bluuebunny/crossref_metadata_2025 huggingface dataset:
Behavioural diversity of bonobo prey preference as a potential cultural trait
Authors: Samuni L. , Wegdell F. , Surbeck M.
Published: June 2020

The importance of cultural processes to behavioural diversity, especially in our closest living relatives, is central for revealing the evolutionary origins of human culture. Whereas potential cultural traits are extensively investigated in chimpanzees, our other closest living relative, the bonobo, is often overlooked as a candidate model. Further, a prominent critique to many examples of proposed animal cultures is premature exclusions of environmental confounds known to shape behavioural phenotypes. We addressed these gaps by investigating variation in prey preference expression between neighbouring bonobo groups that associate and share largely overlapping home ranges. We find specific group preference for duiker or anomalure hunting that are otherwise unexplained by variation in spatial usage of hunt locations, seasonality or sizes of hunting parties. Our findings demonstrate that group-specific behaviours emerge independently of the local ecology, indicating that hunting techniques in bonobos may be culturally transmitted. We suggest that the tolerant intergroup relations of bonobos offer an ideal context to explore drivers of behavioural phenotypes, the essential investigations for phylogenetic constructs of the evolutionary origins of culture.
Comparing the electrophysiology and morphology of human and mouse layer 2/3 pyramidal neurons with Bayesian networks
Authors: Mihaljević Bojan , Larrañaga Pedro , Bielza Concha
Published: June 2020

Pyramidal neurons are the most common neurons in the cerebral cortex. Understanding how they differ between species is a key challenge in neuroscience. We compared human temporal cortex and mouse visual cortex pyramidal neurons from the Allen Cell Types Database in terms of their electrophysiology and basal dendrites’ morphology. We found that, among other differences, human pyramidal neurons had a higher threshold voltage, a lower input resistance, and a larger basal dendritic arbor. We learned Gaussian Bayesian networks from the data in order to identify correlations and conditional independencies between the variables and compare them between the species. We found strong correlations between electrophysiological and morphological variables in both species. One result is that, in human cells, dendritic arbor width had the strongest effect on input resistance after accounting for the remaining variables. Electrophysiological variables were correlated, in both species, even with morphological variables that are not directly related to dendritic arbor size or diameter, such as mean bifurcation angle and mean branch tortuosity. Contrary to previous results, cortical depth was correlated with both electrophysiological and morphological variables, and its effect on electrophysiological could not be explained in terms of the morphological variables. Overall, the correlations among the variables differed strikingly between human and mouse neurons. Besides identifying correlations and conditional independencies, the learned Bayesian networks might be useful for probabilistic reasoning regarding the morphology and electrophysiology of pyramidal neurons.
Neuromotor impairment, hearing loss and blindness in a preclinical mouse model of Charcot Marie-Tooth disorder
Authors: Gonzalez-Gonzalez Sergio , Cazevieille Chantal
Published: June 2020

Schwann cells produce myelin sheath around peripheral nerve axons. Myelination is critical for rapid propagation of action potentials, as illustrated by the large number of acquired and hereditary peripheral neuropathies, such as diabetic neuropathy or Charcot-Marie-Tooth (CMT) diseases, that are commonly associated with a process of demyelination. Peripheral neuropathy is a major complication of diabetes, and the pathomechanism of the disease remains poorly studied. Here, we studied the progressive demyelinating process, hearing impairment and blindness observed in the CMT1A mouse model C3. Our results confirm that these mice represent a robust and validated model to study the peripheral neuropathy induced by CMT disorder allowing to determine the efficacy of new pharmacological candidates targeting demyelinating diseases such as CMT1A disorder.
Microbiota control of maternal behavior regulates early postnatal growth of offspring
Authors: Lee Yujung Michelle , Wallace Martina , Gengatharan Jivani M. , Furst Annalee J. , Bode Lars , Metallo Christian M. , Ayres Janelle S.
Published: June 2020

Maternal-offspring bonding and maturation of maternal behavior is necessary during the early postnatal period of an infant to promote optimal development and growth. The regulation of maternal behavior is multifactorial relying both on sensory cues including auditory and olfactory signals emitted by the infant and received by the mother, as well as proper neuroendocrine responses including that of the oxytocin system. The intestinal microbiota has emerged as a critical regulator of growth and development in the early postnatal period of an individual’s life. While, this is best appreciated in the context of direct interactions between the microbiota and the infant, the microbiota can indirectly influence postnatal growth and development by regulating maternal factors. Here, we describe the identification of an intestinalE. colistrain that is pathogenic to the maternal-offspring system during the early postnatal stage of life and results in growth stunting of the offspring. However, rather than having a direct pathogenic effect on the infant, we found that this particularE. colistrain was pathogenic to the dams by interfering with the maturation of maternal behavior. The poor maternal behavior resulted in malnourishment of the pups and impaired IGF-1 signaling leading to the consequential stunted growth. Our work provides a new understanding of how the microbiota regulates postnatal growth and an additional variable that must be considered when studying the regulation of maternal behavior.
Simulating the Impact of Glenohumeral Capsulorrhaphy on Movement Kinematics and Muscle Function in Activities of Daily Living
Authors: Fox Aaron S. , Gill Stephen D. , Bonacci Jason , Page Richard S.
Published: June 2020

