bluuebunny/crossref_metadata_2025 huggingface dataset:
Modelling the effect of a border closure between Switzerland and Italy on the spatiotemporal spread of COVID-19 in Switzerland
Authors: Grimée Mathilde , Dunbar Maria Bekker-Nielsen , Hofmann Felix , Held Leonhard
Published: May 2021

We present an approach to extend the Endemic-Epidemic (EE) modelling framework for the analysis of infectious disease data. In its spatiotemporal application, spatial dependencies have originally been captured by a power law applied to static neighbourhood matrices. We propose to adjust these weight matrices over time to reflect changes in spatial connectivity between geographical units. We illustrate this extension by modelling the spread of coronavirus disease 2019 (COVID-19) between Swiss and bordering Italian regions in the first wave of the COVID-19 pandemic. We adjust the spatial weights with data describing the daily changes in population mobility patterns, and indicators of border closures describing the state of travel restrictions since the beginning of the pandemic. We use these time-dependent weights to fit an EE model to the region-stratified time series of new COVID-19 cases. We then adjust the weight matrices to reflect two counterfactual scenarios of border closures and draw counterfactual predictions based on these, to retrospectively assess the usefulness of border closures. We observed that predictions based on a scenario where no closure of the Swiss-Italian border occurred increased the number of cumulative cases in Switzerland by a factor of 2.5 over the study period. Conversely, a closure of the Swiss-Italian border two weeks earlier than implemented would have resulted in only a 12% decrease in the number of cases and merely delayed the epidemic spread by a couple weeks. Despite limitations in the current study, we believe it provides useful insight into modelling the effect of epidemic countermeasures on the spatiotemporal spread of COVID-19.
Silica-encapsulated DNA tracers for measuring aerosol distribution dynamics in real-world settings
Authors: Luescher Anne M. , Koch Julian , Stark Wendelin J. , Grass Robert N.
Published: May 2021

Aerosolized particles play a significant role in human health and environmental risk management. The global importance of aerosol-related hazards, such as the circulation of pathogens and high levels of air pollutants, have led to a surging demand for suitable surrogate tracers to investigate the complex dynamics of airborne particles in real-world scenarios. In this study, we propose a novel approach using silica particles with encapsulated DNA (SPED) as a tracing agent for measuring aerosol distribution indoors. In a series of experiments with a portable setup, SPED were successfully aerosolized, re-captured and quantified using quantitative polymerase chain reaction (qPCR). Position-dependency and ventilation effects within a confined space could be shown in a quantitative fashion achieving detection limits below 0.1 ng particles per m3 of sampled air. In conclusion, SPED show promise for a flexible, cost-effective and low-impact characterization of aerosol dynamics in a wide range of settings.

PRACTICAL IMPLICATIONS

For the first time, silica particles with encapsulated DNA were used to characterize a confined indoor space regarding position- and ventilation-dependent effects of aerosol distribution. The method described here introduces SPED as a novel, non-toxic, low-impact, cost-effective and easy-to-use aerosol tracing platform that can be used to examine real-world environments. The mobile setup presented here as a proof of concept shows that SPED can be aerosolized and re-captured, followed by highly sensitive quantitative barcode-specific PCR analysis. The results revealed that this tracing method can detect position-dependent differences in exposure and ventilation effects influencing distribution dynamics. In the future, SPED could be engineered to exhibit custom-designed properties and be employed within a wide range of setups and high-capacity multi-tracing combinations.
CovidMulti-Net: A Parallel-Dilated Multi Scale Feature Fusion Architecture for the Identification of COVID-19 Cases from Chest X-ray Images
Authors: Islam Khan Md. Saikat , Rahman Anichur , Karim Md. Razaul , Bithi Nasima Islam , Band Shahab S. , Dehzangi Abdollah , Alinejad-Rokny Hamid
Published: May 2021

The COVID-19 pandemic is an emerging respiratory infectious disease, having a significant impact on the health and life of many people around the world. Therefore, early identification of COVID-19 patients is the fastest way to restrain the spread of the pandemic. However, as the number of cases grows at an alarming pace, most developing countries are now facing a shortage of medical resources and testing kits. Besides, using testing kits to detect COVID-19 cases is a time-consuming, expensive, and cumbersome procedure. Faced with these obstacles, most physicians, researchers, and engineers have advocated for the advancement of computer-aided deep learning models to assist healthcare professionals in quickly and inexpensively recognize COVID-19 cases from chest X-ray (CXR) images. With this motivation, this paper proposes a “CovidMulti-Net” architecture based on the transfer learning concept to classify COVID-19 cases from normal and other pneumonia cases using three publicly available datasets that include 1341, 1341, and 446 CXR images from healthy samples and 902, 1564, and 1193 CXR images infected with Viral Pneumonia, Bacterial Pneumonia, and COVID-19 diseases. In the proposed framework, features from CXR images are extracted using three well-known pre-trained models, including DenseNet-169, ResNet-50, and VGG-19. The extracted features are then fed into a concatenate layer, making a robust hybrid model. The proposed framework achieved a classification accuracy of 99.4%, 95.2%, and 94.8% for 2-Class, 3-Class, and 4-Class datasets, exceeding all the other state-of-the-art models. These results suggest that the “CovidMulti-Net” framework’s ability to discriminate individuals with COVID-19 infection from healthy ones and provides the opportunity to be used as a diagnostic model in clinics and hospitals. We also made all the materials publicly accessible for the research community at:https://github.com/saikat15010/CovidMulti-Net-Architecture.git.
Analysis of the Second COVID-19 Wave in India Using a Birth-Death Model
Authors: Viswanath Narayanan C.
Published: May 2021

