bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence of Post-Covid Syndrome and Associated Symptoms in Outpatient Care in Bavaria, Germany
Authors: Donnachie Ewan , Hapfelmeier Alexander , Linde Klaus , Tauscher Martin , Gerlach Roman , Greißel Anna , Schneider Antonius
Published: May 2022

Objectives

To estimate the treatment incidence of Post-Covid Syndrome in the context of office-based care in Bavaria, Germany, and to establish whether related diagnoses occur more frequently than in patients with no known history of COVID-19.

Design

Retrospective analysis of routinely collected claims data.

Setting

Office-based care in Bavaria, Germany.

Participants

391,990 patients with confirmed COVID-19 diagnosis, 62,659 patients with other respiratory infection, and a control group of 659,579 patients with no confirmed or suspected diagnosis COVID-19.

Primary and Secondary Outcome Measures

Primary outcome is diagnosis of a Post-COVID Syndrome by an office-based physician. Secondary outcomes are: Chronic Fatigue Syndrome (CFS), psychological disorder, fatigue, mild cognitive impairment, disturbances of taste and smell, dyspnea, pulmonary embolism and myalgia.

Results

Among all patients with confirmed COVID-19 infection, 14.2% (95% CI: 14.0-14.5) received a diagnosis of a Post-COVID Syndrome, and 6.7% (6.5-6.9) received the diagnosis in at least two quarterly periods during a two-year follow-up. Compared with patients with other respiratory infections and with controls, patients with COVID-19 more frequently received a variety of diagnoses including CFS (1.6% vs. 0.6% and 0.3%, respectively), fatigue (13.3% vs. 9.2% and 6.0%), dyspnea (9.9% vs. 5.1% and 3.2%) and disturbances of taste and smell (3.2% vs. 1.2% and 0.5%). The treatment incidence of Post-COVID Syndrome was highest among adults aged 40-59 (19.0%) and lowest among children aged below 12 years (2.6%).

Conclusions

Our results demonstrate a moderately high incidence of Post-COVID Syndrome two years after infection with COVID-19. There is an urgent need to find efficient and effective solutions to help patients with mental disorders, dyspnea, fatigue and loss of smell. Guidelines and treatment algorithms, including referral criteria, occupational and physical therapy, require promptly and coherent implementation. Further research is required both to find new therapeutic options and to assess the implications of Post-COVID Syndrome for health services.

Strengths and Limitations of the Study

The data cover all statutory health insurance companies in Bavaria and have high generalisability to the general population.

By considering the proportion of COVID-19 patients consulting a physician, our results are better able to differentiate between everyday complaints and medically significant illness than data from a self-reported questionnaire.

Follow-up of up to two years enables first assessment of the proportion requiring continuous care for a Post-COVID Syndrome.

The routinely collected data are not audited and contain little information regarding the severity of the symptoms.
The SARS-CoV-2 accessory factor ORF7a downregulates MHC class I surface expression
Authors: Zheng Shuxuan , de Buhr Hendrik , Praest Patrique , Evers Anouk , Brak-Boer Ingrid , van Grinsven Mariëlle , Longo Ylenia , de Vries Liset , Nijenhuis Wilco , Kapitein Lukas C. , Beekman Jeffrey M. , Nijhuis Monique , Drexler Ingo , Wiertz Emmanuel J. H. J. , Lebbink Robert Jan
Published: May 2022

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 500 million infections and more than six million deaths worldwide. Although the viral genomes of SARS-CoV-1 and SARS-CoV-2 share high sequence homology, the clinical and pathological features of COVID-19 differ profoundly from those of SARS. It is apparent that changes in viral genes contribute to the increased transmissibility of SARS-CoV-2 and pathology of COVID-19.

