bluuebunny/crossref_metadata_2025 huggingface dataset:
Strategic anti-SARS-CoV-2 serology testing in a low prevalence pandemic: The COVID-19 Contact (CoCo) Study in health care professionals
Authors: Behrens Georg , Cossmann Anne , Stankov Metodi V. , Schulte Bianca , Streeck Hendrik , Förster Reinhold , Bosnjak Berislav , Willenzon Stefanie , Boeck Anna-Lena , Tran Anh Thu , Thiele Thea , Graalmann Theresa , Kayser Moritz Z. , Scharff Anna Zychlinsky , Dopfer Christian , Horke Alexander , Pink Isabell , Witte Torsten , Wetzke Martin , Ernst Diana , Jablonka Alexandra , Happle Christine
Published: August 2020

Background

Serology testing is explored for epidemiological research and to inform individuals after suspected infection. During the COVID-19 pandemic, frontline healthcare professionals (HCP) may be at particular risk for infection. No longitudinal data on functional seroconversion in HCP in regions with low COVID-19 prevalence and low pre-test probability exist.

Methods

In a large German university hospital, we performed weekly questionnaire assessments and anti-SARS-CoV-2 IgG measurements with various commercial tests, a novel surrogate virus neutralization test, and a neutralization assay using live SARS-CoV-2.

Results

From baseline to week six, n=1,080 screening measurements for anti-SARS CoV-2 (S1) IgG from n=217 frontline HCP (65% female) were performed. Overall, 75.6% of HCP reported at least one symptom of respiratory infection. Self-perceived infection probability declined over time (from mean 20.1% at baseline to 12·4 % in week six, p<0.001). In sera of convalescent PCR-confirmed COVID-19 patients, we measured high anti-SARS-CoV-2 IgG levels, obtained highly concordant results from ELISAs using e.g. the S1 spike protein domain and the nucleocapsid protein (NCP) as targets, and confirmed antiviral neutralization. However, in HCP the cumulative incidence for anti-SARS-CoV-2 (S1) IgG was 1.86% for positive and 0.93% for equivocal positive results over the six week study period. Except for one HCP, none of the eight initial positive results were confirmed by alternative serology tests or showed in vitro neutralization against live SARS CoV-2. The only true seroconversion occurred without symptoms and mounted strong functional humoral immunity. Thus, the confirmed cumulative incidence for neutralizing anti-SARS-CoV-2 IgG was 0.47%.

Conclusion

When assessing anti-SARS-CoV-2 immune status in individuals with low pre-test probability, we suggest confirming positive results from single measurements by alternative serology tests or functional assays. Our data highlight the need for a methodical serology screening approach in regions with low SARS-CoV-2 infection rates.
Dynamics of neutralizing antibody titers in the months after SARS-CoV-2 infection
Authors: Crawford Katharine H.D. , Dingens Adam S. , Eguia Rachel , Wolf Caitlin R. , Wilcox Naomi , Logue Jennifer K. , Shuey Kiel , Casto Amanda M. , Fiala Brooke , Wrenn Samuel , Pettie Deleah , King Neil P. , Chu Helen Y. , Bloom Jesse D.
Published: August 2020

Most individuals infected with SARS-CoV-2 develop neutralizing antibodies that target the viral spike protein. Here we quantify how levels of these antibodies change in the months following SARS-CoV-2 infection by examining longitudinal samples collected between ~30 and 152 days post-symptom onset from a prospective cohort of 34 recovered individuals with asymptomatic, mild, or moderate-severe disease. Neutralizing antibody titers declined an average of about four-fold from one to four months post-symptom onset. This decline in neutralizing antibody titers was accompanied by a decline in total antibodies capable of binding the viral spike or its receptor-binding domain. Importantly, our data are consistent with the expected early immune response to viral infection, where an initial peak in antibody levels is followed by a decline to a lower plateau. Additional studies of long-lived B-cells and antibody titers over longer time frames are necessary to determine the durability of immunity to SARS-CoV-2.
The SARS-COV-2 outbreak around the Amazon rainforest: the relevance of the airborne transmission
Authors: Crema Edilson
Published: August 2020

Background

This paper presents a global analysis of the SARS-COV-2 outbreak in Brazil.

Amazonian States have a much higher contamination rate than the southern and southeastern States. So far, no explanation has been provided for this striking difference that can shed light on the airborne transmission of the virus.

Minimizing airborne transmission, health authorities recommend two meters as a safe distance. However, recent experiments reveal that this can be the main form of contagion. There is a lack of theoretical explanation on how airborne transmission works.

Methods

To investigate the spread of SARS-COV-2 in different macro environments, we analyzed the daily official data on the evolution of COVID-19 in Brazil. We compared our epidemiologic results obtained in States with very different climatic characteristics, and that had adopted, almost simultaneously, similar social isolation measures. To understand the virus spread, it was necessary to calculate theoretically the movement and behavior in the air of saliva droplets.

Findings

The transmission of SARS-COV-2 is much faster in the Amazon rainforest region.

Our theoretical calculations explain and support the empirical results observed in recent experiments that demonstrate the relevance of aerial transmission of the coronavirus.