India is witnessing the second wave of the COVID-19 disease from the first half of February 2021. The method in [5] is applied here to analyze the second wave in India. We start with fitting a birth-death model to the active and total cases data for the period from 13th to 28th February 2021. This initial dataset is expanded step by step by adding the two future week’s data to it until 14th May 2021. This resulted in six models in total. The efficacy of each model is tested in terms of predictions made for the next two weeks. The infectivity rates are found to be ever-increasing in the case of the five initial models. The infectivity rate for the sixth model, which is based on the data from 13th February to 14th May 2021, shows a decreasing nature with an increase in time. This indicates a decline in the second wave, which may start from 4th June 2021 according to the fitted parameters.
External Cues Improve Visual Working Memory Encoding in the Presence of Salient Distractors in Schizophrenia
Authors: Barnes-Scheufler Catherine V. , Rösler Lara , Schaum Michael , Schiweck Carmen , Peters Benjamin , Mayer Jutta S. , Reif Andreas , Wibral Michael , Bittner Robert A.
Published: May 2021

Background

People with schizophrenia (PSZ) are impaired in attentional prioritization of non-salient but relevant stimuli over salient distractors during visual working memory (VWM) encoding. Conversely, guidance of top-down attention by external predictive cues is intact. Yet, it is unknown whether this preserved ability can help PSZ encode more information in the presence of salient distractors.

Methods

We employed a visuospatial change-detection task using four Gabor patches with differing orientations in 66 PSZ and 74 healthy controls (HCS). Two Gabor patches flickered which were designated either as targets or distractors and either a predictive or a non-predictive cue was displayed to manipulate top-down attention, resulting in four conditions.

Results

We observed significant effects of group, salience and cue as well as significant interactions of salience by cue, group by salience and group by cue. Across all conditions, PSZ stored significantly less information in VWM than HCS. PSZ stored significantly less non-flickering than flickering information with a non-predictive cue. However, PSZ stored significantly more flickering and non-flickering information with a predictive cue.

Conclusions

Our findings indicate that control of attentional selection is impaired in schizophrenia. We demonstrate that additional top-down information significantly improves performance in PSZ. The observed deficit in attentional control suggests a disturbance of GABAergic inhibition in early visual areas. Moreover, our findings are indicative of a mechanism for enhancing attentional control in PSZ, which could be utilized by pro-cognitive interventions. Thus, the current paradigm is suitable to reveal both preserved and compromised cognitive component processes in schizophrenia.
Kel1 is a phosphorylation-regulated noise suppressor of the pheromone signaling pathway
Authors: Garcia Ignacio , Orellana-Muñoz Sara , Ramos-Alonso Lucía , Andersen Aram N. , Zimmermann Christine , Eriksson Jens , Bøe Stig Ove , Kaferle Petra , Papamichos-Chronakis Manolis , Chymkowitch Pierre , Enserink Jorrit M.
Published: May 2021

Mechanisms have evolved that allow cells to detect signals and generate an appropriate response. The accuracy of these responses relies on the ability of cells to discriminate between signal and noise. How cells filter noise in signaling pathways is not well understood. Here, we analyze noise suppression in the yeast pheromone signaling pathway and show that the poorly characterized protein Kel1 serves as a major noise suppressor and prevents cell death. At the molecular level, Kel1 prevents spontaneous activation of the pheromone response by inhibiting membrane recruitment of Ste5 and Far1. Only a hypophosphorylated form of Kel1 suppresses signaling, reduces noise and prevents pheromone-associated cell death, and our data indicate that the MAPK Fus3 contributes to Kel1 phosphorylation. Taken together, Kel1 serves as a phospho-regulated suppressor of the pheromone pathway to reduce noise, inhibit spontaneous activation of the pathway, regulate mating efficiency, and to prevent pheromone-associated cell death.
Cortical Representations of Concrete and Abstract Concepts in Language Combine Visual and Linguistic Representations
Authors: Tang Jerry , LeBel Amanda , Huth Alexander G.
Published: May 2021

The human semantic system stores knowledge acquired through both perception and language. To study how semantic representations in cortex integrate perceptual and linguistic information, we created semantic word embedding spaces that combine models of visual and linguistic processing. We then used these visually-grounded semantic spaces to fit voxelwise encoding models to fMRI data collected while subjects listened to hours of narrative stories. We found that cortical regions near the visual system represent concepts by combining visual and linguistic information, while regions near the language system represent concepts using mostly linguistic information. Assessing individual representations near visual cortex, we found that more concrete concepts contain more visual information, while even abstract concepts contain some amount of visual information from associated concrete concepts. Finally we found that these visual grounding effects are localized near visual cortex, suggesting that semantic representations specifically reflect the modality of adjacent perceptual systems. Our results provide a computational account of how visual and linguistic information are combined to represent concrete and abstract concepts across cortex.
c-di-AMP is essential for the virulence of Enterococcus faecalis
Authors: Kundra Shivani , Lam Ling Ning , Kajfasz Jessica K. , Casella Leila G. , Andersen Marissa J. , Abranches Jacqueline , Flores-Mireles Ana L. , Lemos José A.
Published: May 2021