Cytotoxic T lymphocytes play a key role in the elimination of virus-infected cells, mediated by recognition of virus-derived peptides that are presented on MHC class I molecules. Here, we show that SARS-CoV-2 can interfere with antigen presentation thereby evading immune surveillance. SARS-CoV-2 infection of monkey and human cell lines resulted in reduced cell-surface expression of MHC class I molecules. We identified a single viral gene product, the accessory factor open reading frame 7a (ORF7a), that mediates this effect. ORF7a interacts with HLA class I molecules in the ER, resulting in ER retention or impaired HLA heavy chain (HC) trafficking to the Golgi. Ultimately, these actions result in reduced HLA class I surface expression on infected cells. Whereas ORF7a from SARS-CoV-2 reduces surface HLA class I levels, the homologous ORF7a from the 2002 pandemic SARS-CoV-1 did not, suggesting that SARS-CoV-2 ORF7a acquired the ability to downregulate HLA-I during evolution of the virus. We identified a single amino acid in the SARS-CoV-1 ORF7a luminal domain that, upon mutating to the corresponding SARS-CoV-2 ORF7a sequence, induced a gain-of-function in HLA surface downregulation. By abrogating HLA class I antigen presentation via ORF7a, SARS-CoV-2 may evade host immune responses by inhibiting anti-viral cytotoxic T cell activity, thereby contributing to the pathology of COVID-19.
Genome similarities between human-derived and mink-derived SARS-CoV-2 make mink a potential reservoir of the virus
Authors: Khalid Mohammad , Al-ebini Yousef
Published: May 2022

The SARS-CoV-2 has RNA as the genome, which makes the virus more prone to mutations. Occasionally, mutations help a virus to cross the species barrier. The SARS-CoV-2 infection to humans and minks (Neovison vison) are examples of zoonotic spillover. Many studies have been published on the analysis of human-derived SARS-CoV-2, here we performed mutation analysis on the minks-derived SARS-CoV-2 genome sequences. We analyzed all available full-length mink derived SARS-CoV-2 genome sequences on GISAID (214 from Netherlands and 133 from Denmark). We found that the mutation pattern in the Netherlands and Denmark derived samples were different. Out of a total of 201 mutations, we found in this study, only 13 mutations were common in the Netherlands and Denmark derived samples. We found 4 mutations prevailed in the Netherlands and Denmark mink derived samples and these 4 mutations are also reported to prevail in human-derived SARS-CoV-2.
The generic status ofAnacolosa(Olacaceae) in Africa withA. deniseaea new species to science of Endangered submontane forest liana from Simandou, Republic of Guinea
Authors: Cheek Martin , Molmou Denise , Gosline George , Magassouba Sekou
Published: May 2022

Anacolosa deniseaeCheek (Olacaceae) a submontane gallery forest canopy liana is described as a new species to science and assessed as Endangered using the IUCN 2012 standard due to threats of habitat destruction connected with mining. The roots smell of benzaldehyde when scraped, and the plant reproduces from root suckers. The species is restricted globally to two locations in the Loma-Man Highlands of the Republic of Guinea, all records but one being in the Pic de Fon Fôret Classé of the Simandou Range.

We show that this and the only other continental African species ascribed to the genusAnacolosa, A. unciferaof DRC, Gabon & C.A.R., differ in so many architectural, floral and vegetative characters from the remaining species of the genus, which occur from Madagascar to the Western Pacific, including the typeA. frutescens(S.E. Asia and Indo-China), that they clearly represent a separate genus. The African genus represented by these two species is unique within the Olacaceae (excluding Erythropalaceae) in being a climber (vs. shrubs or trees inAnacolosa sensu stricto). Climbing in the two African species is achieved by perennial hook-like structures formed by a combination of five separate traits each of which is unknown elsewhere in the Olacaceae. We formally delimit and describe this new genus, discussing its characteristics, but in the absence of molecular phylogenetic data, refrain from naming it.
A VPSl5-like kinase regulates apicoplast biogenesis and autophagy by promoting PI3P generation in Toxoplasma gondii
Authors: Rawat Rahul Singh , Bansal Priyanka , Sharma Pushkar
Published: May 2022