Interpretation

An onset of collective immunity may have been achieved with a contamination rate of about 15% of the Amazonian population. If confirmed, this result will have an essential impact on the management of the pandemic across the planet.

The airborne transmission played a decisive role in the striking difference in the evolution of the pandemic among Brazilian regions.

Air humidity is the most important climatic factor in viral spreading, while usual ambient temperatures do not have strong influence.

There is no safe indoor distance for the coronavirus transmission. So, mask and eye protection are essential.
CRISPR-based and RT-qPCR surveillance of SARS-CoV-2 in asymptomatic individuals uncovers a shift in viral prevalence among a university population
Authors: Rauch Jennifer N. , Valois Eric , Ponce-Rojas Jose Carlos , Aralis Zach , Lach Ryan S. , Zappa Francesca , Audouard Morgane , Solley Sabrina C. , Vaidya Chinmay , Costello Michael , Smith Holly , Javanbakht Ali , Malear Betsy , Polito Laura , Comer Stewart , Arn Katherine , Kosik Kenneth S. , Acosta-Alvear Diego , Wilson Maxwell Z. , Fitzgibbons Lynn , Arias Carolina
Published: August 2020

The progress of the COVID-19 pandemic profoundly impacts the health of communities around the world, with unique effects on colleges and universities. Here, we examined the prevalence of SARS-CoV-2 in 1808 asymptomatic individuals on a university campus in California, and compared for the first time the performance of CRISPR- and PCR-based assays for large-scale virus surveillance. Our study revealed that there were no COVID-19 cases in our study population in May/June of 2020. Using the same methods, we demonstrated a substantial shift in prevalence approximately one month later, which coincided with changes in community restrictions and public interactions. This increase in prevalence, in a young and asymptomatic population, indicated the leading wave of a local outbreak, and reflected the rising case counts in the surrounding county. Our results substantiate that large, population-level asymptomatic screening using CRISPR- or PCR-based assays is a feasible and instructive aspect of the public health approach within large campus communities.
Outcome of Conservative Therapy in COVID-19 Patients Presenting with Gastrointestinal Bleeding
Authors: Shalimar DM , Vaishnav Manas , Elhence Anshuman , Kumar Ramesh , Mohta Srikant , Palle Chandan , Kumar Peeyush , Ranjan Mukesh , Vajpai Tanmay , Prasad Shubham , Yegurla Jatin , Dhooria Anugrah , Banyal Vikas , Agarwal Samagra , Bansal Rajat , Bhattacharjee Sulagna , Aggarwal Richa , Soni Kapil Dev , Rudravaram Swetha , Singh Ashutosh Kumar , Altaf Irfan , Choudekar Avinash , Mahapatra Soumya Jagannath , Gunjan Deepak , Kedia Saurabh , Makharia Govind , Trikha Anjan , Garg Pramod , Saraya Anoop
Published: August 2020

Background/Objective

There is a paucity of data on the management of gastrointestinal (GI) bleeding in patients with COVID-19 amid concerns about the risk of transmission during endoscopic procedures. We aimed to study the outcomes of conservative treatment for GI bleeding in patients with COVID-19.

Methods

In this retrospective analysis, 24 of 1342 (1.8%) patients with COVID-19, presenting with GI bleeding from 22 April to 22 July 2020, were included.

Results

The mean age of patients was 45.8±12.7 years; 17 (70.8%) were males; upper GI (UGI) bleeding: lower GI (LGI) 23:1. Twenty-two (91.6%) patients had evidence of cirrhosis-21 presented with UGI bleeding while one had bleeding from hemorrhoids. Two patients without cirrhosis were presumed to have non-variceal bleeding. The medical therapy for UGI bleeding included vasoconstrictors-somatostatin in 17 (73.9%) and terlipressin in 4 (17.4%) patients. All patients with UGI bleeding received proton pump inhibitors and antibiotics. Packed red blood cells (PRBCs), fresh frozen plasma and platelets were transfused in 14 (60.9%), 3 (13.0%) and 3 (13.0%), respectively. The median PRBCs transfused was 1 (0-3) unit(s). The initial control of UGI bleeding was achieved in all 23 patients and none required an emergency endoscopy. At 5-day follow-up, none rebled or died. Two patients later rebled, one had intermittent bleed due to gastric antral vascular ectasia, while another had rebleed 19 days after discharge. Three (12.5%) cirrhosis patients succumbed to acute hypoxemic respiratory failure during hospital stay.

Conclusion

Conservative management strategies including pharmacotherapy, restrictive transfusion strategy, and close hemodynamic monitoring can successfully manage GI bleeding in COVID-19 patients and reduce need for urgent endoscopy. The decision for proceeding with endoscopy should be taken by a multidisciplinary team after consideration of the patient’s condition, response to treatment, resources and the risks involved, on a case to case basis.
Patterns of population genomic diversity in the invasive Japanese knotweed species complex
Authors: VanWallendael Acer , Alvarez Mariano , Franks Steven J.
Published: August 2020

Premise

Invasive species are expected to experience a reduction in genetic diversity due to founder effects, which should limit their ability to adapt to new habitats. Still, many invasive species achieve widespread distributions and dense populations. This paradox of invasions could potentially be overcome through multiple introductions or hybridization, both of which increase genetic diversity. We conducted a population genomics study of Japanese knotweed (Reynoutria japonica), which is a polyploid, clonally reproducing invasive species that has been notoriously successful worldwide despite supposedly low genetic diversity.

