bluuebunny/crossref_metadata_2025 huggingface dataset:
Stability of mitomycin in polypropylene syringes for use in glaucoma surgery
Authors: Nisse Yann-Eric , Vigneron Jean , Zenier Hubert , D’Huart Elise , Demoré Béatrice
Published: January 2021

Introduction:

Outside the oncology field, mitomycin is used in glaucoma surgery. Solutions at 0.2 mg/mL are usually used to fully saturate sterile sponges that are applied to the treatment area. In hospital pharmacies, mitomycin 10 and 40 mg are classically used to prepare the solutions with a lot of losses. The objective of this work was to study the long-term stability to consider preparation in advance and reduce losses in a context of drug shortage.

Methods:

Two different products were used: Ametycine, which contains sodium chloride as excipient, and Mitomycin medac, which contains urea as excipient.

Solutions at 0.1 mg/mL (sometimes used in our hospital) and the more classically used 0.2 mg/mL were prepared and stored in polypropylene syringes. Solutions were kept at −20°C or at 5°C and analyzed on day 28, 63, and 91. Chemical stability was studied by using a previously validated high-performance liquid chromatography stability-indicating method. pH was measured and a visual inspection was performed.

Results:

For each condition, solutions were not stable after long-term storage with concentrations below 90% of the initial concentration after 28 days. Frozen solutions were less stable than refrigerated solutions. pH values increased by more than 1 pH unit after 3 months. Ametycine shows precipitate after freezing but not solutions prepared with Mitomycin medac.

The color of frozen solutions was changed from light blue to light green at −20°C but became light blue after thawing.

Conclusion:

Mitomycin 0.1 and 0.2 mg/mL showed an instability after long-term storage at 5°C or −20°C. These results do not allow the preparation in advance of large batches.
Efficacy of Second Operation for Hemifacial Spasm Within 1 Week After Ineffective Microvascular Decompression
Authors: Sun Qiuyang , Li Bin , Kang Xu , Bai Peng , Zhou Houjun , Zhang Wenbo , Sun Hui , Wang Xiaoqiang
Published: January 2021

Objective:

To evaluate the efficacy of the second operation within 1 week after ineffective microvascular decompression (MVD) for patients with primary hemifacial spasm (HFS), and to find out the causes of failure.

Methods:

The surgery records and postoperative follow-ups of 52 primary HFS patients who had poor relief of spasm after their first MVDs were investigated. Patients were divided into 2 groups. Group A included 46 patients (16 males and 30 females) that went through the second operation within 1 week after the failure of the first MVD. Group B included 6 patients (3 males and 3 females) which did not take the reoperation. The level of spasm of each patient was then re-evaluated 1 year after the first surgery.

Results:

Among 52 patients who had poor relief after the first MVD between April 2016 and October 2019, 46 patients underwent a second MVD within 1 week while 6 patients refused to take the reoperation. Their mean duration of HFS was 102.4 ± 57.9 months. During reoperations for patients in group A, we discovered additional sites of neurovascular compression in 11 cases (23.91%). Forty-five patients (97.82%) in group A achieved complete relief 1 year after the second surgery while there was 1 recurrent case. Four patients (66.67%) in group B achieved delayed relief 1 year after the first surgery, while the other 2 patients were still suffering facial spasm in the 1-year follow-up. Group A demonstrated higher relief rate compared to group B in the 1 year follow up (P = 0.032). Although no severe complications occurred on patients in both group, 4 of them suffered grade II facial palsy, and another 3 patients had developed mild temporary hearing loss on the operation side.

Conclusion:

The second operation within 1 week after an ineffective MVD is safe and effective. Full revealing of root exit zone and making sure no neurovascular compression missed with abnormal muscle response monitoring are the keys to a successful MVD.
Developing Communication Access Standards to Maximize Community Inclusion for People With Communication Support Needs
Authors: Solarsh Barbara , Johnson Hilary
Published: January 2021

People with communication support needs experience barriers that limit their social inclusion in society. A community approach such as communication access that targets changing attitudes, skills, and resources may assist in facilitating community participation. The authors describe the development of communication access from 2008 in Victoria, Australia. We present the rationale underpinning the need for communication access and the identification of a communication access symbol. A collaborative partnership between people with communication support needs, speech–language pathologists, and community members established a rigorous approach for devising the communication access standards and supporting checklists. The process for awarding a communication access license includes 4 phases: engagement, preparation, assessment, and review. Currently, 200 customer service points in businesses and organizations have been licensed as communication accessible. Further research is needed to establish replicability and sustainability of the communication access initiative and outcomes for a range of people with communication support needs.
Optimizing the Experience of Flow for Adults With Aphasia
Authors: Sather Thomas W. , Howe Tami , Nelson Nickola Wolf , Lagerwey Mary
Published: January 2021

