs) in the corpus callosum of female C57BL/6 mice after cuprizone demyelination. However, DHF did not alter the percentage of axons myelinated or increase the density of post-mitotic oligodendrocytes in this model. Direct cerebrospinal fluid infusion of DHF also had no effect on the clinical course of EAE, and examination of the lumbar spinal cord after 21 days of treatment revealed extensive demyelination. These results indicate that direct cerebrospinal fluid infusion of DHF is ineffective at promoting myelin repair in toxin-induced and inflammatory models of demyelination.
Spatially resolved analysis ofPseudomonas aeruginosabiofilm proteomes measured by laser ablation sample transfer
Authors: Pulukkody Aruni Chathurya , Yung Yeni P. , Donnarumma Fabrizio , Murray Kermit K. , Carlson Ross P. , Hanley Luke
Published: April 2021

Heterogeneity in the distribution of nutrients and O2gradients during biofilm growth gives rise to changes in phenotype. There has been long term interest in identifying spatial differences during biofilm development including clues that identify chemical heterogeneity. Laser ablation sample transfer (LAST) allows site-specific sampling combined with label free proteomics to distinguish radially and axially resolved proteomes forPseudomonas aeruginosabiofilms. Specifically, differential protein abundances on oxic vs. anoxic regions of a biofilm was observed by combining LAST with bottom up proteomics. This study reveals active metabolism in the anoxic region of the biofilm with respect to the oxic region inP. aeruginosa, an aerobe by nature. Protein abundance data related to cellular acclimations to chemical gradients include identification of glucose catabolizing proteins, high abundance of proteins from arginine and polyamine metabolism, and proteins that could also support virulence and environmental stress mediation on the anoxic region. Finally, this methodology requires only a few mm2of biofilm area to identify hundreds of proteins.
Vocal correlates of arousal in bottlenose dolphins (Tursiopsspp.) in human care
Authors: Probert Rachel , Bastian Anna , Elwen Simon H. , James Bridget S. , Gridley Tess
Published: April 2021

Human-controlled regimes can entrain behavioural responses and may impact animal welfare. Therefore, understanding the impact of schedules on animal behaviour can be a valuable tool to improve welfare, however information on overnight behaviour and behaviour in the absence of husbandry staff remains rare. Bottlenose dolphins (Tursiopsspp.) are highly social marine mammals and the most common cetacean found in captivity. They communicate using frequency modulated signature whistles which are individually distinctive and used as a contact call. We investigated the vocal behaviour of ten dolphins housed in three social groups at uShaka Sea World dolphinarium to determine how acoustic behavioural patterns link to dolphinarium routines. Investigation focused on overnight behaviour, housing decisions, weekly patterns, and transitional periods between presence and absence of husbandry staff. Recordings were made from 17h00 – 07h00 over 24 nights, spanning May to August 2018. Whistle production rate decreased soon after husbandry staff left the facility, was low over night, and increased upon arrival. Results indicated elevate arousal states associated with the morning arrival and presence of husbandry staff and heightened excitement associated with feeding. Housing in pool configurations which limited visual contact between certain groups were characterised by lower vocal production rates. Production of signature whistles was greater over the weekends compared to weekdays however total whistle production did not differ between weekends and weekdays. Heightened arousal associated with staff arrival was reflected in the structural characteristics of signature whistles, particularly maximum frequency, frequency range and number of whistle loops. Overall, these results revealed a link between scheduled activity and associated behavioural responses, which can be used as a baseline for future welfare monitoring where changes in normal behaviour may reflect shifts in welfare state.
Multiparametric Platform for Profiling Lipid Trafficking in Human Leukocytes: Application for Hypercholesterolemia
Authors: Pfisterer Simon G. , Brock Ivonne , Kanerva Kristiina , Hlushchenko Iryna , Paavolainen Lassi , Ripatti Pietari , Islam Mohammad M. , Kyttälä Aija , Di Taranto Maria D. , di Frega Annalisa Scotto , Fortunato Giuliana , Kuusisto Johanna , Horvath Peter , Ripatti Samuli , Laakso Markku , Ikonen Elina
Published: April 2021

Systematic insight into cellular dysfunctions can improve understanding of disease etiology, risk assessment and patient stratification. We present a multiparametric high-content imaging platform enabling quantification of low-density lipoprotein (LDL) uptake and lipid storage in cytoplasmic droplets of primary leukocyte subpopulations. We validated this platform with samples from 65 individuals with variable blood LDL-cholesterol (LDL-c) levels, including familial hypercholesterolemia (FH) and non-FH subjects. We integrated lipid storage data into a novel readout, lipid mobilization, measuring the efficiency with which cells deplete lipid reservoirs. Lipid mobilization correlated positively with LDL uptake and negatively with hypercholesterolemia and age, improving differentiation of individuals with normal and elevated LDL-c. Moreover, combination of cell-based readouts with a polygenic risk score for LDL-c explained hypercholesterolemia better than the genetic risk score alone. This platform provides functional insights into cellular lipid trafficking from a few ml’s of blood and is applicable to dissect metabolic disorders, such as hypercholesterolemia.