Methods

We used Genotyping-by-Sequencing to collect 12,912 SNP markers from 88 samples collected at 38 locations across North America for the species complex. We used non-alignment based k-mer hashing analysis in addition to traditional population genetic analyses to account for the challenges of genotyping polyploids.

Results

Genotypes conformed to three genetic clusters, likely representing Japanese knotweed, Giant knotweed, and hybrid Bohemian knotweed. We found that, contrary to previous findings, the Japanese knotweed cluster had substantial genetic diversity, though it had no apparent genetic structure across the landscape. In contrast, Giant knotweed and hybrids showed distinct population groups. We did not find evidence of Isolation-by-Distance in the species complex, likely reflecting the stochastic introduction history of this species complex. Among species, we found no correlations between SNPs and several temperature- and precipitation-based climatic variables.

Conclusions

The results indicate that clonal invasive species can show substantial genetic diversity and can be successful at colonizing a variety of habitats without showing evidence of local adaptation or genetic structure.
Neurofeedback fMRI in the motor system elicits bi-directional changes in activity and white-matter structure in the healthy adult human brain
Authors: Sampaio-Baptista Cassandra , Neyedli Heather F. , Sanders Zeena-Britt , Diosi Kata , Havard David , Huang YunYing , Andersson Jesper L. R. , Lührs Michael , Goebel Rainer , Johansen-Berg Heidi
Published: August 2020

Neurofeedback can be used to alter brain activity and is therefore an attractive tool for neuromodulation in clinical contexts. Different contexts might call for different patterns of activity modulation. For example, following stroke, alternative therapeutic strategies could involve up or down-regulation of activity in the ipsilateral motor cortex. However, effects of such strategies on activity and brain structure are unknown. In a proof of concept study in healthy individuals, we showed that fMRI neurofeedback can be used to drive activity up or down in ipsilateral motor cortex during hand movement. Given evidence for activitydependent white matter plasticity, we also tested effects of activity modulation on white matter microstructure using diffusion tensor imaging (DTI). We show rapid opposing changes in corpus callosum microstructure that depend on the direction of activity modulation. Bidirectional modulation of ipsilateral motor cortex activity is therefore possible, and results not only in online changes in activity patterns, but also in changes in microstructure detectable 24 hours later.
Structural analysis of full-length SARS-CoV-2 spike protein from an advanced vaccine candidate
Authors: Bangaru Sandhya , Ozorowski Gabriel , Turner Hannah L. , Antanasijevic Aleksandar , Huang Deli , Wang Xiaoning , Torres Jonathan L. , Diedrich Jolene K. , Tian Jing-Hui , Portnoff Alyse D. , Patel Nita , Massare Michael J. , Yates John R. , Nemazee David , Paulson James C. , Glenn Greg , Smith Gale , Ward Andrew B.
Published: August 2020

Vaccine efforts against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the current COVID-19 pandemic are focused on SARS-CoV-2 spike glycoprotein, the primary target for neutralizing antibodies. Here, we performed cryo-EM and site-specific glycan analysis of one of the leading subunit vaccine candidates from Novavax based on a full-length spike protein formulated in polysorbate 80 (PS 80) detergent. Our studies reveal a stable prefusion conformation of the spike immunogen with slight differences in the S1 subunit compared to published spike ectodomain structures. Interestingly, we also observed novel interactions between the spike trimers allowing formation of higher order spike complexes. This study confirms the structural integrity of the full-length spike protein immunogen and provides a basis for interpreting immune responses to this multivalent nanoparticle immunogen.
Viromes outperform total metagenomes in revealing the spatiotemporal patterns of agricultural soil viral communities
Authors: Santos-Medellin Christian , Zinke Laura A. , ter Horst Anneliek M. , Gelardi Danielle L. , Parikh Sanjai J. , Emerson Joanne B.
Published: August 2020

Viruses are abundant yet understudied members of soil environments that influence terrestrial biogeochemical cycles. Here, we characterized the dsDNA viral diversity in biochar-amended agricultural soils at the pre-planting and harvesting stages of a tomato growing season via paired total metagenomes and viromes. Size fractionation prior to DNA extraction reduced sources of non-viral DNA in viromes, enabling the recovery of a vaster richness of viral populations (vOTUs), greater viral taxonomic diversity, broader range of predicted hosts, and better access to the rare virosphere, relative to total metagenomes, which tended to recover only the most persistent and abundant vOTUs. Of 2,961 detected vOTUs, 2,684 were recovered exclusively from viromes, while only three were recovered from total metagenomes alone. Both viral and microbial communities differed significantly over time, suggesting a coupled response to rhizosphere recruitment processes and nitrogen amendments. Viral communities alone were also structured along a spatial gradient. Overall, our results highlight the utility of soil viromics and reveal similarities between viral and microbial community dynamics throughout the tomato growing season yet suggest a partial decoupling of the processes driving their spatial distributions, potentially due to differences in dispersal, decay rates, and/or sensitivities to soil heterogeneity.
Optogenetic delivery of trophic signals in a genetic model of Parkinson’s disease
Authors: Inglés-Prieto Álvaro , Furthmann Nikolas , Crossman Samuel , Hoyer Nina , Petersen Meike , Zheden Vanessa , Biebl Julia , Reichhart Eva , György Attila , Siekhaus Daria , Soba Peter , Winklhofer Konstanze F. , Janovjak Harald
Published: August 2020