This study aimed to use a predictive simulation framework to examine shoulder kinematics, muscular effort and task performance during functional upper limb movements under simulated selective glenohumeral capsulorrhaphy. A musculoskeletal model of the torso and upper limb was adapted to include passive restraints that simulated the changes in shoulder range of motion stemming from selective glenohumeral capsulorrhaphy procedures (anteroinferior, anterosuperior, posteroinferior, posterosuperior, and total anterior, inferior, posterior and superior). Predictive muscle-driven simulations of three functional movements (upward reach, forward reach and head touch) were generated with each model. Shoulder kinematics (elevation, elevation plane and axial rotation), muscle cost (i.e. muscular effort) and task performance time were compared to a baseline model to assess the impact of the capsulorrhaphy procedures. Minimal differences in shoulder kinematics and task performance times were observed, suggesting that task performance could be maintained across the capsulorrhaphy conditions. Increased muscle cost was observed under the selective capsulorrhaphy conditions, however this was dependent on the task and capsulorrhaphy condition. Larger increases in muscle cost were observed under the capsulorrhaphy conditions that incurred the greatest reductions in shoulder range of motion (i.e. total inferior, total anterior, anteroinferior and total posterior conditions) and during tasks that required shoulder kinematics closer to end range of motion (i.e. upward reach and head touch). The elevated muscle loading observed could present a risk to joint capsule repair. Appropriate rehabilitation following glenohumeral capsulorrhaphy is required to account for the elevated demands placed on muscles, particularly when significant range of motion loss presents.
Estimating Microbial Interaction Network:Zero-inflated Latent Ising Model Based Approach
Authors: Zhou Jie , Viles Weston D. , Lu Boran , Li Zhigang , Madan Juliette C. , Karagas Margaret R. , Gui Jiang , Hoen Anne G.
Published: June 2020

Motivation

Throughout their lifespans, humans continually interact with the microbial world, including those organisms which live in and on the human body. Research in this domain has revealed the extensive links between the human-associated microbiota and health. In particular, the microbiota of the human gut plays essential roles in digestion, nutrient metabolism, immune maturation and homeostasis, neurological signaling, and endocrine regulation. Microbial interaction networks are frequently estimated from data and are an indispensable tool for representing and understanding the relationships among the microbes of a microbiota. In this high-dimensional setting, the zero-inflated and compositional data structure (subject to unit-sum constraint) pose challenges to the accurate estimation of microbial interaction networks.

Method

We propose thezero-inflated latent Ising(ZILI) model for microbial interaction network which assumes that the distribution of relative abundance of microbiota is determined by finite latent states. This assumption is partly supported by the existing findings in literature [20]. The ZILI model can circumvents the unit-sum constraint and alleviates the zero-inflation problem under given assumptions. As for the model selection of ZILI, a two-step algorithm is proposed. ZILI and two-step algorithm are evaluated through simulated data and subsequently applied in our investigation of an infant gut microbiome dataset from New Hampshire Birth Cohort Study. The results are compared with results from traditional Gaussian graphical model (GGM) and dichotomous Ising model (DIS).

Results

Through the simulation studies, provided that the ZILI model is the true generative model for the data, it is shown that the two-step algorithm can estimate the graphical structure effectively and is robust to a range of alternative settings of the related factors. Both GGM and DIS can not achieve a satisfying performance in these settings. For the infant gut microbiome dataset, we use both ZILI and GGM to estimate microbial interaction network. The final estimated networks turn out to share a statistically significant overlap in which the ZILI and two-step algorithm tend to select the sparser network than those modeled by GGM. From the shared subnetwork, a hub taxon Lachnospiraceae is identified whose involvement in human disease development has been discovered recently in literature.

Availability

The data and programs involved in Section 4 and 5 are available on request from the correspondence author.

Contact

Anne.G.Hoen@dartmouth.edu

Supplementary information

Supplementary materials are available atBioinformatics
Molecular Basis of Far-red Sensing in Cyanobacteriochrome
Authors: Bandara Sepalika , Rockwell Nathan , Zeng Xiaoli , Ren Zhong , Wang Cong , Shin Heewhan , Martin Shelley S. , Moreno Marcus V. , Lagarias J. Clark , Yang Xiaojing
Published: June 2020

Cyanobacteriochromes are small, panchromatic photoreceptors in the phytochrome superfamily that regulate diverse light-mediated adaptive processes in cyanobacteria. The molecular basis of far-red (FR) light perception by cyanobacteriochromes is currently unknown. Here we report the crystal structure of a far-red-sensing cyanobacteriochrome fromAnabaena cylindricaPCC 7122, which exhibits a reversible far-red/orange photocycle. The 2.7 Å structure of its FR-absorbing dark state, determined by room temperature serial crystallography and cryo-crystallography, reveals anall-Z,synconfiguration of its bound linear tetrapyrrole (bilin) chromophore that is less extended than the bilin chromophores of all known phytochromes. Based on structural comparisons with other bilin-binding proteins and extensive spectral analyses on mutants, we identify key protein-chromophore interactions that enable far-red sensing in bilin-binding proteins. We propose that FR-CBCRs employ two distinct tuning mechanisms, which work together to produce a large batho-chromatic shift. Findings of this work have important implications for development and improvement of photoproteins with far-red absorption and fluorescence.