Motivation

We have limited information on how cellular lipid uptake and processing differ between individuals and influence the development of metabolic diseases, such as hypercholesterolemia. Available assays are labor intensive, require skilled personnel and are difficult to scale to higher throughput, making it challenging to obtain systematic functional cell-based data from individuals. To overcome this problem, we established a scalable automated analysis pipeline enabling reliable quantification of multiple cellular readouts, including lipid uptake, storage and mobilization, from different white blood cell populations. This approach provides new personalized insights into the cellular basis of hypercholesterolemia and obesity.

Graphical Abstract
Multivariate analysis reveals shared genetic architecture of brain morphology and human behavior
Authors: de Vlaming R. , Slob Eric A.W. , Jansen Philip R. , Dagher Alain , Koellinger Philipp D. , Groenen Patrick J.F. , Rietveld Cornelius A.
Published: April 2021

Human variation in brain morphology and behavior are related and highly heritable. Yet, it is largely unknown to what extent specific features of brain morphology and behavior are genetically related. Here, we introduce multivariate genomic-relatedness restricted maximum likelihood (MGREML) and provide estimates of the heritability of grey-matter volume in 74 regions of interest (ROIs) in the brain. We map genetic correlations between these ROIs and health-relevant behavioral outcomes including intelligence. We find four genetically distinct clusters in the brain that are aligned with standard anatomical subdivision in neuroscience. Behavioral traits have distinct genetic correlations with brain morphology which suggests trait-specific relevance of ROIs.
Ultrapotent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants
Authors: Li Tingting , Han Xiaojian , Gu Chenjian , Guo Hangtian , Zhang Huajun , Wang Yingming , Hu Chao , Wang Kai , Liu Fengjiang , Luo Feiyang , Zhang Yanan , Hu Jie , Wang Wang , Li Shenglong , Hao Yanan , Shen Meiying , Huang Jingjing , Long Yingyi , Song Shuyi , Wu Ruixin , Mu Song , Chen Qian , Gao Fengxia , Wang Jianwei , Long Shunhua , Li Luo , Wu Yang , Gao Yan , Xu Wei , Cai Xia , Qu Di , Zhang Zherui , Zhang Hongqing , Li Na , Gao Qingzhu , Zhang Guiji , He Changlong , Wang Wei , Ji Xiaoyun , Tang Ni , Yuan Zhenghong , Xie Youhua , Yang Haitao , Zhang Bo , Huang Ailong , Jin Aishun
Published: April 2021

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus displayed remarkable efficacy against authentic B.1.351 virus. Each of these 3 mAbs in combination with one neutralizing Ab recognizing non-competing epitope exhibited synergistic effect against authentic SARS-CoV-2 virus. Surprisingly, structural analysis revealed that 58G6 and 13G9, encoded by the IGHV1-58 and the IGKV3-20 germline genes, both recognized the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly bound to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrated prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. These 2 ultrapotent neutralizing Abs can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.
Spatial alignment between faces and voices improves selective attention to audio-visual speech
Authors: Fleming Justin T. , Maddox Ross K. , Shinn-Cunningham Barbara G.
Published: April 2021