Second messenger nucleotides are produced by bacteria in response to environmental stimuli and play a major role in the regulation of processes associated with bacterial fitness, including but not limited to osmoregulation, envelope homeostasis, central metabolism, and biofilm formation. In this study, we uncovered the biological significance of c-di-AMP in the opportunistic pathogen Enterococcus faecalis by isolating and characterizing strains lacking genes responsible for c-di-AMP synthesis (cdaA) and degradation (dhhP and gdpP). Using complementary approaches, we demonstrated that either complete loss of c-di-AMP (ΔcdaA strain) or c-di-AMP accumulation (ΔdhhP, ΔgdpP and ΔdhhPΔgdpP strains) drastically impaired general cell fitness and virulence of E. faecalis. In particular, the ΔcdaA strain was highly sensitive to envelope-targeting antibiotics, was unable to multiply and quickly lost viability in human serum or urine ex vivo, and was avirulent in an invertebrate (Galleria mellonella) and in two catheter-associated mouse infection models that recapitulate key aspects of enterococcal infections in humans. In addition to evidence linking these phenotypes to altered activity of metabolite and peptide transporters and inability to maintain osmobalance, we found that the attenuated virulence of ΔcdaA could be also attributed to a defect in Ebp pilus production and activity that severely impaired biofilm formation under both in vitro and in vivo conditions. Collectively, these results reveal that c-di-AMP signaling is essential for E. faecalis pathogenesis and a desirable target for drug development.

IMPORTANCE

Enterococcus faecalis is an opportunistic pathogen and leading cause of multidrug resistant hospital-acquired infections. During the course of an infection, bacteria encounter multiple adverse (stress) conditions and understanding the adaptive mechanisms used by pathogens to survive these stresses can facilitate the development of new antimicrobial therapies. Here, we used in vitro, ex vivo and in vivo approaches to determine the importance of the second messenger nucleotide c-di-AMP, a global regulator essential for bacterial adaptation to osmotic stress, to E. faecalis pathophysiology. We demonstrated that either accumulation of c-di-AMP or complete loss of c-di-AMP impaired cell fitness and virulence of E. faecalis. Remarkably, the strain that was unable to produce c-di-AMP was avirulent in three animal infection models indicating that c-di-AMP signaling is essential for E. faecalis pathogenesis and a suitable antimicrobial target.
Epi-mutations for spermatogenic defects by maternal exposure to Di (2-ethylhexyl) phthalate
Authors: Tando Yukiko , Hiura Hitoshi , Takehara Asuka , Ito-Matsuoka Yumi , Arima Takahiro , Matsui Yasuhisa
Published: May 2021

Exposure to environmental factors during fetal development may lead to epigenomic modifications in fetal germ cells, altering gene expression and promoting diseases in successive generations. In mouse, maternal exposure to Di (2-ethylhexyl) phthalate (DEHP) is known to induce defects in spermatogenesis in successive generations, but the mechanism(s) of impaired spermatogenesis are unclear. Here, we showed that maternal DEHP exposure results in DNA hypermethylation of promoters of spermatogenesis-related genes in fetal testicular germ cells in F1 mice, and hypermethylation ofHist1h2ba, Sycp1andTaf7l,which are crucial for spermatogenesis, persisted from fetal testicular cells to adult spermatogonia, resulting in the downregulation of expression of these genes. Forced methylation of these gene promoters silenced expression of these loci in a reporter assay. Expression and methylation of those genes tended to be downregulated and increased, respectively in F2 spermatogonia following maternal DEHP exposure. These results suggested that DEHP-induced hypermethylation ofHist1h2ba, Sycp1andTaf7lin fetal germ cells results in downregulation of these genes in spermatogonia and subsequent defects in spermatogenesis, at least in the F1 generation.
Lung mesenchymal cell diversity rapidly increases at birth and is profoundly altered by hyperoxia
Authors: Zanini Fabio , Che Xibing , Suresh Nina E , Knutsen Carsten , Klavina Paula , Xie Yike , Domingo-Gonzalez Racquel , Liu Min , Jones Robert C , Quake Stephen R , Alvira Cristina M. , Cornfield David N.
Published: May 2021