Significance Statement

Phytochromes are well known far-red-light sensors found in plants that trigger adaptive responses to facilitate competition for light capture with neighboring plants. Red- and far-red-sensing are critical to cyanobacteria living in the far-red-enriched shade of plants. Here we report the crystal structure of a far-red-sensing cyanobacteriochrome, a distant cyanobacterial relative of phytochrome. These studies shed insight into the poorly understood molecular basis of far-red-sensing by phytobilin-based photoreceptors. Owing to the deep tissue penetration of far-red light, far-red-sensing photoreceptors offer promising protein scaffolds for developing gene-based photoswitches, optoacoustic contrast agents and fluorescent probes forin situimaging and optogenetic applications.
Identification of repurposable cytoprotective drugs for Vanishing White Matter Disease
Authors: Ng Neville , Cabral-da-Silva Mauricio Castro , Maksour Simon , Berg Tracey , Engel Martin , Silva Dina M. , Do-Ha Dzung , Lum Jeremy S. , Muñoz Sonia Sanz , Suarez-Bosche Nadia , Stevens Claire H. , Ooi Lezanne
Published: June 2020

Vanishing white matter disease (VWMD) is a rare leukodystrophy involving loss of function mutations of the guanine exchange factor eIF2B and typically presenting with juvenile onset. We aimed to identify repurposable FDA approved drugs in anin vitrodrug screen using patient-derived fibroblasts and induced pluripotent stem cell (iPSC)-derived astrocytes. Dysregulated GADD34 and CHOP were identified in patient fibroblasts and iPSC-derived astrocytes under proteasomal stress conditions. A drug screen from a 2400 FDA approved drug library withEIF2B5disease patient fibroblasts identified 113 anti-inflammatory drugs as a major class of hits with cytoprotective effects. A panel of potential candidate drugs including berberine, deflazacort, ursodiol, zileuton, guanabenz and Anavex 2-73, and preclinical ISRIB, increased cell survival of MG132-stressedEIF2B2andEIF2B5disease VWMD astrocytes, and were further investigated for their effect on the integrated stress response and mitochondrial stress. ISRIB but not other drugs significantly affected eIF2α phosphorylation and GADD34 expression. Ursodiol demonstrated capacity to reduce complex I subunit upregulation, ameliorate oxidative stress, loss of mitochondrial membrane potential and upregulation of eIF2B subunits in VWMD astrocytes, highlighting its potential as a cytoprotective compound for VWMD.
Learning Peptide Recognition Rules for a Low-Specificity Protein
Authors: Wheeler Lucas C. , Perkins Arden , Wong Caitlyn E. , Harms Michael J.
Published: June 2020

Many proteins interact with short linear regions of target proteins. For some proteins, however, it is difficult to identify a well-defined sequence motif that defines its target peptides. To overcome this difficulty, we used supervised machine learning to train a model that treats each peptide as a collection of easily-calculated biochemical features rather than as an amino acid sequence. As a test case, we dissected the peptide-recognition rules for human S100A5 (hA5), a low-specificity calcium binding protein. We trained a Random Forest model against a recently released, high-throughput phage display dataset collected for hA5. The model identifies hydrophobicity and shape complementarity, rather than polar contacts, as the primary determinants of peptide binding specificity in hA5. We tested this hypothesis by solving a crystal structure of hA5 and through computational docking studies of diverse peptides onto hA5. These structural studies revealed that peptides exhibit multiple binding modes at the hA5 peptide interface—all of which have few polar contacts with hA5. Finally, we used our trained model to predict new, plausible binding targets in the human proteome. This revealed a fragment of the protein α-1-syntrophin binds to hA5. Our work helps better understand the biochemistry and biology of hA5, as well as demonstrating how high-throughput experiments coupled with machine learning of biochemical features can reveal the determinants of binding specificity in low-specificity proteins.
The Role of Swab Tests to Decrease the Stress by COVID-19 on the Health System using AI, MLR & Statistical Analysis
Authors: Pirouz Behzad , Nejad Hana Javadi , Violini Galileo , Pirouz Behrouz
Published: June 2020

The outbreak of the new Coronavirus (COVID-19) pandemic has prompted investigations on various aspects. This research aims to study the possible correlation between the numbers of swab tests and confirmed cases of infection, with special attention to the sickness level. The study is carried out with reference to the Italian case, but the result is of more general importance, in particular for countries with limited availability of ICUs (intensive care units). The statistical analysis shows correlation between the number of swab tests and those of daily positive cases, mild cases admitted to hospital, intensive care cases, recovery, and death rate, and provides a basis to carry on an AI study. The results were validated using a multivariate linear regression (MLR) approach. Our main result is the identification of a significant statistical effect of reduction of the pressure on the Health system as result of the increase of the tests. The relevance of this result is not confined to the COVID-19 outbreak, because the high demand of hospitalizations and ICU treatments due to this pandemic has an indirect effect on the possibility of guaranteeing an adequate treatment for other high-fatality disease, such as e.g. cardiological, and oncological. Our results show that swab testing may play a major role to decrease the stress on the Health system of a country. Therefore, this case study is relevant in particular for the planning of the control of the pandemic in countries with a limited capacity of admission to ICU’s units.
The Relationship Between COVID-19 Infection and Risk Perception, Knowledge, Attitude As Well As Four Non-pharmaceutical Interventions (NPIs) During the Late Period Of The COVID-19 Epidemic In China – An Online Cross-sectional Survey of 8158 Adults
Authors: Xu Hong , Gan Yong , Zheng Daikun , Wu Bo , Zhu Xian , Xu Chang , Liu Chenglu , Tao Zhou , Hu Yaoyue , Chen Min , Li Mingjing , Lu Zuxun , Chen Jack
Published: June 2020

Background

So far, there has been no published population study on the relationship between COVID-19 infection and public’s risk perception, information source, knowledge, attitude and four non-pharmaceutical interventions(NPI: hand washing, proper coughing habits, social distancing and mask wearing) during the COVID-19 outbreak in China.