The ability to see a talker’s face has long been known to improve speech intelligibility in noise. This perceptual benefit depends on approximate temporal alignment between the auditory and visual speech components. However, the practical role that cross-modal spatial alignment plays in integrating audio-visual (AV) speech remains unresolved, particularly when competing talkers are present. In a series of online experiments, we investigated the importance of spatial alignment between corresponding faces and voices using a paradigm that featured both acoustic masking (speech-shaped noise) and attentional demands from a competing talker. Participants selectively attended a Target Talker’s speech, then identified a word spoken by the Target Talker. In Exp. 1, we found improved task performance when the talkers’ faces were visible, but only when corresponding faces and voices were presented in the same hemifield (spatially aligned). In Exp. 2, we tested for possible influences of eye position on this result. In auditory-only conditions, directing gaze toward the distractor voice reduced performance as predicted, but this effect could not fully explain the cost of AV spatial misalignment. Finally, in Exp. 3 and 4, we show that the effect of AV spatial alignment changes with noise level, but this was limited by a floor effect: due to the use of closed-set stimuli, participants were able to perform the task relatively well using lipreading alone. However, comparison between the results of Exp. 1 and Exp. 3 suggests that the cost of AV misalignment is larger at high noise levels. Overall, these results indicate that spatial alignment between corresponding faces and voices is important for AV speech integration in attentionally demanding communication settings.
Ligands binding to the cellular prion protein induce its protective proteolytic release with therapeutic potential in neurodegenerative proteinopathies
Authors: Linsenmeier Luise , Mohammadi Behnam , Shafiq Mohsin , Frontzek Karl , Bär Julia , Shrivastava Amulya N. , Damme Markus , Schwarz Alexander , Da Vela Stefano , Massignan Tania , Jung Sebastian , Correia Angela , Schmitz Matthias , Puig Berta , Hornemann Simone , Zerr Inga , Tatzelt Jörg , Biasini Emiliano , Saftig Paul , Schweizer Michaela , Svergun Dimitri , Amin Ladan , Mazzola Federica , Varani Luca , Thapa Simrika , Gilch Sabine , Schätzl Hermann , Harris David A. , Triller Antoine , Mikhaylova Marina , Aguzzi Adriano , Altmeppen Hermann C. , Glatzel Markus
Published: April 2021

The cellular prion protein (PrPC) is a central player in neurodegenerative diseases caused by protein misfolding, such as prion diseases or Alzheimer’s disease (AD). Expression levels of this GPI-anchored glycoprotein, especially at the neuronal cell surface, critically correlate with various pathomechanistic aspects underlying these diseases, such as templated misfolding (in prion diseases) and neurotoxicity and, hence, with disease progression and severity. In stark contrast to cell-associated PrPC, soluble extracellular forms or fragments of PrP are linked with neuroprotective effects, which is likely due to their ability to interfere with neurotoxic disease-associated protein conformers in the interstitial fluid. Fittingly, the endogenous proteolytic release of PrPCby the metalloprotease ADAM10 (‘shedding’) was characterized as a protective mechanism. Here, using a recently generated cleavage-site specific antibody, we shed new light on earlier studies by demonstrating that shed PrP (sPrP) negatively correlates with conformational conversion (in prion disease) and is markedly redistributed in murine brain in the presence of prion deposits or AD-associated amyloid plaques indicating a blocking and sequestrating activity. Importantly, we reveal that administration of certain PrP-directed antibodies and other ligands results in increased PrP shedding in cells and organotypic brain slice cultures. We also provide mechanistic and structural insight into this shedding-stimulating effect. In addition, we identified a striking exception to this, as one particular neuroprotective antibody, due to its special binding characteristics, did not cause increased shedding but rather strong surface clustering followed by fast endocytosis and degradation of PrPC. Both mechanisms may contribute to the beneficial action described for some PrP-directed antibodies/ligands and pave the way for new therapeutic strategies against devastating and currently incurable neurodegenerative diseases.
Hierarchical Computational Anatomy: Unifying the Molecular to Tissue Continuum Via Measure Representations of the Brain
Authors: Miller Michael , Tward Daniel , Trouvé Alain
Published: April 2021

Objective

The objective of this research is to unify the molecular representations of spatial transcriptomics and cellular scale histology with the tissue scales of Computational Anatomy for brain mapping.

Impact statement

We present a unified representation theory for brain mapping based on geometric measures of the micro-scale phenotypes of molecular disease simultaneously with the connectomic scales of complex interacting brain circuits.

Introduction

Mapping across coordinate systems in computational anatomy allows us to understand structural and functional properties of the brain at the millimeter scale. New measurement technologies in digital pathology and spatial transcriptomics allow us to measure the brain molecule by molecule and cell by cell based on protein and transcriptomic identity. We currently have no mathematical representations for integrating consistently the tissue limits with the molecular particle descriptions. The formalism derived here demonstrates the methodology for transitioning consistently from the molecular scale of quantized particles – as first introduced by Dirac as the class of generalized functions – to the continuum and fluid mechanics scales appropriate for tissue.

Methods

We introduce two methods based on notions of generalized function geometric measures and statistical mechanics. We use generalized functions expanded to include functional geometric descriptions - electrophysiology, transcriptomic, molecular histology – to represent the molecular biology scale integrated with a Boltzman like procedure to pass from the sparse particles to empirical probability laws on the functional state of the tissue.