Optogenetics has been harnessed to shed new mechanistic light on current therapies and to develop future treatment strategies. This has been to date achieved by the correction of electrical signals in neuronal cells and neural circuits that are affected by disease. In contrast, the optogenetic delivery of trophic biochemical signals, which support cell survival and thereby may modify progression of degenerative disorders, has never been demonstrated in an animal disease model. Here, we reengineered the human andDrosophila melanogasterREarranged during Transfection (hRET and dRET) receptors to be activated by light, creating one-component optogenetic tools termed Opto-hRET and Opto-dRET. Upon blue light stimulation, these receptors robustly induced the MAPK/ERK proliferative signaling pathway in cultured cells. In PINK1B9flies that exhibit loss of PTEN-induced putative kinase 1 (PINK1), a kinase associated with familial Parkinson’s disease (PD), light activation of Opto-dRET suppressed mitochondrial defects, tissue degeneration and behavioral deficits. In human cells with PINK1 loss-of-function, mitochondrial fragmentation was rescued using Opto-dRETviathe PI3K/NF-кB pathway. Our results demonstrate that a light-activated receptor can ameliorate disease hallmarks in a genetic model of PD. The optogenetic delivery of trophic signals is cell type-specific and reversible and thus has the potential to overcome limitations of current strategies towards a spatio-temporal regulation of tissue repair.

Significance Statement

The death of physiologically important cell populations underlies of a wide range of degenerative disorders, including Parkinson’s disease (PD). Two major strategies to counter cell degeneration, soluble growth factor injection and growth factor gene therapy, can lead to the undesired activation of bystander cells and non-natural permanent signaling responses. Here, we employed optogenetics to deliver cell type-specific pro-survival signals in a genetic model of PD. InDrosophilaand human cells exhibiting loss of the PINK1 kinase, akin to autosomal recessive PD, we efficiently suppressed disease phenotypes using a light-activated tyrosine kinase receptor. This work demonstrates a spatio-temporally precise strategy to interfere with degeneration and may open new avenues towards tissue repair in disease models.
A novel method for tri-clustering dynamic functional network connectivity (dFNC) identifies significant schizophrenia effects across multiple states in distinct subgroups of individuals
Authors: Rahaman Md Abdur , Damaraju Eswar , Turner Jessica A. , van Erp Theo G.M. , Mathalon Daniel , Vaidya Jatin , Muller Bryon , Pearlson Godfrey , Calhoun Vince D.
Published: August 2020

Background

Brain imaging data collected from individuals are highly complex with unique variation; however, such variation is typically ignored in approaches that focus on group averages or even supervised prediction. State-of-the-art methods for analyzing dynamic functional network connectivity (dFNC) subdivide the entire time course into several (possibly overlapping) connectivity states (i.e., sliding window clusters). Though, such an approach does not factor in the homogeneity of underlying data and may end up with a less meaningful subgrouping of the dataset.

Methods

Dynamic-N-way tri-clustering (dNTiC) incorporates a homogeneity benchmark to approximate clusters that provide a more apples-to-apples comparison between groups within analogous subsets of time-space and subjects. dNTiC sorts the dFNC states by maximizing similarity across individuals and minimizing variance among the pairs of components within a state.

Results

Resulting tri-clusters show significant differences between schizophrenia (SZ) and healthy control (HC) in distinct brain regions. Compared to HC, SZ in most tri-clusters show hypoconnectivity (low positive) among subcortical, default mode, cognitive control but hyper-connectivity (high positive) between sensory networks. In tri-cluster 3, HC subjects show significantly stronger connectivity among sensory networks and anticorrelation between subcortical and sensory networks compared to SZ. Results also provide statistically significant difference in reoccurrence time between SZ and HC subjects for two distinct dFNC states.

Conclusions

Outcomes emphasize the utility of the proposed method for characterizing and leveraging variance within high-dimensional data to enhance the interpretability and sensitivity of measurements in the study of a heterogeneous disorder like schizophrenia and in unconstrained experimental conditions such as resting fMRI.
Modeling Parent-Specific Genetic Nurture in Families with Missing Parental Genotypes: Application to Birthweight and BMI
Authors: Tubbs Justin D. , Hwang Liang-Dar , Luong Justin , Evans David M. , Sham Pak C.
Published: August 2020