Lung mesenchymal cells play an essential role in development and at birth, as the lung moves from a fluid-filled to an oxygen-rich environment with a stable gas-liquid interface. The molecular details and cellular changes accompanying this highly coordinated process remain incompletely understood. Therefore, we performed single cell transcriptomics and in-situ imaging of the developing lung in both health and disease to characterize the spectrum of mesenchymal cell states prior to the onset of air-breathing life through late alveolarization to gain insight into their role in orchestrating tissue maturation. We found that cell type diversity in the mesenchymal compartment increases rapidly during normal development but is delayed during neonatal exposure to 80% O2hyperoxia, a model for bronchopulmonary dysplasia. This study identifies the molecular transitions between populations of mesenchymal cells at discrete developmental time points across fibroblast, smooth muscle, and mural compartments and elucidates the global and cell type-specific effects of neonatal hyperoxia, including the emergence ofActa1+ cells which are absent in normoxic neonatal lungs. These granular insights hold the promise of targeted treatment for neonatal lung disease, which remains a major cause of infant morbidity and mortality across the world.
Hif1α is required for Wnt regulated gene expression during Xenopus tropicalis tail regeneration
Authors: Patel Jeet H. , Schattinger Preston A. , Takayoshi Evan E. , Wills Andrea E.
Published: May 2021

Regeneration of complex tissues is initiated by an injury-induced stress response, eventually leading to activation of developmental signaling pathways such as Wnt signaling. How early injury cues are interpreted and coupled to activation of these developmental signals and their targets is not well understood. Here, we show that Hif1α, a stress induced transcription factor, is required for tail regeneration in Xenopus tropicalis. We find that Hif1α is required for regeneration of differentiated axial tissues, including axons and muscle. Using RNA-sequencing, we find that Hif1α and Wnt converge on a broad set of genes required for posterior specification and differentiation, including the posterior hox genes. We further show that Hif1α is required for transcription via a Wnt-responsive element, a function that is conserved in both regeneration and early neural patterning. Our findings indicate a regulatory role for Hif1α in Wnt mediated gene expression across multiple tissue contexts.
Perineuronal nets in HVC and plasticity in male canary song
Authors: Cornez Gilles , Valle Shelley , dos Santos Ednei Barros , Chiver Ioana , Müller Wendt , Ball Gregory F. , Cornil Charlotte A. , Balthazart Jacques
Published: May 2021

Songbirds learn their vocalizations during developmental sensitive periods of song memorization and sensorimotor learning. Some seasonal songbirds, called open-ended learners, recapitulate transitions from sensorimotor learning and song crystallization on a seasonal basis during adulthood. In adult male canaries, sensorimotor learning occurs each year in autumn and leads to modifications of the syllable repertoire during successive breeding seasons. We previously showed that perineuronal nets (PNN) expression in song control nuclei decreases during this sensorimotor learning period. Here we explored the causal link between PNN expression in adult canaries and song modification by enzymatically degrading PNN in HVC, a key song control system nucleus. Three independent experiments identified limited effects of the PNN degradation in HVC on the song structure of male canaries. They clearly establish that presence of PNN in HVC is not required to maintain general features of crystallized song. Some suggestion was collected that PNN are implicated in the stability of song repertoires but this evidence is too preliminary to draw firm conclusions and additional investigations should consider producing PNN degradations at specified time points of the seasonal cycle. It also remains possible that once song has been crystallized at the beginning of the first breeding season, PNN no longer play a key role in determining song structure which could be tested by treatments with ChABC at key step in ontogeny. It would in this context be important to develop multiple stereotaxic procedures allowing the simultaneous bilateral degradation of PNN in several song control nuclei for extended periods.
Development of a multi-primer metabarcoding approach to understand trophic interactions in agroecosystems
Authors: Batuecas Ivan , Alomar Oscar , Castañe Cristina , Piñol Josep , Boyer Stéphane , Gallardo-Montoya Lorena , Agustí Nuria
Published: May 2021

Knowing which arthropod and plant resources are used by generalist predators in agroecosystems is important to understand trophic interactions and the precise ecological role of each predatory species. To achieve this objective, molecular approaches, such as the use of high-throughput sequencing (HTS) platforms are key. This study develops a multi-primer metabarcoding approach and explores its suitability for the screening of the most common trophic interactions of two predatory species of arthropod with contrasted morphology, Rhagonycha fulva (Coleoptera: Cantharidae) and Anthocoris nemoralis (Hemiptera: Anthocoridae) collected in an organic peach crop. To save time and cost in this metabarcoding approach, we first evaluated the effect of two different predator-pool sizes (10 and 23 individuals of the same species), as well as the performance of using one or two primer pairs in the same library. Our results show that the analysis of 23 individuals together with the use of two primer pairs in the same library optimizes the HTS analysis. With these best-performing conditions, we analyzed whole bodies of field-collected predators as well as the washing solutions used to clean the insect bodies. Results showed that we were able to identify both, gut content (i.e. diet) as well as external pollen load (i.e. on the insects’ body), respectively. This study also demonstrates the need of washing predatory insects prior to HTS analysis when the target species have a considerable size and hairy structures. This metabarcoding approach has a high potential for the study of trophic links in agriculture, revealing both expected and unexpected trophic relationships.
Starvation-induced cell fusion and heterokaryosis frequently escape imperfect allorecognition systems to enable parasexual interactions in an asexual fungal pathogen
Authors: Vangalis Vasileios , Likhotkin Ilya , Knop Michael , Typas Milton A. , Papaioannou Ioannis A.
Published: May 2021

Asexual fungi include important pathogens of plants and other organisms, and their effective management requires understanding of their evolutionary dynamics. Genetic recombination is critical for species adaptability and could be achieved via heterokaryosis and the parasexual cycle in asexual fungi. Here, we investigate the extent and mechanisms of heterokaryosis in the asexual plant pathogen Verticillium dahliae.