Results

We demonstrate a unified mapping methodology for transferring molecular information in the transcriptome and histological scales to the human atlas scales for understanding Alzheimer’s disease.

Conclusions

We demonstrate a unified brain mapping theory for molecular and tissue scales based on geometric measure representations.
Protective efficacy of an orf virus-vector encoding the hemmagglutinin and the nucleoprotein of influenza A virus in swine
Authors: Joshi Lok R. , Knudsen David , Pineyro Pablo , Dhakal Santhosh , Renukaradhya Gourapura J. , Diel Diego G.
Published: April 2021

Swine influenza is a highly contagious respiratory disease of pigs caused by influenza A viruses (IAV-S). IAV-S causes significant economic losses to the swine industry and poses constant challenges to public health due to its zoonotic potential. Thus effective IAV-S vaccines are highly desirable and would benefit both animal and human health. Here, we developed two recombinant orf viruses, expressing the hemagglutinin (HA) gene (OV-HA) or both the HA and the nucleoprotein (NP) genes of IAV-S (OV-HA-NP). The immunogenicity and protective efficacy of these two recombinant viruses were evaluated in pigs. Both OV-HA and OV-HA-NP recombinants elicited robust virus neutralizing antibody response in pigs. Notably, although both recombinant viruses elicited IAV-S-specific T-cell responses, the frequency of IAV-S specific proliferating T cells secreting IFN-γ upon re-stimulation was higher in OV-HA-NP-immunized animals than in the OV-HA group. Importantly, IgG1/IgG2 isotype ELISAs revealed that immunization with OV-HA induced Th2-biased immune responses, whereas immunization with OV-HA-NP virus resulted in a Th1-biased immune response. While pigs immunized with either OV-HA or OV-HA-NP were protected when compared to non-immunized controls, immunization with OV-HA-NP resulted in better protective efficacy as evidenced by reduced virus shedding in nasal secretions and reduced viral load in the lung. This study demonstrates the potential of ORFV-based vector for control of swine influenza virus in swine.

Importance

Effective influenza A virus (IAV-S) vaccines capable of providing robust protection to genetically diverse IAV-S in swine are lacking. Here, we explored the potential of orf virus based vectors expressing the hemagglutining (HA) or both the HA and the nucleoprotein (NP) genes of influena A virus (IAV-S) in eliciting protection against IAV-S in pigs. We observed that both recombinant viruses elicited IAV-S-specific humoral and cell-mediated immune responses in pigs. Addition of the NP and co-expression of this protein with HA, another major influenza protective antigen, resulted in higher T cell responses which presumably led to better protection in OV-HA-NP immunized animals, as evidenced by lower levels of virus shedding and viral load in lungs. This study highlights the the potential of ORFV as a vector platform for vaccine delivery against IAV-S. Results here provide the foundation for future development of broadly protective ORFV-based vectors for IAV-S for use in swine.
Cuticular hydrocarbons are associated with mating success and insecticide resistance in malaria vectors
Authors: Adams Kelsey L. , Sawadogo Simon P. , Nignan Charles , Niang Abdoulaye , Paton Douglas G. , Shaw W. Robert , South Adam , Wang Jennifer , Itoe Maurice A. , Werling Kristine , Dabiré Roch K. , Diabaté Abdoulaye , Catteruccia Flaminia
Published: April 2021

Anopheles coluzziifemales, important malaria vectors in Africa, mate only once in their lifetime. Mating occurs in aerial swarms with a high male-to-female ratio, where the traits underlying male mating success are largely unknown. Here, we investigated whether cuticular hydrocarbons (CHCs) influence mating success in natural mating swarms in Burkina Faso. As insecticides are widely used in this area for malaria control, we also determined whether CHCs affect insecticide resistance levels. We find that mated males have higher CHC abundance than unmated controls, suggesting CHCs could be a determinant of mating success. Additionally, mated males have higher insecticide resistance under pyrethroid challenge, and we show a link between resistance intensity and CHC abundance. Taken together, our results reveal overlapping roles played by CHCs in mate choice and insecticide resistance, and point to sexual selection for insecticide resistance traits that limit the efficacy of our best malaria control tools.
Pivotal role of PDE10A in the integration of dopamine signals in mice striatal D1 and D2 medium-sized spiny neurones
Authors: Mota Élia , Bompierre Ségolène , Betolngar Dahdjim , Castro Liliana R.V. , Vincent Pierre
Published: April 2021