Disaggregation and estimation of genetic effects from offspring and parents has long been of interest to statistical geneticists. Recently, technical and methodological advances have made the genome-wide and loci-specific estimation of direct offspring and parental genetic nurture effects more possible. However, unbiased estimation using these methods requires datasets where both parents and at least one child have been genotyped, which are relatively scarce. Our group has recently developed a method and accompanying software (IMPISH; Hwang et al., 2020) which is able to impute missing parental genotypes from observed data on sibships and estimate their effects on an offspring phenotype conditional on the effects of genetic transmission. However, this method is unable to disentangle maternal and paternal effects, which may differ in magnitude and direction. Here, we introduce an extension to the original IMPISH routine which takes advantage of all available nuclear families to impute parent-specific missing genotypes and obtain asymptotically unbiased estimates of genetic effects on offspring phenotypes. We apply this this method to data from related individuals in the UK Biobank, showing concordance with previous estimates of maternal genetic effects on offspring birthweight. We also conduct the first GWAS jointly estimating offspring-, maternal-, and paternal-specific genetic effects on body mass index.
The mutational load in natural populations is significantly affected by high primary rates of retroposition
Authors: Zhang Wenyu , Xie Chen , Ullrich Kristian , Zhang Yong E. , Tautz Diethard
Published: August 2020

Gene retroposition is known to contribute to patterns of gene evolution and adaptations. However, possible negative effects of gene retroposition remain largely unexplored, since most previous studies have focussed on between-species comparisons where negatively selected copies are mostly not observed, as they are quickly lost from the populations. Here, we show for natural house mouse populations that the primary rate of retroposition is orders of magnitude higher than previously thought. Comparisons with SNP distribution patterns in the same populations show that most retroposition events are deleterious. Transcriptomic profiling analysis shows that new retroposed copies become easily subject to transcription and have an influence on the expression level of their parental genes, especially when transcribed in the antisense direction. Our results imply that the impact of retroposition on the mutational load in natural populations has been highly underestimated, which has also implications for strategies of disease allele detection in humans.

Significance statement

The phenomenon or retroposition (re-integration of reverse transcribed RNA into the genome), has been well studied in comparisons between genomes and has been identified as a source of evolutionary innovation. However, the negative effects of retroposition have been overlooked so far. Our study makes use of a unique population genomic dataset from natural mouse populations. It shows that the retroposition rate is magnitudes higher than previously suspected. We show that most of the newly transposed retrocopies have a deleterious impact through modifying the expression of their parental genes. In humans, this effect is expected to cause disease alleles and we propose that genetic screening needs to take into account the search for newly transposed retrocopies.
Increased oscillatory power in a computational model of the olfactory bulb due to synaptic degeneration
Authors: Berry J. Kendall , Cox Daniel
Published: August 2020

Several neurodegenerative diseases impact the olfactory system, and in particular the olfactory bulb, early in disease progression. One mechanism by which damage occurs is via synaptic dysfunction. Here, we implement a computational model of the olfactory bulb and investigate the effect of weakened connection weights on network oscillatory behavior. Olfactory bulb network activity can be modeled by a system of equations that describes a set of coupled nonlinear oscillators. In this modeling framework, we propagate damage to synaptic weights using several strategies, varying from localized to global. Damage propagated in a dispersed or spreading manner leads to greater oscillatory power at moderate levels of damage. This increase arises from a higher average level of mitral cell activity due to a shift in the balance between excitation and inhibition. That this shift leads to greater oscillations critically depends on the nonlinearity of the activation function. Linearized analysis of the network dynamics predicts when this shift leads to loss of oscillatory activity. We thus demonstrate one potential mechanism involved in the increased gamma oscillations seen in some animal models of Alzheimer’s disease and highlight the potential that pathological olfactory bulb behavior presents as an early biomarker of disease.
Prime editing primarily induces undesired outcomes in mice
Authors: Aida Tomomi , Wilde Jonathan J. , Yang Lixin , Hou Yuanyuan , Li Mengqi , Xu Dongdong , Lin Jianbang , Qi Peimin , Lu Zhonghua , Feng Guoping
Published: August 2020

Genome editing has transformed biomedical science, but is still unpredictable and often induces undesired outcomes. Prime editing (PE) is a promising new approach due to its proposed flexibility and ability to avoid unwanted indels. Here, we show highly efficient PE-mediated genome editing in mammalian zygotes. Utilizing chemically modified guideRNAs, PE efficiently introduced 10 targeted modifications including substitutions, deletions, and insertions across 6 genes in mouse embryos. However, we unexpectedly observed a high frequency of undesired outcomes such as large deletions and found that these occurred more often than pure intended edits across all of the edits/genes. We show that undesired outcomes result from the double-nicking PE3 strategy, but that omission of the second nick largely ablates PE function. However, sequential double-nicking with PE3b, which is only applicable to a fraction of edits, eliminated undesired outcomes. Overall, our findings demonstrate the promising potential of PE for predictable, flexible, and highly efficientin vivogenome editing, but highlight the need for improved variations of PE before it is ready for widespread use.
Molecular motion and tridimensional nanoscale localization of kindlin control integrin activation in focal adhesions
Authors: Orré Thomas , Karatas Zeynep , Kastberger Birgit , Cabriel Clément , Böttcher Ralph T. , Lévêque-Fort Sandrine , Sibarita Jean-Baptiste , Fässler Reinhard , Wehrle-Haller Bernhard , Rossier Olivier , Giannone Grégory
Published: August 2020