Flow has been described as positive experiences of intense concentration, distorted time passage, and a loss of self-consciousness that result from matching task difficulty to a person's skill level. It has been studied in many different populations and has been associated with a number of positive outcomes, including improved life satisfaction and well-being, enhancement of identity, and the development of skills. Although flow has been identified as being important for adults with aphasia, it had not been studied in this population until recently. In this article, the authors describe the concept of flow and explain why it is important for clinicians to consider when working with adults with aphasia. Next, the authors review the literature related to barriers and facilitators that influence the experience of flow for adults with aphasia and conclude by identifying clinical implications for optimizing the experience of flow in this population.
Facilitating the Involvement of People with Aphasia in Stroke Research by Developing Communicatively Accessible Research Resources
Authors: Pearl Gill , Cruice Madeline
Published: January 2021

People with aphasia can be marginalized by a communicatively inaccessible society. Compounding this problem, routinized exclusion from stroke research leads to bias in the evidence base and subsequent inequalities in service provision. Within the United Kingdom, the Clinical Research Network of the National Institute of Health identified this problem and funded a 6-month project in 2013–2014 that resulted in the creation of practical and freely available resources to equip researchers to engage more people with aphasia in research. Critical elements enabled authentic coconstruction of new knowledge regarding accessible research documentation, including the process structure, timescale, and crucially, the fundamental engagement of people with aphasia. Stages in this process included mapping existing resources; engaging with researchers and with people affected by aphasia; and developing a new set of resources comprising images, accessible text, and templates for research forms. These resulted in high-quality outputs, as indicated by preliminary feedback from the research community and people with aphasia.
Found Opportunities for Social Participation
Authors: Howe Tami
Published: January 2021

Lack of communicatively supportive opportunities for social participation is a critical barrier for many people with aphasia. Speech–language pathologists need to address this barrier by playing a key role in ensuring that adults with aphasia have appropriate social participation choices in their communities. Speech–language pathologists may provide these services themselves or may draw on their unique expertise in communication and aphasia to work with people with aphasia, family, friends, other health care professionals, and disability support organizations to advocate for and/or develop opportunities. This article provides examples of specific approaches that can help achieve this important goal in relation to 4 levels of social participation: interacting with others without doing a specific activity with them (e.g., having satisfying conversations), interacting with others during activities in which there is a common goal (e.g., participating in enjoyable recreational activities), interacting with others to help a specific person or group of people (e.g., volunteering), and interacting with others to make a contribution to society (e.g., being involved in an aphasia advocacy organization).
Artificial Intelligence for Emotion-Semantic Trending and People Emotion Detection During COVID-19 Social Isolation
Authors: Jelodar Hamed , Orji Rita , Matwin Stan , Weerasinghe Swarna , Oyebode Oladapo , Wang Yongli
Published: January 2021

Taking advantage of social media platforms, such as Twitter, this paper provides an effective framework for emotion detection among those who are quarantined. Early detection of emotional feelings and their trends help implement timely intervention strategies. Given the limitations of medical diagnosis of early emotional change signs during the quarantine period, artificial intelligence models provide effective mechanisms in uncovering early signs, symptoms and escalating trends. Novelty of the approach presented herein is a multitask methodological framework of text data processing, implemented as a pipeline for meaningful emotion detection and analysis, based on the Plutchik/Ekman approach to emotion detection and trend detection. We present an evaluation of the framework and a pilot system. Results of confirm the effectiveness of the proposed framework for topic trends and emotion detection of COVID-19 tweets. Our findings revealed Stay-At-Home restrictions result in people expressing on twitter both negative and positive emotional semantics (feelings), where negatives are “Anger” (8.5% of tweets), followed by “Fear” (5.2%), “Anticipation” (53.6%) and positive emotional semantics are “Joy” (14.7%) and “Trust” (11.7%). Semantic trends of safety issues related to staying at home rapidly decreased within the 28 days and also negative feelings related to friends dying and quarantined life increased in some days. These findings have potential to impact public health policy decisions through monitoring trends of emotional feelings of those who are quarantined. The framework presented here has potential to assist in such monitoring by using as an online emotion detection tool kit.
SARS-CoV-2 recruits a haem metabolite to evade antibody immunity
Authors: Rosa Annachiara , Pye Valerie E. , Graham Carl , Muir Luke , Seow Jeffrey , Ng Kevin W. , Cook Nicola J. , Rees-Spear Chloe , Parker Eleanor , dos Santos Mariana Silva , Rosadas Carolina , Susana Alberto , Rhys Hefin , Nans Andrea , Masino Laura , Roustan Chloe , Christodoulou Evangelos , Ulferts Rachel , Wrobel Antoni , Short Charlotte-Eve , Fertleman Michael , Sanders Rogier W. , Heaney Judith , Spyer Moira , Kjær Svend , Riddell Andy , Malim Michael H. , Beale Rupert , MacRae James I. , Taylor Graham P. , Nastouli Eleni , van Gils Marit J. , Rosenthal Peter B. , Pizzato Massimo , McClure Myra O. , Tedder Richard S. , Kassiotis George , McCoy Laura E. , Doores Katie J. , Cherepanov Peter
Published: January 2021