Dopamine in the striatum plays a crucial role in reward processes and action selection. Dopamine signals are transduced by D1and D2dopamine receptors which trigger mirror effects through the cAMP/PKA signalling cascade in D1 and D2 medium-sized spiny neurones (MSNs). Phosphodiesterases (PDEs), which determine the profile of cAMP signals, are highly expressed in MSNs, but their respective roles in dopamine signal integration remain poorly understood. We used genetically-encoded FRET biosensors to monitor at the single cell level the functional contribution of PDE2A, PDE4 and PDE10A in the changes of the cAMP/PKA response to transient and continuous dopamine in mouse striatal brain slices. We found that PDE2A, PDE4 and PDE10A operate on the moderate to high cAMP levels elicited by D1or A2Areceptor stimulation. In contrast, only PDE10A is able to reduce cAMP down to baseline in both type of neurones, leading to the dephosphorylation of PKA substrates. PDE10A is therefore critically required for dopamine signal integration in both D1 and D2 MSNs.
Assessing the origins of the European Plagues following the Black Death: a synthesis of genomic, historical and ecological information
Authors: Bramanti Barbara , Wu Yarong , Yang Ruifu , Cui Yujun , Stenseth Nils Chr.
Published: April 2021

The Second Plague Pandemic started in Europe with the Black Death in 1346 and lasted until the 19thcentury. Based on ancient DNA studies, there is a scientific disagreement over whether the bacterium,Yersinia pestis, came into Europe once (Hypothesis 1), or repeatedly over the following four centuries (Hypothesis 2). Here we synthesize the most updated phylogeny together with historical, archeological, evolutionary and ecological information. On the basis of this holistic view, we conclude that Hypothesis 2 is the most plausible. We also suggest thatY. pestislineages might have developed attenuated virulence during transmission, which can explain the convergent evolutionary signals, includingpla-decay, that appeared at the end of the pandemics.

Significance Statement

Over the last few years there has been a great deal of scientific debate regarding whether the plague bacterium,Yersinia pestis, spread from a Western European reservoir during the Second Plague Pandemic, or if it repeatedly came to Europe from Asia. Here we make a synthesis of the available evidence, including genomes of ancient DNA, historical, archeological and ecological information. We conclude that the bacterium most likely came to Europe from Asia several times during the Second Plague Pandemic.
Unique metabolic strategies in Hadean analogues reveal hints for primordial physiology
Authors: Nobu Masaru Konishi , Nakai Ryosuke , Tamazawa Satoshi , Mori Hiroshi , Toyoda Atsushi , Ijiri Akira , Suzuki Shino , Kurokawa Ken , Kamagata Yoichi , Tamaki Hideyuki
Published: April 2021

Primordial microorganisms are postulated to have emerged in H2-rich alkaline Hadean serpentinite-hosted environments with homoacetogenesis as a core metabolism. However, investigation of two modern serpentinization-active analogues of early Earth reveals that conventional H2-/CO2-dependent homoacetogenesis is thermodynamically unfavorable in situ due to picomolar CO2 levels. Through metagenomics and thermodynamics, we discover unique taxa capable of metabolism adapted to the habitat. This included a novel deep-branching phylum, “Ca. Lithoacetigenota”, that exclusively inhabits Hadean analogues and harbors genes encoding alternative modes of H2-utilizing lithotrophy. Rather than CO2, these metabolisms utilize reduced carbon compounds detected in situ presumably serpentinization-derived: formate and glycine. The former employs a partial homoacetogenesis pathway and the latter a distinct pathway mediated by a rare selenoprotein – the glycine reductase. A survey of serpentinite-hosted system microbiomes shows that glycine reductases are diverse and nearly ubiquitous in Hadean analogues. “Ca. Lithoacetigenota” glycine reductases represent a basal lineage, suggesting that catabolic glycine reduction is an ancient bacterial innovation for gaining energy from geogenic H2 even under serpentinization-associated hyperalkaline, CO2-poor conditions. This draws remarkable parallels with ancestral archaeal H2-driven methyl-reducing methanogenesis recently proposed. Unique non-CO2-reducing metabolic strategies presented here may provide a new view into metabolisms that supported primordial life and the diversification of LUCA towards Archaea and Bacteria.
Antibody Conversion rates to SARS-CoV-2 in Saliva from Children Attending Summer Schools in Barcelona, Spain
Authors: Dobaño Carlota , Alonso Selena , Fernández de Sevilla Mariona , Vidal Marta , Jiménez Alfons , Tomas Gemma Pons , Jairoce Chenjerai , Melé Casas María , Rubio Rocío , Hernández García María , Ruiz-Olalla Gemma , Girona-Alarcón Mònica , Barrios Diana , Santano Rebeca , Mitchell Robert A. , Puyol Laura , Mayer Leonie , Chi Jordi , Melero Natalia Rodrigo , Carolis Carlo , Garcia-Miquel Aleix , Bonet-Carne Elisenda , Claverol Joana , Cubells Marta , Fortuny Claudia , Fumadó Victoria , Jou Cristina , Muñoz-Almagro Carmen , Izquierdo Luis , Bassat Quique , Gratacós Eduard , Aguilar Ruth , García-García Juan José , Moncunill Gemma , Jordan Iolanda
Published: April 2021