We used live-cell imaging and genetic complementation assays of tagged V. dahliae strains to analyze the extent of nonself vegetative fusion, heterokaryotic cell fate and nuclear behavior. An efficient CRISPR/Cas9-mediated system was developed to investigate the involvement of autophagy in heterokaryosis.

Under starvation, nonself fusion of germinating spores occurs frequently regardless of the previously assessed vegetative compatibility of the partners. Supposedly “incompatible” fusions often establish viable heterokaryotic cells and mosaic mycelia, where nuclei can engage in fusion or transfer of genetic material. The molecular machinery of autophagy has a protective function against destruction of “incompatible” heterokaryons.

Our results suggest an autophagy-mediated trade-off between parasexual interactions for genetic exchange and allorecognition systems possibly for mycelial protection from parasitic elements. Our study reveals unexpected capacity for heterokaryosis in V. dahliae and suggests, therefore, important roles of parasexuality in the evolution of asexual fungi.
Single molecule characterization of the binding kinetics of a transcription factor and its modulation by DNA sequence and methylation
Authors: Khamis Hadeel , Rudnizky Sergei , Melamed Philippa , Kaplan Ariel
Published: May 2021

The interaction of transcription factors with their response elements in DNA is emerging as a highly complex process, whose characterization requires measuring the full distribution of binding and dissociation times in a well-controlled assay. Here, we present a single-molecule assay that exploits the thermal fluctuations of a DNA hairpin, to detect the association and dissociation of individual, unlabeled transcription factors. We demonstrate this new approach by following the binding of Egr1 to its consensus motif and the three binding sites found in the promoter of the Lhb gene, and find that both association and dissociation are modulated by the 9 bp core motif and the sequences around it. In addition, CpG methylation modulates the dissociation kinetics in a sequence and position-dependent manner, which can both stabilize or destabilize the complex. Together, our findings show how variations in sequence and methylation patterns synergistically extend the spectrum of a protein’s binding properties, and demonstrate how the proposed approach can provide new insights on the function of transcription factors.
A specific set of heterogeneous native interactions yields efficient knotting in protein folding
Authors: Especial João NC , Faísca Patrícia FN
Published: May 2021

Native interactions are crucial for folding, and non-native interactions appear to be critical for efficiently knotting proteins. Therefore, it is important to understand both their roles in the folding of knotted proteins. It has been proposed that non-native interactions drive the correct order of contact formation, which is essential to avoid backtracking and efficiently self-tie. In this study we ask if non-native interactions are strictly necessary to tangle a protein, or if the correct order of contact formation can be assured by a specific set of native, but otherwise heterogeneous, interactions. In order to address this problem we conducted extensive Monte Carlo simulations of lattice models of proteinlike sequences designed to fold into a pre-selected knotted conformation embedding a trefoil knot. We were able to identify a specific set of heterogeneous native interactions that drives efficient knotting, and is able to fold the protein when combined with the remaining native interactions modeled as homogeneous. This specific set of heterogeneous native interactions is strictly enough to efficiently self-tie. A distinctive feature of these native interactions is that they do not backtrack, because their energies ensure the correct order of contact formation. Furthermore, they stabilize a knotted intermediate state, which is enroute to the native structure. Our results thus show that - at least in the context of the adopted model - non-native interactions are not necessary to knot a protein. However, when they are taken into account into protein energetics it is possible to find specific, non-local non-native interactions that operate as a scaffold that assists the knotting step.
Variation in female songbird state determines signal strength needed to evoke copulation
Authors: Perkes Ammon , Pfrommer Bernd , Daniilidis Kostas , White David , Schmidt Marc
Published: May 2021

It is the female response to male signals that determines courtship success. In most songbirds, females control reproduction via the copulation solicitation display (CSD), an innate, stereotyped posture produced in direct response to male displays. Because CSD can be elicited in the absence of males by the presentation of recorded song, CSD production enables investigations into the effects of underlying signal features and behavioral state on female mating preferences. Using computer vision to quantify CSD trajectory in female brown-headed cowbirds (Molothrus ater), we show that both song quality and a female’s internal state predict CSD production, as well as the onset latency and duration of the display. We also show that CSD can be produced in a graded fashion based on both signal strength and internal state. These results emphasize the importance of underlying receiver state in determining behavioral responses and suggest that female responsiveness acts in conjunction with male signal strength to determine the efficacy of male courtship.
Variable expression of linguistic laws in ape gesture: a case study from chimpanzee sexual solicitation
Authors: Safryghin Alexandra , Cross Catharine , Fallon Brittany , Heesen Raphaela , Ferrer-i-Cancho Ramon , Hobaiter Catherine
Published: May 2021