Methods

An online survey of 8158 Chinese adults between 22 February to 5 March 2020 was conducted. Bivariate associations between categorical variables were examined using Fisher exact test. We also explored the determinants of four NPIs as well as their association with COVID-19 infection using logistic regression.

Results

Of 8158 adults included, 57 (0.73%) were infected with COVID-19. The overwhelming majority of respondents showed a positive attitude (99.2%), positive risk perception (99.9%) and high knowledge levels that were among the strongest predictors of four highly adopted NPIs (hand washing:96.8%; proper coughing: 93.1%; social distancing:87.1%; mask wearing:97.9%). There was an increased risk of COVID-19 infection for those who not washing hands (2.28% vs 0.65%; RR=3.53: 95%CI: 1.53-8.15; P<0.009); not practicing proper coughing (1.79% vs 0.73%; RR=2.44: 95%CI: 1.15-5.15;P=0.026); not practicing social distancing (1.52% vs 0.58%; RR=2.63:95%CI:1.48 – 4.67; P=0.002); and not wearing a mask (7.41% vs 0.6%; RR=12.38:95%CI:5.81-26.36; P<0.001). For those who did practice all other three NPIs, wearing mask was associated with significantly reduced risk of infection compared to those who did not wear a mask (0.6% vs 16.7%; p=0.035). Similarly, for those who did not practice all or part of the other three NPIs, wearing mask was also associated with significantly reduced risk of infection. In a penalised logistic regression model including all four NPIs, wearing a mask was the only significant predictor of COVID-19 infection among four NPIs (OR=7.20; 95%CI:2.24-23.11; p<0.001).

Conclusions

We found high levels of risk perception, positive attitude, desirable knowledge as well as a high level of adopting four NPIs. The relevant knowledge, risk perception and attitude were strong predictors of adapting the four NPIs. Mask wearing, among four personal NPIs, was the most effective protective measure against COVID-19 infection with added preventive effect among those who practised all or part of the other three NPIs.
Purification of age-distinct insulin secretory granules through antigen restriction
Authors: Neukam Martin , Sala Pia , Brunner Andreas-David , Ganß Katharina , Palladini Alessandra , Grzybek Michal , Vasiljević Jovana , Broichhagen Johannes , Johnsson Kai , Kurth Thomas , Mann Matthias , Coskun Ünal , Solimena Michele
Published: June 2020

Endocrine cells employ regulated exocytosis of secretory granules to secrete hormones and neurotransmitters. The competence of secretory granules for exocytosis depends on spatio-temporal variables such as proximity to the plasma membrane and age, with newly-generated granules being preferentially released. Despite recent advances, we still lack a comprehensive view about the molecular composition of insulin granules and how this may change over the lifetime of the organelles. Here we report a strategy for the purification of insulin secretory granules of distinct age from insulinoma INS-1 cells. Tagging the granule-resident protein phogrin with a cleavable CLIP tag, we obtained intact fractions of age-distinct granules for proteomic and lipidomic analyses. We find that the lipid composition changes over time along with the physical properties of the membrane.
Lipin-1 regulates lipid catabolism in pro-resolving macrophages
Authors: Schilke Robert M. , Blackburn Cassidy M.R. , Rao Shashanka , Krzywanski David , Finck Brian N. , Woolard Matthew D.
Published: June 2020

Macrophages reprogram their metabolism to promote appropriate responses. Pro-resolving macrophages primarily utilize fatty acid oxidation as an energy source. Metabolites generated during the catabolism of fatty acids aid in the resolution of inflammation and tissue repair, but the regulatory mechanisms that control lipid metabolism in macrophages is not fully elucidated. In this current study we show that lipin-1, a phosphatidic acid phosphatase and regulator of lipid metabolism, is required for increased oxidative phosphorylation during IL-4 mediated responses. We also show that the transcriptional coregulatory function of lipin-1 is required for β-oxidation in response to palmitate (free fatty acid) and apoptotic cell derived lipids. BMDMs lacking lipin-1 have a reduction in critical TCA cycle metabolites following IL-4 stimulation, suggesting a break in the TCA cycle that is supportive of lipid synthesis rather than lipid catabolism. Together, our data demonstrate that lipin-1 regulates intermediary metabolism within pro-resolving macrophages and highlights the importance of aligning macrophage metabolism with proper responses to stimuli.
Modelling live fuel moisture content at leaf and canopy scale under extreme drought using a lumped plant hydraulic model
Authors: Martin-StPaul N , Ruffault J , Blackmann C , Cochard H , De Cáceres M , Delzon S , Dupuy JL , Fargeon H , Lamarque L , Moreno M , Parsell R , Pimont F , Ourcival JM , Torres-Ruiz J , Limousin JM
Published: June 2020

Water content in living vegetation (or live fuel moisture content, LFMC), is increasingly recognized as a key factor linked to vegetation mortality and wildfire ignition and spread. Most often, empirical indices are used as surrogates for direct LFMC measurements.