Abstract

Focal adhesions (FAs) initiate chemical and mechanical signals involved in cell polarity, migration, proliferation and differentiation. Super-resolution microscopy revealed that FAs are organized at the nanoscale into functional layers from the lower plasma membrane to the upper actin cytoskeleton. Yet, how FAs proteins are guided into specific nano-layers to promote interaction with given targets is unknown. Using single protein tracking, super-resolution microscopy and functional assays, we linked the molecular behavior and tridimensional nanoscale localization of kindlin with its function in integrin activation inside FAs. We show that immobilization of integrins in FAs depends on interaction with kindlin. Unlike talin, kindlin displayed free diffusion along the plasma membrane outside and inside FAs. We demonstrate that the kindlin Pleckstrin Homology domain promotes membrane diffusion and localization to the membrane-proximal integrin nano-layer, necessary for kindlin enrichment and function in FAs. Using kindlin-deficient cells, we show that kindlin membrane localization and diffusion are crucial for integrin activation during cell adhesion and spreading. Thus, kindlin uses a different route than talin to reach and activate integrins, providing a possible molecular basis for their complementarity during integrin activation.
Moving toward versus away from another: how body motion direction changes the representation of bodies and actions in the visual cortex
Authors: Bellot Emmanuelle , Abassi Etienne , Papeo Liuba
Published: August 2020

Representing multiple agents and their mutual relations is a prerequisite to understand social events. Using functional MRI on human adults, we show that visual areas dedicated to body-form and body-motion perception contribute to processing social events, by holding the representation of multiple moving bodies and encoding the spatial relations between them. In particular, seeing animations of human bodies facing and moving toward (vs. away from) each other, increased neural activity in the body-selective cortex (extrastriate body area -EBA) and posterior superior temporal sulcus for biological-motion perception (bm-pSTS). In those areas, representation of body postures and movements, as well as of the overall scene, was more accurate for facing-body (vs. non-facing body) stimuli. Effective connectivity analysis with Dynamic Causal Modeling revealed increased coupling between EBA and bm-pSTS during perception of facing-body stimuli. The attunement of human vision to multiple-body scenes involving perceptual cues of interaction such as face-to-face positioning and approaching behaviour, was further supported by the participants’ better performance in a match-to-sample task with facing-bodyvs. non-facing body stimuli. Thus, visuo-spatial cues of interaction in multiple-person scenarios affect the perceptual representation of body and body motion and, by promoting functional integration, streamline the process from body perception to action representation.
Task-dependent vocal adjustments to optimize biosonar-based information acquisition
Authors: Lewanzik Daniel , Goerlitz Holger R.
Published: August 2020

Animals need to acquire adequate and sufficient information to guide movements, yet information acquisition and processing is costly. Animals thus face a trade-off between gathering too little and too much information and, accordingly, actively adapt sensory input through motor control. Echolocating animals provide the unique opportunity to study the dynamics of adaptive sensing in naturally behaving animals, since every change in the outgoing echolocation signal directly affects information acquisition and the perception of the dynamic acoustic scene. Here we investigated the flexibility with which bats dynamically adapt information acquisition depending on a task. We recorded the echolocation signals of wild-caught Western barbastelle bats (Barbastella barbastellus) while flying through an opening, drinking on the wing, landing on a wall, and capturing prey. We show that the echolocation signal sequences during target approach differed in a task-dependent manner; bats started target approach earlier and increased information update rate more when the task became increasingly difficult, and bats also adjusted dynamics of call duration shortening and peak frequency shifts accordingly. These task-specific differences existed from the onset of object approach, implying that bats plan their sensory-motor program for object approach exclusively based on information received from search call echoes. We provide insights into how echolocating animals deal with the constraints they face when sequentially sampling the world through sound by adjusting acoustic information flow from slow to extremely fast in a highly dynamic manner. Our results further highlight the paramount importance of high behavioural flexibility for acquiring information.

Summary statement

Having the right information for a specific job is crucial. Echolocating bats flexibly and independently adjust different call parameters to match the sensory-motor challenges of four different tasks.
The microtubule organization in the zebrafish yolk adapts to transgene-mediated phenotypic variations
Authors: Marsal Maria , Bernardello Matteo , Gualda Emilio J. , Loza-Alvarez Pablo
Published: August 2020

The organization of microtubule networks in the cells is orchestrated by subcellular structures named microtubule organizing centers (MTOCs). In zebrafish embryos, the yolk is surrounded by a cytoplasmic layer containing a vast network of microtubules. In order to understand how this complex network is organized, we use dclk2-GFP zebrafish embryos, as a microtubule reporter line, and Light Sheet Fluorescence Microscopy. We find that this organization is mediated by a variable number of aster-like MTOCs during epiboly, and that it does not follow a rigid scheme, exemplifying developmental robustness. We characterize asters morphology, dynamics, and their uniform distribution in the yolk sphere. Consistent with their role as MTOCs we find that they contain key molecular machinery for MTs dynamics, amongst which centrin marks the assignation of MTOCs over time. Finally, we demonstrate that merely the overexpression of dclk2-GFP in wild type embryos can induce the formation of asters. We propose dclk2-GFP embryos as a model for the study of the collective behaviour of microtubules in complex systems.
A simulation study of the use of temporal occupancy for identifying core and transient species
Authors: Snell Taylor Sara , Coyle Jessica R. , White Ethan P. , Hurlbert Allen H.
Published: August 2020