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of haem metabolism, with nanomolar affinity. Using cryo-electron microscopy and X-ray crystallography we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that the virus co-opts the haem metabolite for the evasion of humoral immunity via allosteric shielding of a sensitive epitope and demonstrate the remarkable structural plasticity of the NTD.
NOMA: a high-throughput microchip for robust, sequential measurements of secretions from the same single-cells
Authors: Liu Meimei , Ji Yahui , Zhu Fengjiao , Bai Xue , Li Linmei , Xie Hua , Liu Xianming , Luo Yong , Liu Tingjiao , Lin Bingcheng , Lu Yao
Published: January 2021

Despite recent advances in single-cell analysis technologies, lacking simple methods to keep the live single-cells traceable for longitudinal detection reliably poses a significant obstacle in single-cell secretion analysis. Here we reported the high-density NOMA (narrow-opening microwell array) microchip that realized the retention of≥97% of trapped single cells in dedicated spatial locations during repetitive detection procedures, verified with both adherent and suspension cells by two researchers independently. We applied it in monitoring single-cell protein secretions sequentially from the same single cells, and we found the digital protein secretion patterns dominate the protein secretion. We also demonstrated the microchip for longitudinally tracking IL-8 and the CD81+EV secretions from the same single-cells over days, which revealed the presence of “super secretors” within the cell population be more persistent to secrete protein or extracellular vesicle for an extended period. The NOMA platform reported here is simple, robust, and easy to operate for tracking sequential measurements from the same single cells, representing a novel and informative tool to inspire new observations in biomedical research.

Table of Contents Graphic
Molecular basis of small-molecule binding to α-synuclein
Authors: Robustelli Paul , Ibanez-de-Opakua Alain , Campbell-Bezat Cecily , Giordanetto Fabrizio , Becker Stefan , Zweckstetter Markus , Pan Albert C. , Shaw David E.
Published: January 2021

Intrinsically disordered proteins (IDPs) are implicated in many human diseases. They have generally not been amenable to conventional structure-based drug design, however, because their intrinsic conformational variability has precluded an atomic-level understanding of their binding to small molecules. Here we present long-timescale, atomic-level molecular dynamics (MD) simulations of monomeric α-synuclein (an IDP whose aggregation is associated with Parkinson’s disease) binding the small-molecule drug fasudil in which the observed protein-ligand interactions were found to be in good agreement with previously reported NMR chemical shift data. In our simulations, fasudil, when bound, favored certain charge-charge and π-stacking interactions near the C terminus of α-synuclein, but tended not to form these interactions simultaneously, rather breaking one of these interactions and forming another nearby (a mechanism we termdynamic shuttling). Further simulations with small molecules chosen to modify these interactions yielded binding affinities and key structural features of binding consistent with subsequent NMR experiments, suggesting the potential for MD-based strategies to facilitate the rational design of small molecules that bind with disordered proteins.
Ancient genomes reveal long range influence of the site and culture of Tiwanaku
Authors: Popović Danijela , Molak Martyna , Ziołkowski Mariusz , Vranich Alexei , Sobczyk Maciej , Vidaurre Delfor Ulloa , Agresti Guido , Skrzypczak Magdalena , Ginalski Krzysztof , Lamnidis Thiseas Christos , Nakatsuka Nathan , Mallick Swapan , Baca Mateusz
Published: January 2021

Tiwanaku was a civilization that flourished in the Lake Titicaca Basin (present-day Bolivia) between 500 and 1000 CE. At its apogee, Tiwanaku controlled the lake’s southern shores and influenced certain areas of the Southern Andes. There is a considerable amount of archaeological and anthropological data concerning the Tiwanaku culture; however, our understanding of the population of the site of Tiwanaku is limited. To understand the population dynamics at different stages of the Tiwanaku cultural development, we analyzed 17 low-coverage genomes from individuals dated between 300 and 1500 CE. We found that the population from the Lake Titicaca Basin remained genetically unchanged throughout more than 1200 years, indicating that significant cultural and political changes were not associated with large scale population movements. In contrast, individuals excavated from Tiwanaku’s ritual core were highly heterogeneous, some with genetic ancestry from as far away as the Amazon, supporting the proposition of foreign presence at the site. However, mixed-ancestry individuals’ presence suggests they were local descendants of incomers from afar rather than captives or visiting pilgrims. A number of human offerings from the Akapana Platform dating to ca. 950 CE mark the end of active construction and maintenance of the monumental core and the wane of Tiwanaku culture.

Significance Statement

Tiwanaku was an important pre-Inca polity in South America and an example of primary social complexity on par with civilizations in the Indus and Nile river valley. Flourishing between 500 and 1000 CE, Tiwanaku exercised control in the south Titicaca basin and influenced a vast area in southern Peru, Bolivia, and northern Chile. Comprehensive archeological studies provided information about the rise, expansion, and fall of the Tiwanaku culture, but little is known about the monumental site’s population. To address this lacuna, we generated low coverage genomes for 17 individuals, revealing that while the Titicaca basin’s residential population was homogenous, the individuals excavated from the ritual core of Tiwanaku drew their ancestry from distant regions.
Fine-grained temporal mapping of derived high-frequency variants supports the mosaic nature of the evolution ofHomo sapiens
Authors: Andirkó Alejandro , Moriano Juan , Vitriolo Alessandro , Kuhlwilm Martin , Testa Giuseppe , Boeckx Cedric
Published: January 2021