In this paper, we explore the functional and ecophysiological drivers of LFMC during drought at the leaf and canopy scale using the SurEau-Ecos model, and a three years dataset of leaf and canopy scale measurements on a matureQuercus ilexforest, including an extreme drought. The model is based on forest hydrology and plant hydraulics and allows to simulate temporal variations of water potential and content at a daily time step. At leaf level, it simulates the relationship between water potential and water content by separating the apoplasm and the symplasm. Symplasm water content is modeled using the pressure volume curve theory, and apoplasm water content is modelled using the xylem vulnerability to cavitation. Fuel moisture content was upscaled to the canopy level by accounting for foliage mortality estimated from drought induced cavitation.

The model was parameterized either with site-measured traits or using a calibration procedure, and compared with water potential and LFMC measured at leaf level, and NDVI variation measured at canopy level and taken as a surrogate for foliage mortality.

At leaf level, LFMC prediction using measured hydraulic traits could be improved by considering year-to-year osmotic adjustments. At canopy level, foliage mortality due to drought induced cavitation was a key driver of LFMC decline during the most extreme drought.

A sensitivity analysis showed that parameters driving soil water balance (leaf area index, soil water capacity, and regulation of transpiration) and parameters determining pressure volume curves are key traits driving LFMC dynamics at leaf level. At the canopy level, parameters that drives hydraulic failure were the most sensitive and included, both soil water balance parameters and hydraulic traits (the leaf vulnerability to cavitation) were the main drivers of LFMC decline during extreme drought.

We also showed that under normal historic weather conditions, most variation of LFMC are linked to reversible symplasm dehydration, however under future, hotter and dryer conditions, most variations are due to the decline canopy of LFMC driven by foliage mortality.
Chromatin Mechanics Dictates Subdiffusion and Coarsening Dynamics of Embedded Condensates
Authors: Lee Daniel S.W. , Wingreen Ned S. , Brangwynne Clifford P.
Published: June 2020

DNA is organized into chromatin, a complex polymeric material which stores information and controls gene expression. An emerging mechanism for biological organization, particularly within the crowded nucleus, is biomolecular phase separation into condensed droplets of protein and nucleic acids. However, the way in which chromatin impacts the dynamics of phase separation and condensate formation is poorly understood. Here, we utilize a powerful optogenetic strategy to examine the interplay of droplet coarsening with the surrounding viscoelastic chromatin network. We demonstrate that droplet growth dynamics are directly inhibited by the chromatin-dense environment, which gives rise to an anomalously slow coarsening exponent,β∼0.12, contrasting with the classical prediction ofβ∼ 1/3. Using scaling arguments and simulations, we show how this arrested growth can arise due to subdiffusion of individual condensates, predictingβ∼α/3, where α is the diffusion exponent. Tracking the fluctuating motion of condensates within chromatin reveals a subdiffusive exponent, α∼0.5, which explains the anomalous coarsening behavior and is also consistent with Rouse-like dynamics arising from the entangled chromatin. Our findings have implications for the biophysical regulation of the size and shape of biomolecular condensates, and suggest that condensate emulsions can be used to probe the viscoelastic mechanical environment within living cells.
Naturally occurring SARS-CoV-2 gene deletions close to the spike S1/S2 cleavage site in the viral quasispecies of COVID19 patients
Authors: Andres Cristina , Garcia-Cehic Damir , Gregori Josep , Piñana Maria , Rodriguez-Frias Francisco , Guerrero-Murillo Mercedes , Esperalba Juliana , Rando Ariadna , Goterris Lidia , Codina Maria Gema , Quer Susanna , Martín Maria Carmen , Campins Magda , Ferrer Ricard , Almirante Benito , Esteban Juan Ignacio , Pumarola Tomás , Antón Andrés , Quer Josep
Published: June 2020

The SARS-CoV-2 spike (S) protein, the viral mediator for binding and entry into the host cell, has sparked great interest as a target for vaccine development and treatments with neutralizing antibodies. Initial data suggest that the virus has low mutation rates, but its large genome could facilitate recombination, insertions, and deletions, as has been described in other coronaviruses. Here, we deep-sequenced the complete SARS-CoV-2Sgene from 18 patients (10 with mild and 8 with severe COVID-19), and found that the virus accumulates deletions upstream and very close to the S1/S2 cleavage site, generating a frameshift with appearance of a stop codon. These deletions were found in a small percentage of the viral quasispecies (2.2%) in samples from all the mild and only half the severe COVID-19 patients. Our results suggest that the virus may generate free S1 protein released to the circulation. We propose that natural selection has favored a “Don’t burn down the house” strategy, in which free S1 protein may compete with viral particles for the ACE2 receptor, thus reducing the severity of the infection and tissue damage without losing transmission capability.
Mutations inBBS2Cause Apparent Nonsyndromic Retinitis Pigmentosa
Authors: DeBenedictis Meghan , Fogerty Joseph , Pauer Gayle , Chiang John , Hagstrom Stephanie A. , Traboulsi Elias I. , Perkins Brian D.
Published: June 2020

Purpose

To identify and functionally test the causative mutations in theBBS2gene in a family presenting with retinitis pigmentosa and infertility and to generate abbs2−/−mutant zebrafish.