Transient species, which do not maintain self-sustaining populations in a system where they are observed, are ubiquitous in nature and their presence often impacts the interpretation of ecological patterns and processes. Identifying transient species from temporal occupancy, the proportion of time a species is observed at a given site over a time series, is subject to classification errors as a result of imperfect detection and source-sink dynamics. We use a simulation-based approach to assess how often errors in detection or classification occur in order to validate the use of temporal occupancy as a metric for inferring whether a species is a core or transient member of a community. We found that low detection increases error in the classification of core species, while high habitat heterogeneity and high detection increase error in classification of transient species. These findings confirm that temporal occupancy is a valid metric for inferring whether a species can maintain a self-sustaining population, but imperfect detection, low abundance, and highly heterogeneous landscapes may yield high misclassification rates.
Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors
Authors: Osipiuk Jerzy , Azizi Saara-Anne , Dvorkin Steve , Endres Michael , Jedrzejczak Robert , Jones Krysten A. , Kang Soowon , Kathayat Rahul S. , Kim Youngchang , Lisnyak Vladislav G. , Maki Samantha L. , Nicolaescu Vlad , Taylor Cooper A. , Tesar Christine , Zhang Yu-An , Zhou Zhiyao , Randall Glenn , Michalska Karolina , Snyder Scott A. , Dickinson Bryan C. , Joachimiak Andrzej
Published: August 2020

The number of new cases world-wide for the COVID-19 disease is increasing dramatically, while efforts to contain Severe Acute Respiratory Syndrome Coronavirus 2 is producing varied results in different countries. There are three key SARS-CoV-2 enzymes potentially targetable with antivirals: papain-like protease (PLpro), main protease (Mpro), and RNA-dependent RNA polymerase. Of these, PLpro is an especially attractive target because it plays an essential role in several viral replication processes, including cleavage and maturation of viral polyproteins, assembly of the replicase-transcriptase complex (RTC), and disruption of host viral response machinery to facilitate viral proliferation and replication. Moreover, this enzyme is conserved across different coronaviruses and promising inhibitors have already been discovered for its SARS-CoV variant. Here we report a substantive body of structural, biochemical, and virus replication studies that identify several inhibitors of the enzyme from SARS-CoV-2 in both wild-type and mutant forms. These efforts include the first structures of wild-type PLpro, the active site C111S mutant, and their complexes with inhibitors, determined at 1.60–2.70 Angstroms. This collection of structures provides fundamental molecular and mechanistic insight to PLpro, and critically, illustrates details for inhibitors recognition and interactions. All presented compounds inhibit the peptidase activity of PLproin vitro, and some molecules block SARS-CoV-2 replication in cell culture assays. These collated findings will accelerate further structure-based drug design efforts targeting PLpro, with the ultimate goal of identifying high-affinity inhibitors of clinical value for SARS-CoV-2.
Modified base-binding EVE and DCD Domains Implicated in the Origins of Programmed Cell Death and the piRNA Pathway
Authors: Bell Ryan T. , Wolf Yuri I. , Koonin Eugene V.
Published: August 2020

Background

DNA and RNA of most cellular life forms and many viruses contain an expansive repertoire of modified bases. The modified bases play diverse biological roles that include both regulation of transcription and translation, and protection against restriction endonucleases and antibiotics. Modified bases are often recognized by dedicated protein domains. However, the elaborate networks of interactions and processes mediated by modified bases are far from being completely understood.

Results

We present a comprehensive census and classification of EVE domains that belong to the PUA/ASCH domain superfamily and bind various modified bases in DNA and RNA. Prokaryotes encode two classes of EVE domain proteins, slow-evolving and fast-evolving. The slow-evolving EVE domains in α-proteobacteria are embedded in a conserved operonic context that implies involvement in coupling between translation and respiration, in particular, cytochrome c biogenesis, potentially, via binding 5-methylcytosine in tRNAs. In β and γ-proteobacteria, the conserved associations implicate the EVE domains in the coordination of cell division, biofilm formation, and global transcriptional regulation by non-coding 6S small RNAs, which are potentially modified and bound by the EVE domains. Down-regulation of the EVE-encoding operons might cause dormancy or programmed cell death (PCD). In eukaryotes, the EVE-domain-containing THYN1-like proteins appear to inhibit PCD and regulate the cell cycle, likely, via binding 5-methylcytosine and its derivatives in DNA and/or RNA. Thus, the link between PCD and cytochrome c that appears to be universal in eukaryotes might have been inherited from the α-proteobacterial, proto-mitochondrial endosymbiont and, unexpectedly, could involve modified base recognition by EVE domains. In numerous prokaryotic genomes, fast-evolving EVE domains are embedded in defense contexts, including toxin-antitoxin modules and Type IV restriction systems, all of which can also induce PCD. These EVE domains likely recognize modified bases in invading DNA molecules and target them for restriction. We additionally identified EVE-like prokaryotic Development and Cell Death (DCD) domains that are also implicated in defense functions including PCD. This function was inherited by eukaryotes but, in animals, the DCD proteins apparently were displaced by the extended Tudor family, whose partnership with Piwi-related Argonautes became the centerpiece of the piRNA system.