Two language laws have been identified as consistent patterns shaping animal behaviour, both acting on the organisational level of communicative systems. Zipf’s law of brevity describes a negative relationship between behavioural length and frequency. Menzerath’s law defines a negative correlation between the number of behaviours in a sequence and average length of the behaviour composing it. Both laws have been linked with the information-theoretic principle of compression, which tends to minimise code length. We investigated their presence in a case study of male chimpanzee sexual solicitation gesture. We failed to find evidence supporting Zipf’s law of brevity, but solicitation gestures followed Menzerath’s law: longer sequences had shorter average gesture duration. Our results extend previous findings suggesting gesturing may be limited by individual energetic constraints. However, such patterns may only emerge in sufficiently-large datasets. Chimpanzee gestural repertoires do not appear to manifest a consistent principle of compression previously described in many other close-range systems of communication. Importantly, the same signallers and signals were previously shown to adhere to these laws in subsets of the repertoire when used in play; highlighting that, in addition to selection on the signal repertoire, ape gestural expression appears shaped by factors in the immediate socio-ecological context.
Micafungin-induced Cell Wall Damage Stimulates Microcycle Conidiation in Aspergillus nidulans
Authors: Reese Samantha , Chelius Cynthia , Riekhof Wayne , Marten Mark R. , Harris Steven D.
Published: May 2021

Fungal cell wall receptors relay messages about the state of the cell wall to the nucleus through the Cell Wall Integrity Signaling (CWIS) pathway. The ultimate role of the CWIS pathway is to coordinate repair of cell wall damage and to restore normal hyphal growth. Echinocandins such as micafungin represent a class of antifungals that trigger cell wall damage by affecting synthesis of β-glucans, filamentous fungi’s response to these antifungals are fundamentally unknown. To obtain a better understanding of the dynamics of the CWIS response and its multiple effects, we have coupled dynamic transcriptome analysis with morphological studies of Aspergillus nidulans hyphae responding to micafungin. Our results reveal that expression of the master regulator of asexual development, BrlA, is induced by micafungin exposure. Further study showed that micafungin elicits microcycle conidiation in a BrlA-dependent manner, and that this response is abolished in the absence of MpkA. Our results suggest that microcycle conidiation may be a general response to cell wall perturbation which in some cases would enable fungi to tolerate or survive otherwise lethal damage.
ppe51 variants promote non-replicating Mycobacterium tuberculosis to grow at acidic pH by selectively promoting glycerol uptake
Authors: Dechow Shelby J. , Baker Jacob J. , Murto Megan R. , Abramovitch Robert B.
Published: May 2021

In defined media supplemented with single carbon sources, Mycobacterium tuberculosis (Mtb) exhibits carbon source specific growth restriction. When supplied glycerol as the sole carbon source at pH 5.7, Mtb establishes a metabolically active state of nonreplicating persistence known as acid growth arrest. We hypothesized that acidic growth arrest on glycerol is not a metabolic restriction, but rather an adaptive response. To test this hypothesis, we conducted forward genetic screens that identified several Mtb mutants that could grow under these restrictive conditions. All of the mutants were mapped to the ppe51 gene and resulted in three amino acid substitution – S211R, E215K, and A228D. Expression of the PPE51 variants in Mtb promoted growth at acidic pH showing that the mutant alleles are sufficient to cause the dominant gain-of-function, enhanced acid growth (eag) phenotype. Testing growth on other single carbon sources showed the PPE51 variants specifically enhanced growth on glycerol, suggesting ppe51 plays a role in glycerol uptake. Using radiolabeled glycerol, enhanced glycerol uptake was observed in Mtb expressing the PPE51 (S211R) variant, with glycerol overaccumulation in triacylglycerol. Notably, the eag phenotype is deleterious for growth in macrophages, where the mutants have selectively faster replication and reduced in virulence in activated macrophages as compared to resting macrophages. Recombinant PPE51 protein exhibited differential thermostability in the WT or S211R variants in the presence of glycerol, supporting the eag substitutions alter PPE51-glycerol interactions. Together, these findings support that PPE51 variants selectively promote glycerol uptake and that slowed growth at acidic pH is an important adaptive mechanism required for macrophage pathogenesis.
The folding space of protein β2-microglobulin is modulated by a single disulfide bridge
Authors: Morand Jules , Nunes Ana , Faísca Patrícia F.N.
Published: May 2021

Protein beta-2-microglobulin (β2m) is classically considered the causative agent of dialysis related amyloidosis (DRA), a conformational disorder that affects patients undergoing long-term hemodialysis. Together with the wild type form, the ΔN6 structural variant, and the D76N mutant, have been extensively used as model systems of β2m aggregation. In all of them, the native structure is stabilized by a disulfide bridge between the sulphur atoms of the cysteine residues 25 (at B strand) and 80 (at F strand), which has been considered fundamental in β2m fibrillogenesis. Here, we use extensive Discrete Molecular Dynamics simulations of a full atomistic structurebased model to explore the role of this disulfide bridge as a modulator of the folding space of β2m. In particular, by considering different models for the disulfide bridge, we explore the thermodynamics of the folding transition, and the formation of intermediate states that may have the potential to trigger the aggregation cascade. Our results show that the dissulfide bridge affects folding transition and folding thermodynamics of the considered model systems, although to different extents. In particular, when the interaction between the sulphur atoms is stabilized relative to the other intramolecular interactions, or even locked (i.e. permanently established), the WT form populates an intermediate state featuring a well preserved core, and two unstructured termini, which was previously detected only for the D76N mutant. The formation of this intermediate state may have important implications in our understanding of β2m fibrillogenesis.
RNA interference mediates RNA toxicity with parent-of-origin effects inC. elegansexpressing CTG repeats
Authors: Braun Maya , Shoshani Shachar , Teixeira Joana , Shtern Anna Mellul , Miller Maya , Granot Zvi , Fischer Sylvia E J , Garcia Susana M D A , Tabach Yuval
Published: May 2021