Methods

A female proband and her male sibling were clinically evaluated and genetic testing with targeted next-generation sequencing was performed. Mutations were verified by Sanger sequencing. Protein localization was examined by transient expression and immunocytochemistry in cultured HEK-293T cells. Mutations in the zebrafishbbs2gene were generated by CRISPR/Cas9 and retinal phenotypes were examined by immunohistochemistry.

Results

The proband and her brother exhibited reduced visual fields, retinal degeneration, and bone spicule deposits, consistent with retinitis pigmentosa. The brother also reported symptoms consistent with infertility. Compound heterozygous mutations in theBBS2gene; namely NM_031885.4 (BBS2):c.823C>T (p.R275X) and NM_031885.4 (BBS2):c.401C>G (p.P134R), were identified in the proband and her brother. Both mutations interfered with ciliary localization of Bbs2 in cell culture. Mutation of the zebrafishbbs2gene resulted in progressive cone degeneration and rhodopsin mislocalization.

Conclusion

Missense mutations ofBBS2leads to non-syndromic retinitis pigmentosa, but not Bardet-Biedl Syndrome, even though Bbs2 fails to localize to cilia. In zebrafish, the complete loss ofbbs2results in cone degeneration and ciliopathy phenotypes, indicating a requirement for Bbs2 in photoreceptor survival.
TGN/EE SNARE protein SYP61 is ubiquitinated and required for carbon/nitrogen-nutrient responses in Arabidopsis
Authors: Hasegawa Yoko , Reyes Thais Huarancca , Uemura Tomohiro , Fujimaki Akari , Luo Yongming , Morita Yoshie , Saeki Yasushi , Baral Anirban , Maekawa Shugo , Yasuda Shigetaka , Mukuta Koki , Fukao Yoichiro , Tanaka Keiji , Nakano Akihiko , Bhalerao Rishikesh P. , Sato Takeo , Yamaguchi Junji
Published: June 2020

Ubiquitination is a post-translational modification with reversible attachment of the small protein ubiquitin, which is involved in numerous cellular processes including membrane trafficking. For example, ubiquitination of cargo proteins is known to regulate their subcellular dynamics, and plays important roles in plant growth and stress adaptation. However, the regulatory mechanism of the trafficking machinery components remains elusive. Here, we report Arabidopsistrans-Golgi network/early endosome (TGN/EE) localized solubleN-ethylmaleimide sensitive factor attachment protein receptor (SNARE) protein SYP61 as a novel ubiquitination target of a membrane localized ubiquitin ligase ATL31. SYP61 is a key component of membrane trafficking in Arabidopsis. SYP61 was ubiquitinated with K63-linked chain by ATL31in vitroand in plants. The knockdown mutants ofSYP61were hypersensitive to the disrupted carbon (C)/nitrogen (N)-nutrient stress, suggesting its critical role in plant homeostasis in response to nutrients. We also found the ubiquitination status of SYP61 is affected by C/N-nutrient availability. These results provided possibility that ubiquitination of SNARE protein has important role in plant physiology.
Direct and indirect regulation of Pom1 cell size pathway by the protein phosphatase 2C Ptc1
Authors: Gerganova Veneta , Bhatia Payal , Martin Sophie G
Published: June 2020

The fission yeast cellsSchizosaccharomyces pombedivide at constant cell size regulated by environmental stimuli. An important pathway of cell size control involves the membrane-associated DYRK-family kinase Pom1, which forms decreasing concentration gradients from cell poles and inhibits mitotic inducers at mid-cell. Here, we identify the phosphatase 2C Ptc1 as negative regulator of Pom1. Ptc1 localizes to cell poles in a manner dependent on polarity and cell-wall integrity factors. We show that Ptc1 directly binds Pom1 and can dephosphorylate it in vitro but modulates Pom1 localization indirectly upon growth in low glucose conditions by influencing microtubule stability. Thus, Ptc1 phosphatase plays both direct and indirect roles in the Pom1 cell size control pathway.
Proteogenomics analysis of CUG codon translation in the human pathogenCandida albicans
Authors: Mühlhausen Stefanie , Schmitt Hans Dieter , Plessmann Uwe , Mienkus Peter , Sternisek Pia , Perl Thorsten , Weig Michael , Urlaub Henning , Bader Oliver , Kollmar Martin
Published: June 2020

Candidayeasts causing human infections are spread across the yeast phylum withCandida glabratabeing related toSaccharomyces cerevisiae, Candida kruseigrouping toPichia spp., andCandida albicans, Candida parapsilosisandCandida tropicalisbelonging to the CTG-clade. The latter lineage contains yeasts with an altered genetic code translating CUG codons as serine using a serine-tRNA with a mutated anticodon. It has been suggested that the CTG-clade CUG codons are mistranslated to a small extent as leucine due to mischarging of the serine-tRNA(CAG). The mistranslation was suggested to result in variable surface proteins explaining fast host adaptation and pathogenicity. Here, we re-assessed this potential mistranslation by high-resolution mass spectrometry-based proteogenomics of multiple CTG-clade yeasts, variousC. albicansstrains, isolated from colonized and from infected human body sites, andC. albicansgrown in yeast and hyphal forms. Ourin vivodata do not support CUG codon mistranslation by leucine. Instead, (i) CUG codons are mistranslated only to the extent of ribosomal mistranslation with no preference for specific amino acids, (ii) CUG codons are as unambiguous (or ambiguous) as the related CUU leucine and UCC serine codons, (iii) tRNA anticodon loop variation across the CTG-clade yeasts does not result in any difference of the mistranslation level, and (iv) CUG codon unambiguity is independent ofC. albicans’ strain pathogenicity or growth form.
Distinct gene expression profiles in leukocortical demyelinated white and grey matter areas of Multiple Sclerosis patients
Authors: van Wageningen T.A. , Gerrits E. , Geleijnse A. , Brouwer N. , Geurts J.J.G. , Eggen B.J.L. , Boddeke H.W.G.M. , van Dam A-M.
Published: June 2020