Conclusions

Recognition of modified bases in DNA and RNA by EVE-like domains appears to be an important, but until now, under-appreciated, common denominator in a variety of processes including PCD, cell cycle control, antivirus immunity, stress response and germline development in animals.
An ancient, conserved gene regulatory network led to the rise of oral venom systems
Authors: Barua Agneesh , Mikheyev Alexander S.
Published: August 2020

Oral venom systems evolved multiple times in numerous vertebrates enabling exploitation of unique predatory niches. Yet how and when they evolved remains poorly understood. Up to now, most research on venom evolution has focussed strictly on the toxins. However, using toxins present in modern day animals to trace the origin of the venom system is difficult, since they tend to evolve rapidly, show complex patterns of expression, and were incorporated into the venom arsenal relatively recently. Here we focus on gene regulatory networks associated with the production of toxins in snakes, rather than the toxins themselves. We found that overall venom gland gene expression was surprisingly well conserved when compared to salivary glands of other amniotes. We characterised the ‘meta-venom’, a network of approximately 3000 non-secreted housekeeping genes that are strongly co-expressed with the toxins, and are primarily involved in protein folding and modification. Conserved across amniotes, this network was co-opted for venom evolution by exaptation of existing members and the recruitment of new toxin genes. For instance, starting from this common molecular foundation,Helodermalizards, shrews, and solenodon, evolved venoms in parallel by overexpression of kallikreins, which were common in ancestral saliva and induce vasodilation when injected, causing circulatory shock. Derived venoms, such as those of snakes, incorporated novel toxins, though still rely on hypotension for prey immobilization. These similarities suggest repeated co-option of shared molecular machinery for the evolution of oral venom in mammals and reptiles, blurring the line between truly venomous animals and their ancestors.
SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade
Authors: Romero Octavio A. , Vilarrubi Andrea , Alburquerque-Bejar Juan J. , Gomez Antonio , Andrades Alvaro , Trastulli Deborah , Pros Eva , Verdura Sara , Farré Lourdes , Martín-Tejera Juan F. , Llabata Paula , Oaknin Ana , Saigi Maria , Piulats Josep M. , Matias-Guiu Xavier , Medina Pedro P. , Vidal August , Villanueva Alberto , Sanchez-Cespedes Montse
Published: August 2020

Despite the genetic inactivation ofSMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activatedMYConcogene, cells withSMARCA4inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. This is associated with impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, which confer a strong dependency on the KDM6s in theSMARCA4-mutant cells, so that its inhibition compromises cell viability. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted withSMARCA4-mutant lung cancer cells or primary small cell carcinoma of the hypercalcaemic type (SCCOHT) had strong anti-tumour effects. Our results highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treatingSMARCA4-mutant cancer patients.
Structural (at 100 K) and DFT studies of 2′-nitroflavone
Authors: Oskolkov Evgenii , Kornilova Tatiana , Chavez Preciosa America , Tillotson John P. , Timofeeva Tatiana V.
Published: August 2020

The geometry of the title molecule [systematic name: 2-(2-nitrophenyl)-4H-chromen-4-one], C15H9NO4, is determined by two dihedral angles formed by the mean plane of phenyl ring with the mean planes of chromone moiety and nitro group, being 50.73 (5) and 30.89 (7)°, respectively. The crystal packing is determined by π–π interactions and C—H...O contacts. The results of DFT calculations at the B3LYP/6–31G* level of theory provided an explanation of the unusually large dihedral angle between the chromone moiety and the phenyl group. The electrostatic potential map on the molecular surface was calculated in order to determine the potential binding sites to receptors.
Psychedelic substance use in the Reddit psychonaut community. A qualitative study on motives and modalities
Authors: Pestana Jani , Beccaria Franca , Petrilli Enrico
Published: August 2020

Purpose

The purpose of this paper is to investigate motives and modalities of psychedelic substance use in the psychonaut community that is hosted on the Reddit platform (r/psychonaut). Psychonauts are sometimes described as responsible drug users. Elements of responsible use include sharing stories, advice and experiences, reagent testing substances, proper dosing and education on harm reduction and its practical implication. Investigating psychonauts’ substance use can highlight what responsible use means for them and could inform best practices for psychedelic use.

Design/methodology/approach

Qualitative content analysis of posts and comments on the r/psychonaut subreddit was completed. In total, 350 posts were investigated. A combination of deductive and inductive methods was used to both structure the research and to allow room for novel information. To investigate participant’s motives, this combination was used to both collect and analyse the data. To examine modalities, concepts and keywords were formed out of the collected data and then analysed.

Findings

Motives for use ranged from self-knowledge, self-investigation and self-medication to increasing artistic expression, curiosity and recreation. Concerning modalities, the respondents put a high emphasis on preparation, set and setting, integration, dosage and gathering and sharing information through research, articles and trip reports. These features are identified in the literature as elements of responsible drug use. This investigation can help by unearthing best practices already in use by the community to inform the bourgeoning movement of psychedelic substance use – both in a medical and self-reflexive setting.

Originality/value

This paper is framed in the context of paucity of the academic literature on people taking psychedelic substances in Western society in non-rave and non-medical settings, with findings that indicate important change happening in the psychonaut subculture.