Nucleotide repeat expansions are a hallmark of over 40 neurodegenerative diseases. These repeats cause RNA toxicity and trigger multisystemic symptoms that worsen with age. RNA toxicity can trigger, through an unclear mechanism, severe disease manifestation in infants that inherited repeats from their mothers. Here we show inCaenorhabditis eleganshow RNA interference machinery causes intergenerational toxicity through inheritance of siRNAs derived from CUG repeats. The maternal repeat-derived small RNAs cause transcriptomic changes in the offspring, reduce motility and shorten lifespan. However, the toxicity phenotypes in the offspring can be rescued by perturbing the RNAi machinery in affected mothers. This points to a novel mechanism linking maternal bias and the RNAi machinery and suggests that toxic RNA is transmitted to offspring and causes disease phenotypes through intergenerational epigenetic inheritance.
Mechanisms of translation repression by the EIF4E1-4EIP cap-binding complex of Trypanosoma brucei: potential roles of the NOT complex and a terminal uridylyl transferase
Authors: Falk Franziska , Marucha Kevin Kamanyi , Clayton Christine
Published: May 2021

Most transcription in Trypanosoma brucei is constitutive and polycistronic. Consequently, the parasite relies on post-transcriptional mechanisms, especially affecting translation initiation and mRNA decay, to control gene expression both at steady-state and for adaptation to different environments. The parasite has six isoforms of the cap-binding protein EIF4E as well as five EIF4Gs. EIF4E1 does not bind to any EIF4G, instead being associated with a 4E-binding protein, 4EIP. 4EIP represses translation and reduces the stability of a reporter mRNA when artificially tethered to the 3’-UTR, whether or not EIF4E1 is present. 4EIP is essential during the transition from the mammalian bloodstream form to the procyclic form that lives in the Tsetse vector. In contrast, EIF4E1 is dispensable during differentiation, but is required for establishment of growing procyclic forms. There are two competing models for EIF4E1 function: either EIF4E1 has translation initiation activity that is inhibited by 4EIP, or EIF4E1 acts only as an inhibitor. We here provide evidence for the second hypothesis. Even in the complete absence of 4EIP, EIF4E1 showed no detectable association with other translation initiation factors, and 4EIP loss caused no detectable change in 4E1-associated mRNAs. We found that 4EIP stabilises EIF4E1, probably through co-translational complex assembly, and that 4EIP directly recruits the cytosolic terminal uridylyl transferase TUT3 to EIF4E1/4EIP complexes. There was, however, no evidence that TUT3 is essential for 4EIP function; instead, some evidence implicated the NOT deadenylase complex.
Protein resonance assignment by solid-state NMR based on 1H-detected 13C-based double-quantum spectroscopy at fast MAS
Authors: Lends Alons , Berbon Mélanie , Habenstein Birgit , Nishiyama Yusuke , Loquet Antoine
Published: May 2021

Solid-state NMR spectroscopy is a powerful technique to study insoluble and non-crystalline proteins and protein complexes at atomic resolution. The development of proton (1H) detection at fast magic-angle spinning (MAS) has considerably increased the analytical capabilities of the technique, enabling the acquisition of 1H-detected fingerprint experiments in few hours. Here an approach based on double-quantum (DQ) 13C spectroscopy, detected on 1H, is introduced at fast MAS (70 kHz) to perform the sequential assignment of insoluble proteins of small size, without any specific deuteration requirement. By combining two three-dimensional 1H detected experiments correlating a 13C DQ dimension respectively to its intra-residue and sequential 15N-1H pairs, a sequential walk through DQ (Cα+CO) resonance is obtained. Our approach takes advantage of fast MAS to achieve an efficient sensitivity and the addition of a DQ dimension provides spectral features useful for the resonance assignment process.
Natural variation in the consequences of gene overexpression and its implications for evolutionary trajectories
Authors: Robinson DeElegant , Place Michael , Hose James , Jochem Adam , Gasch Audrey P.
Published: May 2021