As our knowledge about the history of theHomo sapienslineage becomes increasingly complex, large-scale estimations of the time of emergence of derived variants become essential to be able to offer more precise answers to time-sensitive hypotheses concerning human evolution. Using an open repository of genetic variant age estimations recently made available, we offer here a temporal evaluation of various evolutionarily relevant datasets, such asHomo sapiens-specific variants, high-frequency variants found in genetic windows under positive selection, introgressed variants from extinct human species, as well as putative regulatory variants in various brain regions. We find a recurrent bimodal distribution of high-frequency variants, but also evidence for specific enrichments of gene categories in various time windows, which brings into prominence the 300-500k time slice. We also find evidence for very early mutations impacting the facial phenotype, and much more recent molecular events linked to specific brain regions such as the cerebellum or the precuneus. Additionally, we present a case study of an evolutionarily relevant gene,BAZ1B, and its targets, to emphasize the importance of applying temporal data to specific evolutionary questions. Overall, we present a unique resource that informs and complements our previous knowledge ofHomo sapiensevolution using publicly available data, and reinforce the case for the mosaic, temporally very extended nature of the evolutionary trajectory of our species.
Transcriptome variation in human tissues revealed by long-read sequencing
Authors: Glinos Dafni A , Garborcauskas Garrett , Hoffman Paul , Ehsan Nava , Jiang Lihua , Gokden Alper , Dai Xiaoguang , Aguet Francois , Brown Kathleen L. , Garimella Kiran , Bowers Tera , Costello Maura , Ardlie Kristin , Jian Ruiqi , Tucker Nathan R , Ellinor Patrick T , Harrington Eoghan D , Tang Hua , Snyder Michael , Juul Sissel , Mohammadi Pejman , MacArthur Daniel G , Lappalainen Tuuli , Cummings Beryl
Published: January 2021

Regulation of transcript structure generates transcript diversity and plays an important role in human disease. The advent of long-read sequencing technologies offers the opportunity to study the role of genetic variation in transcript structure. In this paper, we present a large human long-read RNA-seq dataset using the Oxford Nanopore Technologies platform from 88 samples from GTEx tissues and cell lines, complementing the GTEx resource. We identified just under 100,000 new transcripts for annotated genes, and validated the protein expression of a similar proportion of novel and annotated transcripts. We developed a new computational package, LORALS, to analyze genetic effects of rare and common variants on the transcriptome via allele-specific analysis of long reads. We called allele-specific expression and transcript structure events, providing novel insights into the specific transcript alterations caused by common and rare genetic variants and highlighting the resolution gained from long-read data. We were able to perturb transcript structure upon knockdown of PTBP1, an RNA binding protein that mediates splicing, thereby finding genetic regulatory effects that are modified by the cellular environment. Finally, we use this dataset to enhance variant interpretation and study rare variants leading to aberrant splicing patterns.
A genetic variant alters the secondary structure of the lncRNA H19 and is associated with Dilated Cardiomyopathy
Authors: Martens Leonie , Rühle Frank , Witten Anika , Meder Benjamin , Katus Hugo A. , Arbustini Eloisa , Hasenfuß Gerd , Sinner Moritz F. , Kääb Stefan , Pankuweit Sabine , Angermann Christiane , Bornberg-Bauer Erich , Stoll Monika
Published: January 2021

lncRNAs are at the core of many regulatory processes and have also been recognized to be involved in various complex diseases. They affect gene regulation through direct interactions with RNA, DNA or proteins. Accordingly, lncRNAs structure is likely to be essential for their regulatory function. Point mutations, which manifest as SNPs (single nucleotide polymorphisms) in genome screens, can substantially alter their function and, subsequently, the expression of their down-stream regulated genes. To test the effect of SNPs on structure, we investigated lncRNAs associated with dilated cardiomyopathy. Among 322 human candidate lncRNAs we demonstrate first the significant association of a SNP located in lncRNA H19 using data from 1084 diseased and 751 control patients. H19 is generally highly expressed in the heart, with a complex expression pattern during heart development. Next, we used MFE (minimum free energy) folding to demonstrate a significant refolding in the secondary structure of this 861 nt long lncRNA. Since MFE folding may overlook the importance of sub-optimal structures, we showed that this refolding also manifests in the overall Boltzmann structure ensemble. There, the composition of structures is tremendously affected in their thermodynamic probabilities through the genetic variant. Finally, we confirmed these results experimentally, using SHAPE-Seq, corroborating that SNPs affecting such structures may explain hidden genetic variance not accounted for through genome wide association studies. Our results suggest that structural changes in lncRNAs, and lncRNA H19 in particular, affect regulatory processes and represent optimal targets for further in-depth studies probing their molecular interactions.
Bio-instantiated recurrent neural networks
Authors: Goulas Alexandros , Damicelli Fabrizio , Hilgetag Claus C
Published: January 2021