Phosphoinositides are important second messengers that regulate key cellular processes in eukaryotes. While it is know that a single phosphoinositol-3 kinase (PI3K) catalyses the formation of 3’-phosphorylated phosphoinositides (PIPs) in apicomplexan parasites Plasmodium and Toxoplasma, how its activity and PI3P formation is regulated has remained unknown. Present studies involving a unique Vps15 like protein (TgVPS15) in Toxoplasma gondii provide insights into the regulation of phosphatidyl-3-phosphate (PI3P) generation and unravel a novel pathway that regulates parasite development. Detailed investigations suggested that TgVPS15 regulates PI3P formation in Toxoplasma gondii, which is important for the inheritance of the apicoplast-a plastid like organelle present in most apicomplexans and parasite replication. Interestingly, TgVPS15 also regulates autophagy in T. gondii under nutrient-limiting conditions as it promotes autophagosome formation. For both these processes, TgVPS15 uses PI3P-binding protein TgATG18 and regulates trafficking and conjugation of TgATG8 to the apicoplast and autophagosomes, which is important for biogenesis of these organelles. TgVPS15 has a protein kinase domain but lacks several key residues conserved in conventional protein kinases. Interestingly, two critical residues in its active site are important for PI3P formation and parasitic functions of this kinase. Collectively, these studies unravel a signalling cascade involving TgVPS15, a novel effector of PI3-kinase in T. gondii and possibly other Apicomplexa, that regulate critical processes like apicoplast biogenesis and autophagy.
Genetic diversity assessment of Pacific oyster Magallana gigas (Crassostrea gigas) populations from the two southern coastal farms in South Korea
Authors: Tran Biet Thanh , Park Su-Jin , Park Hong Keun , Park Dongjin , Choi Youn Hee
Published: May 2022

South Korea is among the major producers of the Pacific oyster, Magallana gigas (Crassostrea gigas), which is one of the most valued aquaculture species. Since the early 1990s, climatic and anthropogenic factors have incurred the reduction of their wild seeds, whereby the dependence on hatchery-produced seeds has constantly increased in South Korea, thus raising concerns about losing genetic diversity and accelerating genetic deterioration. To better understand their genetic make-up, we assessed the genetic diversity of M. gigas populations from two farms (Tongyeong and Gadeokdo) in the southern coast, where about 80% of the cultivated oysters in Korea are produced. Tongyeong showed slightly higher diversity than Gadeokdo, but both populations had a similar genetic structure characterized by low nucleotide diversity. Comparative haplotype analyses provided data supporting unique genetic features of the populations that include (1) weak genotype-locality relationship, (2) low levels of gene flow between populations, and (3) seasonal fluctuation of genetic variation within a population. Furthermore, the highly alike haplotype network patterns were observed between the wild and farm populations as well as among the populations in neighboring countries, which suggests that the genetic structure is conserved between wild and hatchery populations, and geographic proximity has minimal influence on the genetic composition. These results warrant further study in biological and ecological contexts and will be invaluable in formulating genetic monitoring and sustainable long-term management of M. gigas.
Direct activation of an innate immune system in bacteria by a viral capsid protein
Authors: Zhang Tong , Tamman Hedvig , Coppieters’t Wallant Kyo , Kurata Tatsuaki , LeRoux Michele , Srikant Sriram , Brodiazhenko Tetiana , Cepauskas Albinas , Talavera Ariel , Martens Chloe , Atkinson Gemma C. , Hauryliuk Vasili , Garcia-Pino Abel , Laub Michael T.
Published: May 2022

Bacteria have evolved sophisticated and diverse immunity mechanisms to protect themselves against a nearly constant onslaught of bacteriophages1–3. Similar to how eukaryotic innate immune systems sense foreign invaders through pathogen-associated molecular patterns (PAMPs)4, many bacterial immune systems that respond to bacteriophage infection require a phage-specific trigger to be activated. However, the identities of such triggers and the mechanistic basis of sensing remain almost completely unknown. Here, we discover and investigate the anti-phage function of a fused toxin-antitoxin (TA) system called CapRelSJ46 that protects E. coli against diverse phages. Through genetic, biochemical, and structural analysis, we demonstrate that the C-terminal domain of CapRelSJ46 regulates the toxic N-terminal region, serving as both an antitoxin element and a phage-infection sensor. Following infection by certain phages, the newly synthesized major capsid protein binds directly to the C-terminal domain of CapRelSJ46 to relieve autoinhibition, enabling the toxin domain to then pyrophosphorylate tRNAs, which blocks translation to restrict viral infection. Collectively, our results reveal the molecular mechanism by which a bacterial immune system directly senses a conserved, essential component of phages, suggesting a PAMP-like sensing model for TA-mediated innate immunity in bacteria. We provide evidence that CapRels and their phage-encoded triggers are engaged in a Red Queen conflict5, revealing a new front in the intense coevolutionary battle being waged by phage and bacteria. With capsid proteins of some eukaryotic viruses known to stimulate innate immune signaling in mammalian hosts6–10, our results now reveal an ancient, deeply conserved facet of immunity.
The termination of UHRF1-dependent PAF15 ubiquitin signaling is regulated by USP7 and ATAD5
Authors: Miyashita Ryota , Nishiyama Atsuya , Chiba Yoshie , Kori Satomi , Kato Norie , Konishi Chieko , Kumamoto Soichiro , Kozuka-Hata Hiroko , Oyama Masaaki , Kawasoe Yoshitaka , Tsurimoto Toshiki , Takahashi Tatsuro S , Arita Kyohei , Nakanishi Makoto
Published: May 2022