Surveillance tools to estimate infection rates in young populations are essential to guide recommendations for school reopening and management during viral epidemics. Ideally, field-deployable non-invasive, sensitive techniques are required to detect low viral load exposures among asymptomatic children. We determined SARS-CoV-2 antibody conversion by high-throughput Luminex assays in saliva samples collected weekly in 1,509 children and 396 adults in 22 Summer schools and 2 pre-schools in 27 venues in Barcelona, Spain, from June 29thto July 31st2020, between the first and second COVID-19 pandemic waves. Saliva antibody conversion defined as ≥4-fold increase in IgM, IgA and/or IgG levels to SARS-CoV-2 antigens between two visits over a 5-week period was 3.22% (49/1518), or 2.36% if accounting for potentially cross-reactive antibodies, six times higher than the cumulative infection rate (0.53%) by weekly saliva RT-PCR screening. IgG conversion was higher in adults (2.94%, 11/374) than children (1.31%, 15/1144) (p=0.035), IgG and IgA levels moderately increased with age, and antibodies were higher in females. Most antibody converters increased both IgG and IgA antibodies but some augmented either IgG or IgA, with a faster decay over time for IgA than IgG. Nucleocapsid rather than spike was the main antigen target. Anti-spike antibodies were significantly higher in individuals not reporting symptoms than symptomatic individuals, suggesting a protective role against COVID-19. To conclude, saliva antibody profiling including three isotypes and multiplexing antigens is a useful and more user-friendly tool for screening pediatric populations to determine SARS-CoV-2 exposure and guide public health policies during pandemics.
Activation of EGFR signaling by Tc-Vein and Tc-Spitz regulates the metamorphic transition in the red flour beetleTribolium castaneum
Authors: Chafino Sílvia , Martín David , Franch-Marro Xavier
Published: April 2021

Animal development relies on a sequence of specific stages that allow the formation of adult structures with a determined size. In general, juvenile stages are dedicated mainly to growth, whereas last stages are devoted predominantly to the maturation of adult structures. In holometabolous insects, metamorphosis marks the end of the growth period as the animals stops feeding and initiate the final differentiation of the tissues. This transition is controlled by the steroid hormone ecdysone produced in the prothoracic gland. In Drosophila different signals have been shown to regulate the production of ecdysone, such as PTTH/Torso, TGFß and Egfr signaling. However, to which extent the role of these signals is conserved remains unknown. Here, we study the role of Egfr signaling in post-embryonic development of the basal holometabolous beetleTribolium castaneum. We show thatTc-Egfr and Tc-pointedare required to induced a proper larval-pupal transition through the control of the expression of ecdysone biosynthetic genes. Furthermore, we identified an additional Tc-Egfr ligand in theTriboliumgenome, the neuregulin-like protein Tc-Vein (Tc-Vn), which contributes to induce larval-pupal transition together with Tc-Spitz (Tc-Spi). Interestingly, we found that in addition to the redundant role in the control of pupa formation, each ligand possesses different functions in organ morphogenesis. Whereas Tc-Spi acts as the main ligand in urogomphi and gin traps, Tc-Vn is required in wings and elytra. Altogether, our findings show that inTribolium, post-embryonic Tc-Egfr signaling activation depends on the presence of two ligands and that its role in metamorphic transition is conserved in holometabolous insects.
BET family members Bdf1/2 modulate global transcription initiation and elongation inSaccharomyces cerevisiae
Authors: Donczew Rafal , Hahn Steven
Published: April 2021