Biological neuronal networks (BNNs) are a source of inspiration and analogy making for researchers that focus on artificial neuronal networks (ANNs). Moreover, neuroscientists increasingly use ANNs as a model for the brain. Despite certain similarities between these two types of networks, important differences can be discerned. First, biological neural networks are sculpted by evolution and the constraints that it entails, whereas artificial neural networks are engineered to solve particular tasks. Second, the network topology of these systems, apart from some analogies that can be drawn, exhibits pronounced differences. Here, we examine strategies to construct recurrent neural networks (RNNs) that instantiate the network topology of brains of different species. We refer to such RNNs as bio-instantiated. We investigate the performance of bio-instantiated RNNs in terms of: i) the prediction performance itself, that is, the capacity of the network to minimize the desired function at hand in test data, and ii) speed of training, that is, how fast during training the network reaches its optimal performance. We examine bio-instantiated RNNs in working memory tasks where task-relevant information must be tracked as a sequence of events unfolds in time. We highlight the strategies that can be used to construct RNNs with the network topology found in BNNs, without sacrificing performance. Despite that we observe no enhancement of performance when compared to randomly wired RNNs, our approach demonstrates how empirical neural network data can be used for constructing RNNs, thus, facilitating further experimentation with biologically realistic network topologies, in contexts where such aspect is desired.
Detection of hematopoietic stem cell transcriptome in human fetal kidneys and kidney organoids derived from human induced pluripotent stem cells (iPSC)
Authors: Hwang Jin Wook , Desterke Christophe , Loisel-Duwattez Julien , Griscelli Frank , Bennaceur-Griscelli Annelise , Turhan Ali G
Published: January 2021

Background

In mammalians, hematopoietic stem cells (HSC) arise in the dorsal aorta from the hemogenic endothelium, followed by their migration to fetal liver and to bone marrow. In zebrafish, kidney is the site of primary hematopoiesis. In humans, the presence of HSC in the fetal or adult kidney has not been established.

Methods

We analyzed the presence of HSC markers in human fetal kidneys by analysis of single-cell datasets. We then analyzed in kidney organoids derived from iPSC, the presence of hematopoietic markers using transcriptome analyses.

Results

12 clusters were identified of stromal, endothelial, and nephron cell type-specific markers in the two fetal stage (17 weeks) kidney datasets. Among these, expression of hematopoietic cells in Cluster 9 showed expression of primitive markers. Moreover, whole transcriptome analysis of our iPSC-derived kidney organoids revealed induction of the primitive hematopoietic transcription factor RUNX1 as found in the human fetal kidney cortex.

Conclusions

These finding support the presence of cells expressing HSC transcriptome in human kidney. The mechanisms of the appearance of the cells with the same transcriptional features during iPSC-derived kidney organoid generation requires further investigation.
Cell shape anisotropy and motility constrain self-organised feather pattern fidelity in birds
Authors: Curantz Camille , Bailleul Richard , Hidalgo Magdalena , Durande Melina , Graner François , Manceau Marie
Published: January 2021

Cellular self-organisation can emerge from stochastic fluctuations in properties of a developing tissue1–3. This mechanism explains the production of various motifs seen in nature4–7. However, events channelling its outcomes such that patterns are produced with reproducible precision key to fitness remain unexplored. Here, we compared the dynamic emergence of feather primordia arrays in poultry, finch, emu, ostrich and penguin embryos and correlated inter-species differences in pattern fidelity to the amplitude of dermal cell anisotropy in the un-patterned tissue. Using live imaging and ex vivo perturbations in these species, we showed that cell anisotropy optimises cell motility for sharp and precisely located primordia formation, and thus, proper pattern geometry. These results evidence a mechanism through which collective cellular properties of a developmental pattern system ensure stability in its self-organisation and contribute to its evolution.
Inhibition of Quorum Sensing System inPseudomonas aeruginosaby Psammaplin A and Bisaprasin Isolated from the Marine SpongeAplysinella rhax
Authors: Oluwabusola Emmanuel T. , Katermeran Nursheena Parveen , Tan Lik Tong , Diyaolu Oluwatofunmilayo , Tabudravu Jioji , Ebel Rainer , Jaspars Marcel
Published: January 2021

Natural products isolated from marine sponges have exhibited profound bioactivity and, in some cases, serve as potent quorum sensing inhibitory agents by preventing microbial biofilm formation. In this study, the inhibitory potential of the psammaplin type compounds, psammaplin A (1) and bisaprasin (2), isolated from the marine sponge,Aplysinella rhax, was evaluated in the quorum-sensing inhibitory assay based on thePseudomonas aeruginosaPAO1lasB-gfpandP. aeruginosaPAO1rhlA-gfpbiosensor strains. The result indicated that psammaplin A (1) showed moderate inhibition againstlasB-gfpbiosensor strains but significantly inhibited the QS-gene promoters,rhlA-gfpwith IC50value at 30.69 and 2.64 μM, respectively. In contrast, bisaprasin (2) displayed significant inhibition for both biosensor strains,lasB-gfpandrhlA-gfpwith IC50values at 8.70 and 8.53 μM, respectively. To our knowledge, the antiquorum sensing activity of these marine-derived bromotyrosine compounds is described here for the first time.