Demyelination of the CNS is a prominent pathological hallmark of Multiple Sclerosis (MS) and affects both white (WM) and grey matter (GM). However, demyelinated WM and GM areas exhibit clear pathological differences, most notably the presence or absence of inflammation and activated glial cells in WM and GM, respectively. In order to gain more insight into the differential pathology of demyelinated WM and GM areas, we micro-dissected neighbouring WM and GM demyelinated areas as well as normal appearing matter from leukocortical lesions of human post-mortem material and used these samples for RNA-sequencing. Our data show that even neighbouring WM and GM demyelinated areas share only 10% overlap in gene expression, implying a distinct gene expression profile, which is extending to a specific glial cell related signature. We propose that, based on their distinct expression profile, pathological processes in neighbouring WM and GM are likely different which could have implications for the efficacy of current MS treatments.
Antagonism Between Brain Regions Relevant for Cognitive Control and Emotional Memory Facilitates the Generation of Humorous Ideas
Authors: Bitsch Florian , Berger Philipp , Fink Andreas , Nagels Arne , Straube Benjamin , Falkenberg Irina
Published: June 2020

The ability to generate humor gives rise to positive emotions and thus facilitate the successful resolution of adversity. Although there is consensus that inhibitory processes might be related to broaden the way of thinking, the neural underpinnings of these mechanisms are largely unknown. Here, we use functional Magnetic Resonance Imaging, a humorous alternative uses task and a stroop task, to investigate the brain mechanisms underlying the emergence of humorous ideas in 24 subjects. Neuroimaging results indicate that greater cognitive control abilities are associated with increased activation in the amygdala, the hippocampus and the superior and medial frontal gyrus during the generation of humorous ideas. Examining the neural mechanisms more closely shows that the downregulation of frontal brain regions is associated with an upregulation in the amygdala, which is concurrently linked with an increased number of humorous ideas and enhanced amygdala responses during the task. Our data therefore suggests that a neural antagonism previously related to the emergence and regulation of negative affective responses, is linked with the generation of emotionally positive ideas and may represent an important neural pathway supporting mental health.
Landscape heterogeneity buffers biodiversity of meta-food-webs under global change through rescue and drainage effects
Authors: Ryser Remo , Hirt Myriam R. , Häussler Johanna , Gravel Dominique , Brose Ulrich
Published: June 2020

The impacts of habitat fragmentation and eutrophication on biodiversity have been studied in different scientific realms. Metacommunity research1–5has shown that reduction in landscape connectivity may cause biodiversity loss in fragmentated landscapes. Food-web research addressed how eutrophication increases biomass accumulations at high trophic levels causing the breakdown of local biodiversity6–9. However, there is very limited understanding of their cumulative impacts as they could amplify or cancel each other. Here, we show with simulations of meta-food-webs that landscape heterogeneity provides a buffering capacity against increasing nutrient eutrophication. An interaction between eutrophication and landscape homogenization precipitates the decline of biodiversity. We attribute our results to two complementary mechanisms related to source and sink dynamics. First, the “rescue effect” maintains local biodiversity by rapid recolonization after a local crash in population densities. Second, the “drainage effect” allows a more uniform spreading of biomass across the landscape, reducing overall interaction strengths and therefore stabilizing dynamics. In complex food webs on large spatial networks of habitat patches, these effects yield systematically higher biodiversity in heterogeneous than in homogeneous landscapes. Our meta-food-web approach reveals a strong interaction between habitat fragmentation and eutrophication and provides a mechanistic explanation of how landscape heterogeneity promotes biodiversity.
Rapid detection of SARS-CoV-2 and other respiratory viruses by using LAMP method with Nanopore Flongle workflow
Authors: Li Jingjing , Quan Weipeng , Yan Shuge , Wu Shuangju , Qin Jianhu , Yang Tingting , Liang Fan , Wang Depeng , Liang Yu
Published: June 2020

The ongoing novel coronavirus (COVID-19) outbreak as a global public health emergency infected by SARC-CoV-2 has caused devastating loss around the world. Currently, a lot of diagnosis methods have been used to detect the infection. The nucleic acid (NA) testing is reported to be the clinical standard for COVID-19 infection. Evidence shows that a faster and more convenient method to detect in the early phase will control the spreading of SARS-CoV-2. Here, we propose a method to detect SARC-Cov-2 infection within two hours combined with Loop-mediated Isothermal Amplification (LAMP) reaction and nanopore Flongle workflow. In this approach, RNA reverse transcription and nucleic acid amplification reaction with one step in 30 minutes at 60-65°C constant temperature environment, nanopore Flongle rapidly adapter ligated within 10 minutes. Flongle flow cell sequencing and analysis in real-time. This method described here has the advantages of rapid amplification, convenient operation and real-time detection which is the most important for rapid and reliable clinical diagnosis of COVID-19. Moreover, this approach not only can be used for SARS-CoV-2 detection but also can be extended to other respiratory viruses and pathogens.
C. eleganspharyngeal pumping provides a whole organism bio-assay to investigate anti-cholinesterase intoxication and antidotes
Authors: Izquierdo Patricia G. , O’Connor Vincent , Green Christopher , Holden-Dye Lindy , Tattersall John
Published: June 2020