Human bromodomain-containing BET family members are promising targets for therapy of cancer and immunoinflammatory diseases, but their mechanisms of action and functional redundancies are poorly understood. Bdf1/2, yeast homologues of the human BET factors, were previously proposed to target transcription factor TFIID to acetylated histone H4, analogous to bromodomains that are present within the largest subunit of metazoan TFIID. We investigated the genome-wide roles of Bdf1/2 and found that their important contributions to transcription extend beyond TFIID function, as transcription of many genes is more sensitive to Bdf1/2 than to TFIID depletion. Bdf1/2 co-occupy the majority of yeast promoters and affect preinitiation complex formation through recruitment of TFIID, Mediator and basal transcription factors to chromatin. Surprisingly, we discovered that hypersensitivity of genes to Bdf1/2 depletion results from combined defects in transcription initiation and processive elongation, a striking functional similarity to human BET proteins, most notably Brd4. Our results establish Bdf1/2 as critical for yeast transcription and provide important mechanistic insights into the function of BET proteins in all eukaryotes.
A tomato prolyl-4-hydroxylase causes relocation of abscission zone and alters abscission kinetics
Authors: Perrakis Andreas , Denic Dusan , Blazakis Konstantinos N. , Giannoutsou Eleni , Kaloudas Dimitrios , Bita Craita E. , Rizou Myrto , Krokida Afrodite , Kouhen Mohamed , Lazaridou Athina , Mekkaoui Khansa , Belaidi Samia , Zein Zeina El , Khalil Mohab , Ezzat Lamia , Youssef Noureldine , Kosma Maria , González Anna G. , Monzer Aline , Papantoniou Dimitra , Varnava - Tello Antri , Bouzayen Mondher , Adamakis Ioannis-Dimosthenis S. , Driouich Azeddine , Billiaderis Costas G. , Kalogerakis Nicolas , Kalaitzis Panagiotis
Published: April 2021

The detachment of organs is controlled by highly regulated molecular mechanisms. The position of the tomato abscission zone (AZ) is defined by the ratio of the proximal to distal part of the pedicel. In this study, the ratio was altered due to a shift in the position of the AZ which was attributed to shorter and longer pedicels of SlP4H3 RNAi and OEX lines due to changes on cell division and expansion in AZ and distal part. This might be associated with LM2- and JIM8-AGPs which increased in OEX and decreased in RNAi lines throughout the pedicel. The JIM13 AGPs were downregulated in the flower AZ of OEX lines, pointing to a role on abscission regulation. In addition, Co-IP in flower AZ with SlP4H3-GFP fusion proteins showed interaction with LM2-, JIM13- and JIM8-epitopes suggesting proline hydroxylation by SlP4H3. The lower content of methyl-esterified HGs and higher of demethyl-esterified HGs in the AZs of RNAi lines might be responsible for increased rigidity of the AZ cell walls, accounting for the higher force required for AZ tissue detachment to occur. Moreover, ethylene-induced flower abscission was accelerated in the RNAi lines and delayed in OEX lines, while exactly the opposite response was observed in the red ripe fruit AZs. This was partly attributed to alterations in the expression of cell wall hydrolases. Overall, these results indicate that P4Hs might regulate molecular and structural features of cell walls in the AZ as well as abscission progression by regulating the structure and function of AGPs.

Sentence Summary

Alterations on the expression of tomato prolyl 4 hydroxylase 3 shifts the position of the pedicel abscission zone and alters ethylene induced abscission progression according to the developmental context of the pedicel.
Sentinel cells enable genetic detection of SARS-CoV-2 Spike protein
Authors: Weinberg Zara Y. , Hilburger Claire E. , Kim Matthew , Cao Longxing , Khalid Mir , Elmes Sarah , Diwanji Devan , Hernandez Evelyn , Lopez Jocelyne , Schaefer Kaitlin , Smith Amber M. , Zhou Fengbo ,   QCRG Structural Biology Consortium, Renuka Kumar G. , Ott Melanie , Baker David , El-Samad Hana
Published: April 2021

The COVID-19 pandemic has demonstrated the need for exploring different diagnostic and therapeutic modalities to tackle future viral threats. In this vein, we propose the idea of sentinel cells, cellular biosensors capable of detecting viral antigens and responding to them with customizable responses. Using SARS-CoV-2 as a test case, we developed a live cell sensor (SARSNotch) using a de novo-designed protein binder against the SARS-CoV-2 Spike protein. SARSNotch is capable of driving custom genetically-encoded payloads in immortalized cell lines or in primary T lymphocytes in response to purified SARS-CoV-2 Spike or in the presence of Spike-expressing cells. Furthermore, SARSNotch is functional in a cellular system used in directed evolution platforms for development of better binders or therapeutics. In keeping with the rapid dissemination of scientific knowledge that has characterized the incredible scientific response to the ongoing pandemic, we extend an open invitation for others to make use of and improve SARSNotch sentinel cells in the hopes of unlocking the potential of the next generation of smart antiviral therapeutics.
Oxygen depletion and nitric oxide stimulate type IV MSHA pilus retraction inVibrio choleraevia activation of the phosphodiesterase CdpA
Authors: Hughes Hannah Q. , Floyd Kyle A. , Hossain Sajjad , Anantharaman Sweta , Kysela David T. , Yu Yuanchen , Kappler Michael P. , Dalia Triana N. , Podicheti Ram C. , Rusch Douglas B. , Brun Yves V. , Jacobson Stephen C. , McKinlay James B. , Yildiz Fitnat H. , Boon Elizabeth M. , Dalia Ankur B.
Published: April 2021