Significance and Impact of the Study

The attention of the scientific community has been drawn to using marine sources to find novel quorum sensing inhibitors as antipathogenic drugs to combat antimicrobial resistance and pathogenesis caused by the proliferation of pathogenic bacteria mediated by the quorum sensing (QS) system. By blocking the QS signalling communication, the ability to assemble an organised community structure that enables drug resistance and production of virulence factors will be attenuated. The significance of this investigation is based on the discovery of bromotyrosine derivatives as potential new drug leads for the development of antipathogenic agents.
A prioritized and validated resource of mitochondrial proteins in Plasmodium identifies leads to unique biology
Authors: van Esveld Selma L. , Meerstein-Kessel Lisette , Boshoven Cas , Baaij Jochem F. , Barylyuk Konstantin , Coolen Jordy P. M. , van Strien Joeri , Duim Ronald A.J. , Dutilh Bas E. , Garza Daniel R. , Letterie Marijn , Proellochs Nicholas I. , de Ridder Michelle N. , Venkatasubramanian Prashanna Balaji , de Vries Laura E. , Waller Ross F. , Kooij Taco W.A. , Huynen Martijn A.
Published: January 2021

Plasmodium species have a single mitochondrion that is essential for their survival and has been successfully targeted by anti-malarial drugs. Most mitochondrial proteins are imported into this organelle and our picture of the Plasmodium mitochondrial proteome remains incomplete. Many data sources contain information about mitochondrial localization, including proteome and gene expression profiles, orthology to mitochondrial proteins from other species, co-evolutionary relationships, and amino acid sequences, each with different coverage and reliability. To obtain a comprehensive, prioritized list of Plasmodium falciparum mitochondrial proteins, we rigorously analyzed and integrated eight datasets using Bayesian statistics into a predictive score per protein for mitochondrial localization. At a corrected false discovery rate of 25%, we identified 445 proteins with a sensitivity of 87% and a specificity of 97%. They include proteins that have not been identified as mitochondrial in other eukaryotes but have characterized homologs in bacteria that are involved in metabolism or translation. Mitochondrial localization of seven Plasmodium berghei orthologs was confirmed by epitope labeling and co-localization with a mitochondrial marker protein. One of these belongs to a newly identified apicomplexan mitochondrial protein family that in P. falciparum has four members. With the experimentally validated mitochondrial proteins and the complete ranked P. falciparum proteome, which we have named PlasmoMitoCarta, we present a resource to study unique proteins of Plasmodium mitochondria.
eIF4E3 Forms an Active eIF4F Complex during Stresses (eIF4FS) Targeting mTOR and Re-Programs the Translatome
Authors: Weiss B. , Allen G.E. , Kloehn J. , Abid K. , Jaquier-Gubler P. , Curran J.A.
Published: January 2021

The eIF4E are a family of initiation factors that bind the mRNA 5’ cap, regulating the proteome and the cellular phenotype. eIF4E1 mediates global translation and its activity is controlled via the PI3K/AKT/mTOR pathway. mTOR down-regulation results in eIF4E1 sequestration into an inactive complex with the 4E binding proteins (4EBPs). The second member, eIF4E2, regulates the translatome during hypoxia. However, the exact function of the third member, eIF4E3, has remained elusive. We have dissected its function using a range of techniques. Starting from the observation that it does not interact with 4EBP1, we demonstrate that eIF4E3 recruitment into an eIF4F complex occurs when Torin1 inhibits the mTOR pathway. Ribo-seq studies demonstrate that this complex (eIF4FS) is translationally active only during stress and that it selects specific mRNA populations based on 5’ TL (UTR) length. The interactome reveals that it associates with cellular proteins beyond the cognate initiation factors, suggesting that it may have “moon-lighting” functions. Finally, we provide evidence that cellular metabolism is altered in an eIF4E3 KO background but only upon Torin1 treatment. We propose that eIF4E3 acts as a second branch of the integrated stress response, re-programming the translatome to promote “stress resistance” and adaptation.
Quantitative coupling of cell volume and membrane tension during osmotic shocks
Authors: Roffay Chloé , Molinard Guillaume , Kim Kyoohyun , Barbarassa Victoria , Urbanska Marta , Mercier Vincent , García-Calvo José , Matile Stefan , Guck Jochen , Lenz Martin , Roux Aurélien
Published: January 2021

During osmotic changes of their environment, cells actively regulate their volume and plasma membrane tension that can passively change through osmosis. How tension and volume are coupled during osmotic adaptation remains unknown, as a quantitative characterization is lacking. Here, we performed dynamic membrane tension and cell volume measurements during osmotic shocks. During the first few seconds following the shock, cell volume varied to equilibrate osmotic pressures inside and outside the cell, and membrane tension dynamically followed these changes. A theoretical model based on the passive, reversible unfolding of the membrane as it detaches from the actin cortex during volume increase, quantitatively describes our data. After the initial response, tension and volume recovered from hypoosmotic shocks but not from hyperosmotic shocks. During these asymmetric recoveries, tension and volume remained coupled. Pharmacological disruption of the cytoskeleton and functional inhibition of ion channels and mTOR all affected tension and volume responses, proving that a passive mechanism is necessary and critical for the cell to adapt fast. The coupling between them was, nonetheless, maintained for a few exceptions suggesting that volume and tension regulations are independent from the regulation of their coupling.
Zinc Import Mediated by AdcABC is Critical for Colonization of the Dental Biofilm byStreptococcus mutansin an Animal Model
Authors: Ganguly Tridib , Peterson Alexandra M. , Kajfasz Jessica K. , Abranches Jacqueline , Lemos José A.
Published: January 2021