Copy number variation (CNV) through gene or chromosome amplification provides a route for rapid phenotypic variation and supports long-term evolution of gene functions. Although the evolutionary importance of CNV is known, little is understood about how genetic background influences CNV tolerance. Here, we measured fitness costs of over 4,000 over-expressed genes in 15 Saccharomyces cerevisiae strains representing different lineages, to explore natural variation in tolerating gene overexpression (OE). Strain-specific effects dominated the fitness costs of gene OE. We report global differences in the consequences of gene OE, independent of the amplified gene, as well as gene-specific effects that were dependent on the genetic background. Natural variation in the response to gene OE could be explained by several models, including strain-specific physiological differences, resource limitations, and regulatory sensitivities. This work provides new insight on how genetic background influences tolerance to gene amplification and the evolutionary trajectories accessible to different backgrounds.
Structure, immunogenicity, and conformation-dependent receptor binding of the post-fusion human metapneumovirus F protein
Authors: Huang Jiachen , Chopra Pradeep , Liu Lin , Nagy Tamas , Murray Jackelyn , Tripp Ralph A. , Boons Geert-Jan , Mousa Jarrod J.
Published: May 2021

Human metapneumovirus (hMPV) is an important cause of acute viral respiratory infection. As the only target of neutralizing antibodies, the hMPV fusion (F) protein has been a major focus for vaccine development and targeting by drugs and monoclonal antibodies (mAbs). While X-ray structures of trimeric pre-fusion and post-fusion hMPV F proteins from genotype A, and monomeric pre-fusion hMPV F protein from genotype B have been determined, structural data for the post-fusion conformation for genotype B is lacking. We determined the crystal structure of this protein and compared the structural differences of post-fusion hMPV F between hMPV A and B genotypes. We also assessed the receptor binding properties of the hMPV F protein to heparan sulfate. A library of heparan sulfate (HS) oligomers was used to verify the HS binding activity of hMPV F, and several compounds showed binding to predominantly pre-fusion hMPV F, but had limited binding to post-fusion hMPV F. Furthermore, mAbs to antigenic sites III and the 66-87 intratrimeric epitope block heparan binding. In addition, we evaluated the efficacy of post-fusion hMPV B2 F protein as a vaccine candidate in BALB/c mice. Mice immunized with hMPV B2 post-fusion F protein showed a balanced Th1/Th2 immune response and generated neutralizing antibodies against both subgroup A2 and B2 hMPV strains, which protected the mice from hMPV challenge. Antibody competition analysis revealed the antibodies generated by immunization target two known antigenic sites (III and IV) on hMPV F. Overall, this study provides new characteristics of the hMPV F protein informative for vaccine and therapy development.

Importance

Human metapneumovirus (hMPV) is an important cause of viral respiratory disease. In this paper, we report the X-ray crystal structure of the hMPV fusion (F) protein in the post-fusion conformation from genotype B. We also assessed binding of the hMPV F protein to heparin and heparan sulfate, a previously reported receptor for the hMPV F protein. Furthermore, we determined the immunogenicity and protective efficacy of post-fusion hMPV B2 F protein, which is the first study using a homogenous conformation of the protein. Antibodies generated in response to vaccination give a balanced TH1/TH2 response and target two previously discovered neutralizing epitopes.
Protein detection in blood with single-molecule imaging
Authors: Mao Chih-Ping , Wang Shih-Chin , Su Yu-Pin , Tseng Ssu-Hsueh , He Liangmei , Wu Annie A. , Roden Richard B.S. , Xiao Jie , Hung Chien-Fu
Published: May 2021

The ability to identify and characterize individual biomarker protein molecules in patient blood samples could enable diagnosis of diseases at an earlier stage, when treatment is typically more effective. Single-molecule imaging offers a promising approach to accomplish this goal. However, thus far single-molecule imaging methods have only been used to monitor protein molecules in solutions or cell lysates, and have not been translated into the clinical arena. Furthermore, the detection limit of these methods has been confined to the picomolar (10−12 M) range. In many diseases, the circulating concentrations of biomarker proteins fall several orders of magnitude below this range. Here we describe Single-Molecule Augmented Capture (SMAC), a single-molecule imaging technique to visualize, quantify, and characterize individual protein molecules of interest down to the subfemtomolar (<10−15 M) range, even in complex biologic fluids. We demonstrate SMAC in a wide variety of applications with human blood samples, including the analysis of disease-associated secreted proteins, membrane proteins, and rare intracellular proteins. Using ovarian cancer as a model, a lethal malignancy in which high-grade disease is driven almost universally by alterations in the TP53 gene and frequently only diagnosed at a late, incurable stage, we found that mutant pattern p53 proteins are released into the blood in patients at an early stage in disease progression. SMAC opens the door to the application of single-molecule imaging in non-invasive disease profiling and allows for the analysis of circulating mutant proteins as a new class of highly specific disease biomarkers. The SMAC platform can be adapted to multiplex or high-throughput formats to characterize heterogeneous biochemical and structural features of circulating proteins-of-interest.

One Sentence Summary

A single-molecule imaging approach detects individual disease-specific protein molecules, including mutant intracellular proteins, in blood samples.
Circularly permuted LOV domain as an engineering module for optogenetic tools
Authors: Geng Lequn , Shen Jiaqi , Wang Wenjing
Published: May 2021

We re-engineered a commonly-used light-sensing protein, LOV domain, using a circular permutation strategy to allow photoswitchable control of the C-terminus of a peptide. We demonstrate that the use of circularly permuted LOV domain on its own or together with the original LOV could expand the engineering capabilities of optogenetic tools.