UHRF1-dependent ubiquitin signaling plays an integral role in the regulation of maintenance DNA methylation. UHRF1 catalyzes transient dual mono-ubiquitylation of PAF15 (PAF15Ub2), which regulates the localization and activation of DNMT1 at DNA methylation sites during DNA replication. Although the initiation of UHRF1-mediated PAF15 ubiquitin signaling has been relatively well characterized, mechanisms underlying its termination and how they are coordinated with the completion of maintenance DNA methylation have not yet been clarified. This study shows that deubiquitylation by USP7 and unloading by ATAD5 (ELG1 in yeast) are pivotal processes for the removal of PAF15 from chromatin. On replicating chromatin, USP7 specifically interacts with PAF15Ub2 in a complex with DNMT1. USP7 depletion or inhibition of the interaction between USP7 and PAF15 results in abnormal accumulation of PAF15Ub2 on chromatin. Furthermore, we also find that the non-ubiquitylated form of PAF15 (PAF15Ub0) is removed from chromatin in an ATAD5-dependent manner. PAF15Ub2 was retained at high levels on chromatin when the catalytic activity of DNMT1 was inhibited, suggesting that the completion of maintenance DNA methylation is essential for termination of UHRF1-mediated ubiquitin signaling. This finding provides a molecular understanding of how the maintenance DNA methylation machinery is disassembled at the end of the S phase.
Development of fluorescent peptide G Protein Coupled Receptor activation biosensors for NanoBRET characterisation of intracellular allosteric modulators
Authors: Farmer James P , Mistry Shailesh N , Laughton Charles A , Holliday Nicholas D
Published: May 2022

G protein coupled receptors (GPCRs) are widely therapeutically targeted, and recent advances in allosteric modulator development at this class of receptors offer further potential for exploitation. In particular GPCR intracellular allosteric modulators (IAM) represent a class of ligands that bind to the receptor-effector interface (e.g. G protein) and so inhibit agonist responses non-competitively. This potentially offers a tailored mode of action and greater selectivity between conserved receptor subtypes compared to classical orthosteric ligands. However, while specific examples of the IAM class of ligands are well described (particularly for chemokine receptors), a more general methodology for assessing compound interactions at the GPCR IAM site is lacking. Here fluorescent labelled peptides based on the Gα peptide C terminus are developed as novel binding and activation biosensors for the GPCR IAM binding site. In TR-FRET binding studies, unlabelled peptides derived from the GαS subunit C-terminus were first characterised for their ability to positively modulate agonist affinity at the β2-adrenoceptor. On this basis, a tetramethylrhodamine (TMR) labelled tracer was synthesized based on the 19 amino acid C terminal GαS peptide (TMR-GαS19cha18, where cha=cyclohexylalanine). Using NanoBRET technology to detect binding, TMR-GαS19cha18 was recruited to Gs coupled β2-adrenoceptor and EP2 receptors in an agonist dependent manner (correlated with ligand efficacy), but not to the Gi coupled CXCR2 receptor. Moreover, NanoBRET competition binding assays using TMR-GαS19cha18 enabled direct assessment of the affinity of unlabelled ligands for β2-adrenoceptor IAM site. Thus the NanoBRET platform using fluorescent-labelled G protein peptide mimetics offers novel potential for medium-throughput affinity screens to identify new IAMs, applicable across GPCRs coupled to a G protein class. Using the same platform, Gs peptide biosensors also represent useful tools to probe orthosteric agonist efficacy and the dynamics of receptor activation.
Retinoic acid signaling modulation guides in vitro specification of human heart field-specific progenitor pools
Authors: Zawada Dorota , Kornherr Jessica , Meier Anna B. , Santamaria Gianluca , Dorn Tatjana , Ortmann Daniel , Lachmann Mark , Ortiz Mariaestela , Harmer Stephen C. , Nobles Muriel , Tinker Andrew , Pedersen Roger A. , Grote Phillip , Laugwitz Karl-Ludwig , Moretti Alessandra , Goedel Alexander
Published: May 2022