Trace metals are essential to all domains of life but toxic when found at high concentrations. While the importance of iron in host-pathogen interactions is firmly established, contemporary studies indicate that other trace metals, including manganese and zinc, are also critical to the infectious process. In this study, we sought to identify and characterize the zinc uptake system(s) ofS. mutans, a keystone pathogen in dental caries and a causative agent of bacterial endocarditis. Different than other pathogenic bacteria, including several streptococci, that encode multiple zinc import systems, bioinformatic analysis indicated that theS. mutanscore genome encodes a single, highly conserved, zinc importer commonly known as AdcABC. Inactivation of the genes coding for the metal-binding AdcA (ΔadcA) or both AdcC ATPase and AdcB permease (ΔadcCB) severely impaired the ability ofS. mutansto grow under zinc-depleted conditions. Intracellular metal quantifications revealed that both mutants accumulated less zinc when grown in the presence of a sub-inhibitory concentration of a zinc-specific chelator. Notably, the ΔadcCBstrain displayed a severe colonization defect in a rat oral infection model. Both Δadcstrains were hypersensitive to high concentrations of manganese, showed reduced peroxide tolerance, and formed less biofilm in sucrose-containing media when cultivated in the presence of the lowest amount of zinc that support their growth, but not when zinc was supplied in excess. Collectively, this study identifies AdcABC as the lone high affinity zinc importer ofS. mutansand provides preliminary evidence that zinc is a growth-limiting factor within the dental biofilm.
Diversity and prevalence of colibactin- and yersiniabactin encoding mobile genetic elements in enterobacterial populations: insights into evolution and co-existence of two bacterial secondary metabolite determinants
Authors: Wami Haleluya , Wallenstein Alexander , Sauer Daniel , Stoll Monika , von Bünau Rudolf , Oswald Eric , Müller Rolf , Dobrindt Ulrich
Published: January 2021

1 Abstract

The bacterial genotoxin colibactin interferes with the eukaryotic cell cycle by causing double-stranded DNA breaks. It has been linked to bacterially induced colorectal cancer in humans. Colibactin is encoded by a 54-kb genomic region inEnterobacteriaceae. The colibactin genes commonly co-occur with the yersiniabactin biosynthetic determinant. Investigating the prevalence and sequence diversity of the colibactin determinant and its linkage to the yersiniabactin operon in prokaryotic genomes, we discovered mainly species-specific lineages of the colibactin determinant and classified three main structural settings of the colibactin-yersiniabactin genomic region inEnterobacteriaceae. The colibactin gene cluster has a similar but not identical evolutionary track to that of the yersiniabactin operon. Both determinants could have been acquired on several occasions and/or exchanged independently between enterobacteria by horizontal gene transfer. Integrative and conjugative elements play(ed) a central role in the evolution and structural diversity of the colibactin-yersiniabactin genomic region. Addition of an activating and regulating module (clbAR) to the biosynthesis and transport module (clbB-S) represents the most recent step in the evolution of the colibactin determinant. In a first attempt to correlate colibactin expression with individual lineages of colibactin determinants and different bacterial genetic backgrounds, we compared colibactin expression of selected enterobacterial isolatesin vitro. Colibactin production in the testedKlebsiellaspp. andCitrobacter koseristrains was more homogeneous and generally higher than that in most of theE. coliisolates studied. Our results improve the understanding of the diversity of colibactin determinants and its expression level, and may contribute to risk assessment of colibactin-producing enterobacteria.
Circuit organization of the excitatory sensorimotor loop through hand/forelimb S1 and M1
Authors: Yamawaki Naoki , Raineri Tapies Martinna G. , Stults Austin M. , Smith Gregory A. , Shepherd Gordon M. G.
Published: January 2021

Sensory-guided limb control relies on communication across sensorimotor loops. For active touch with the hand, the longest loop is the transcortical continuation of ascending pathways, particularly the lemnisco-cortical and corticocortical pathways carrying tactile signals via the cuneate nucleus, ventral posterior lateral (VPL) thalamus, and primary somatosensory (S1) and motor (M1) cortices to reach corticospinal neurons and influence descending activity. We characterized excitatory connectivity along this pathway in the mouse. In the lemnisco-cortical leg, disynaptic cuneate→VPL→S1 connections excited mainly layer (L) 4 neurons. In the corticocortical leg, S1→M1 connections from L2/3 and L5A neurons mainly excited downstream L2/3 neurons, which excite corticospinal neurons. The findings provide a detailed new wiring diagram for the hand/forelimb-related transcortical circuit, delineating a basic but complex set of cell-type-specific feedforward excitatory connections that selectively and extensively engage diverse intratelencephalic projection neurons, thereby polysynaptically linking subcortical somatosensory input to cortical motor output to spinal cord.
Moderately pathogenic maternal influenza A virus infection disrupts placental integrity but spares the fetal brain
Authors: Antonson Adrienne M. , Kenney Adam D. , Chen Helen J. , Corps Kara N. , Yount Jacob S. , Gur Tamar L.
Published: January 2021