Inhibition of acetylcholinesterase by either organophosphates or carbamates causes anti-cholinesterase poisoning. This arises through a wide range of neurotoxic effects triggered by the overstimulation of the cholinergic receptors at synapses and neuromuscular junctions. Without intervention, this poisoning can lead to profound toxic effects, including death, and the incomplete efficacy of the current treatments, particularly for oxime-insensitive agents, provokes the need to find better antidotes. Here we show how the non-parasitic nematodeCaenorhabditis elegansoffers an excellent tool for investigating the acetylcholinesterase intoxication. TheC. elegansneuromuscular junctions show a high degree of molecular and functional conservation with the cholinergic transmission that operates in the autonomic, central and neuromuscular synapses in mammals. In fact, the anti-cholinesterase intoxication of the worm’s body wall neuromuscular junction has been unprecedented in understanding molecular determinants of cholinergic function in nematodes and other organisms. We extend the use of the model organism’s feeding behaviour as a tool to investigate carbamate and organophosphate mode of action. We show that inhibition of the cholinergic-dependent rhythmic pumping of the pharyngeal muscle correlates with the inhibition of the acetylcholinesterase activity caused by aldicarb, paraoxons and DFP exposure. Further, this bio-assay allows one to address oxime dependent reversal of cholinesterase inhibition in the context of whole organism recovery. Interestingly, the recovery of the pharyngeal function after such anti-cholinesterase poisoning represents a sensitive and easily quantifiable phenotype that is indicative of the spontaneous recovery or irreversible modification of the worm acetylcholinesterase after inhibition. These observations highlight the pharynx ofC. elegansas a new tractable approach to explore anti-cholinesterase intoxication and recovery with the potential to resolve critical genetic determinants of these neurotoxins’ mode of action.
Small dendritic synapses enhance temporal coding in a model of cochlear nucleus bushy cells
Authors: Koert Elisabeth , Kuenzel Thomas
Published: June 2020

Spherical bushy cells (SBC) in the the anteroventral cochlear nucleus can improve the temporal precision of the auditory nerve spiking activity despite receiving sometimes only a single suprathreshold axosomatic input. The interaction with small dendritic inputs could provide a possible explanation for this phenomenon. In a compartment model of spherical bushy cells with a stylized or realistic three-dimensional representation of the bushy dendrite we explored this proposal. Phase-locked dendritic inputs caused both a tonic depolarization and a modulation of the SBC membrane potential at the frequency of the stimulus but for plausible model parameters do not cause output action potentials (AP). The tonic depolarization increased the excitability of the SBC model. The modulation of the membrane potential caused a phase-dependent increase in the efficacy of the main axosomatic input to cause output AP. These effects increased the rate and the temporal precision of output AP. Rate was mainly increased for stimulus frequencies at and below the characteristic frequency of the main input. Precision mostly increased for higher frequencies above about 1 kHz. Dendritic morphological parameters, biophysical parameters of the dendrite and the synaptic inputs and tonotopic parameters of the inputs all affected the impact of dendritic synapses. This suggested the possibility of fine tuning of the effect the dendritic inputs have for different coding demands or input frequency ranges. Excitatory dendritic inputs modulate the processing of the main input and are thus a plausible mechanism for the improvement of temporal precision in spherical bushy cells.
Clustering of loci controlling species differences in male chemical bouquets of sympatricHeliconiusbutterflies
Authors: Byers Kelsey J. R. P. , Darragh Kathy , Garza Sylvia Fernanda , Almeida Diana Abondano , Warren Ian A. , Rastas Pasi M. A. , Merrill Richard M. , Schulz Stefan , McMillan W. Owen , Jiggins Chris D.
Published: June 2020

The degree to which loci promoting reproductive isolation cluster in the genome –i.e.the genetic architecture of reproductive isolation - can influence the tempo and mode of speciation. Tight linkage between these loci can facilitate speciation in the face of gene flow. Pheromones play a role in reproductive isolation in many Lepidoptera species, and the role of endogenously-produced compounds as secondary metabolites decreases the likelihood of pleiotropy associated with many barrier loci.Heliconiusbutterflies use male sex pheromones to both court females (aphrodisiac wing pheromones) and ward off male courtship (male-transferred anti-aphrodisiac genital pheromones), and it is likely that these compounds play a role in reproductive isolation betweenHeliconiusspecies. Using a set of backcross hybrids betweenH. melpomeneandH. cydno, we investigated the genetic architecture of putative male pheromone compound production. We found a set of 40 significant quantitative trait loci (QTL) representing 33 potential pheromone compounds. QTL clustered significantly on two chromosomes, chromosome 8 for genital compounds and chromosome 20 for wing compounds, and chromosome 20 was enriched for potential pheromone biosynthesis genes. There was minimal overlap between pheromone QTL and known QTL for mate choice and color pattern. Nonetheless, we did detect linkage between a QTL for wing androconial area andoptix, a color pattern locus known to play a role in reproductive isolation in these species. This tight clustering of putative pheromone loci might contribute to coincident reproductive isolating barriers, facilitating speciation despite ongoing gene flow.