Bacteria use surface appendages called type IV pili to perform diverse activities including DNA uptake, twitching motility, and attachment to surfaces. Dynamic extension and retraction of pili is often required for these activities, but the stimuli that regulate these dynamics remain poorly characterized. To study this question, we use the bacterial pathogenVibrio cholerae, which uses mannose-sensitive hemagglutinin (MSHA) pili to attach to surfaces in aquatic environments as the first step in biofilm formation. Here, we find thatV. choleraecells retract MSHA pili and detach from a surface in microaerobic conditions. This response is dependent on the phosphodiesterase CdpA, which decreases intracellular levels of cyclic-di-GMP (c-di-GMP) under microaerobic conditions to induce MSHA pilus retraction. CdpA contains a putative NO-sensing NosP domain, and we demonstrate that nitric oxide (NO) is necessary and sufficient to stimulate CdpA-dependent detachment. Thus, we hypothesize that microaerobic conditions result in endogenous production of NO (or an NO-like molecule) inV. cholerae. Together, these results describe a regulatory pathway that allowsV. choleraeto rapidly abort biofilm formation. More broadly, these results show how environmental cues can be integrated into the complex regulatory pathways that control pilus dynamic activity and attachment in bacterial species.
Spatially patterned excitatory neuron subtypes and circuits within the claustrum
Authors: Erwin Sarah R. , Bristow Brianna N. , Sullivan Kaitlin E. , Marriott Brian , Wang Lihua , Clements Jody , Lemire Andrew L. , Jackson Jesse , Cembrowski Mark S.
Published: April 2021

The claustrum is a functionally and structurally complex brain region, whose very spatial extent remains debated. Histochemical-based approaches typically treat the claustrum as a relatively narrow region that primarily projects to the neocortex, whereas circuit-based approaches suggest a broader region embedding neocortical and other neural circuits. Here, we took a bottom-up, cell-type-specific approach to complement and possibly unite these seemingly disparate conclusions. Using single-cell RNA-sequencing, we found that the claustrum is comprised of two excitatory neuron subtypes that are differentiable from the surrounding cortex. Multicolor retrograde tracing in conjunction with 12-channel multiplexedin situhybridization revealed a core-shell spatial arrangement of these subtypes, as well as differential projection targets. Thus, the claustrum is comprised of excitatory neuron subtypes with distinct molecular and circuit properties, whose spatial patterns reflect the narrower and broader claustral extents debated in previous research. This subtype-specific heterogeneity likely shapes the functional complexity of the claustrum.
Genetic characteristics of a small breeding population of ancient murrelets from Teuri Island, Japan, based on mitochondrial DNA sequences and newly‐developed microsatellite markers
Authors: Sugita Norimasa , Matsui Shin , Yoshikawa Natsuhiko , Nishiumi Isao
Published: April 2021

A small population of ancient murrelets (Synthliboramphus antiquus) nests and breeds on vertical sea cliffs in Teuri Island, Japan. Although this small population is at high risk of extinction, practical conservation plans were not established owing to the lack of basic data, for example, ecological and genetic information. Here, mitochondrial DNA and microsatellite analyses were performed on ancient murrelets collected in the Teuri and Aleutian breeding populations, as well as on wintering individuals in Japan and museum specimens. Mitochondrial DNA analysis revealed that the Teuri population shared haplotypes with the Aleutian population, but not with the British Columbian and the Kamchatka populations from a previous study. Microsatellite analysis revealed high gene flow between the Teuri and Aleutian breeding populations. There was no evidence of loss of genetic diversity in the Teuri population. Museum specimens possessed some unique alleles not found in the more recent samples. Our results suggest that strategies for the conservation of Teuri and Aleutian populations should be managed separately from those designed for breeding populations in the eastern Pacific region, at the very least. For conservation of the Teuri population, we do not recommend captive breeding because of gene flow between Teuri and Aleutian populations, but protection of nesting habitats and monitoring of demographic indexes would be more effective for maintaining their genetic diversity and population size.