Maternal infection during pregnancy is a known risk factor for offspring mental health disorders. Animal models of maternal immune activation (MIA) have implicated specific cellular and molecular etiologies of psychiatric illness, but most rely on pathogen mimetics. Here, we developed a mouse model of live H3N2 influenza A virus (IAV) infection during pregnancy that induces a robust inflammatory response but is sublethal to both dams and offspring. We observed lung inflammatory cytokine production and severely diminished weight gain in IAV-infected dams. This was accompanied by immune cell infiltration in the placenta and partial breakdown of placental integrity. However, indications of IL-17A signaling and fetal neuroinflammation, which are hallmarks of mimetic-induced MIA, were not detected. Our results suggest that mild or moderately pathogenic IAV infection during pregnancy does not inflame the developing fetal brain, and highlight the importance of live pathogen infection models for the study of MIA.

Highlights

A mouse model of influenza A virus (IAV) infection during pregnancy was established

Moderate IAV infection induced lung inflammation and blunted weight gain in dams

Maternal IAV infection caused mild pathology in the placenta without pup loss

Moderate gestational IAV infection did not induce fetal brain inflammation

An IAV infection severity threshold may exist for inducing fetal neuroinflammation
Analysis of Spleen Histopathology, Splenocyte composition and Hematological Parameters in Mice Infected withPlasmodium bergheiK173
Authors: Wang Huajing , Li Shuo , Cui Zhao , Qin Tingting , Shi Hang , Ma Ji , Li Lanfang , Yu Guihua , Jiang Tingliang , Li Canghai
Published: January 2021

Malaria is a fatal disease that presents clinically as a continuum of symptoms and severity, which are determined by complex host-parasite interactions. Clearance of infection is believed to be accomplished by the spleen and mononuclear phagocytic system (MPS), both in the presence and absence of artemisinin treatment. The spleen filters infected RBCs from circulation through immune-mediated recognition of the infected RBCs followed by phagocytosis. Using different strains of mice infected withP. bergheiK173 (PbK173), the mechanisms leading to splenomegaly, histopathology, splenocyte activation and proliferation, and their relationship to control of parasitemia and host mortality were examined. Survival time of mice infected with PbK173 varied, although the infection was uniformly lethal. Mice of the C57BL/6 strain were the most resistant, while mice of the strain ICR were the most susceptible. BALB/c and KM mice were intermediate. In the course of PbK173 infection, both strains of mice experienced significant splenomegaly. Parasites were observed in the red pulp at 3 days post infection in all animals. All spleens retained late trophozoite stages as well as a fraction of earlier ring-stage parasites. The percentages of macrophages in infected C57BL/6 and KM mice were higher than uninfected mice on 8 dpi. Spleens of infected ICR and KM mice exhibited structural disorganization and remodeling. Furthermore, parasitemia was significantly higher in KM versus C57BL/6 mice at 8 dpi. The percentages of macrophages in ICR infected mice were lower than uninfected mice, and the parasitemia was higher than other strains. The results presented here demonstrate the rate of splenic mechanical filtration and the splenic macrophages likely contribute to an individual’s total parasite burden. This in turn can influence the pathogenesis of malaria. Finally, different genetic backgrounds of mice have different splenic mechanisms for controlling malaria infection.
Oral epithelial cells distinguish betweenCandidaspecies with high or low pathogenic potential through miRNA regulation
Authors: Horváth Márton , Nagy Gábor , Zsindely Nóra , Bodai László , Horváth Péter , Vágvölgyi Csaba , Nosanchuk Joshua D. , Tóth Renáta , Gácser Attila
Published: January 2021

Oral epithelial cells monitor microbiome composition and initiate immune response upon dysbiosis, as in case ofCandidaimbalances. Comparison of healthy oral epithelial cell responses revealed that the inability ofC. parapsilosisto induce a robust antifungal response was due to activation of various inflammation-independent pathways, whileC. albicansrobustly activated inflammation cascades. Regarding posttranscriptional regulation, several miRNAs were altered by both species. ForC. parapsilosis,the applied dose directly correlated with changes in transcriptomic responses. Carbohydrate metabolism, hypoxia- and cardiovascular development-related responses dominate afterC. parapsilosisstimulus, whereasC. albicansaltered inflammatory responses. Subsequent analyses of HIF1-α and HSC-activation pathways predicted target genes through which miRNA-dependent regulation of yeast-specific functions may occur, supporting the observed responses. Thus,C. parapsilosisis recognized as a commensal at low doses by the oral epithelium; however, increased fungal burden activates different pathways, some of which overlap with inflammatory processes induced byC. albicans.

Impact statement

Altered miRNA regulation discriminates betweenC. albicansandC. parapsilosisin human oral epithelial cells