Cardiogenesis relies on the precise spatiotemporal coordination of multiple progenitor populations. Understanding the specification and differentiation of these distinct progenitor pools during human embryonic development is crucial for advancing our knowledge of congenital cardiac malformations and designing new regenerative therapies. By combining genetic labelling, single-cell transcriptomics, and ex vivo human-mouse embryonic chimeras we uncovered that modulation of retinoic acid signaling instructs human pluripotent stem cells to form heart field-specific progenitors with distinct fate potentials. In addition to the classical first and second heart fields, we observed the appearance of juxta-cardiac field progenitors giving rise to both myocardial and epicardial cells. Applying these findings to stem-cell based disease modelling we identified specific transcriptional dysregulation in first and second heart field progenitors derived from stem cells of a patient with hypoplastic left heart syndrome. This highlights the suitability of our in vitro differentiation platform for studying human cardiac development and disease.
Lipid-mediated organization of prestin in the outer hair cell membrane and its implications in sound amplification
Authors: Dehghani-Ghahnaviyeh Sepehr , Zhao Zhiyu , Tajkhorshid Emad
Published: May 2022

Prestin is a high-density motor protein in the outer hair cells (OHCs), whose conformational response to acoustic signals alters the shape of the cell, thereby playing a major role in sound amplification by the cochlea. Despite recent structural determination in active and inhibited states, the details of prestin’s intimate interactions with the membrane, which are central to its function remained unresolved. Here, employing a large set (collectively, more than 0.5 ms) of coarse-grained molecule dynamics simulations, we characterize the nature of prestin’s lipid-protein interactions, demonstrating their impact on the organization of prestin at densities relevant to the OHCs and its effectiveness in reshaping OHCs. Beyond local enrichment/depletion of various lipid types, prestin causes drastic anisotropic membrane deformation, which in turn mediates a preferential membrane organization of prestin in which deformation patterns by neighboring prestin copies are aligned constructively. The reduced membrane rigidity accompanying this arrangement is hypothesized to maximize the mechanical impact of prestin on OHC reshaping during cochlear sound amplification. Prestin’s preferential arrangement is further verified by extended simulations demonstrating strong correlation between prestin neighbors in their orientations. These results demonstrate a strong case of protein-protein cooperative communication in membrane, purely mediated by their interactions with lipids.
Alcohol, Opioid, and Combined Alcohol and Opioid Use Disorders Affect Shared and Unique Pathways: A Proteomic Analysis of Postmortem Brains
Authors: Leung Edison , Stertz Laura , Teixeira Antonio L. , Meyer Thomas D. , Selvaraj Sudhakar , Walss-Bass Consuelo
Published: May 2022

Substance misuse is a major burden for not only patients but the healthcare system. Understanding how substance misuse alters a patient’s genome, proteome, and neurocircuitry is an important step toward identifying targets for treatments. In this exploratory study, we performed a proteomic analysis of postmortem brain from individuals with substance misuse disorder (n=29), including alcohol (n=11) and opioid misuse disorder (n=12), or comorbidity with both disorders (n=6), compared to controls (n=12). The results demonstrate that these substances affect both common and different biological pathways compared to controls. Alcohol misuse affects primarily protein translation, rRNA processing, and energy metabolism pathways, while opioid influences G-protein signaling, protein translation, rRNA processing, energy metabolism, and angiogenesis pathways. Alcohol and opioid misuse combined appears to have a synergistic effect on protein expression of the TCA cycle, respiratory transport, mitochondrial function, LGI-ADAM interactions, interleukin signaling, neuronal system changes, and actin polymerization. These findings offer new insights into how substance misuse leads to protein alterations and how combined substance misuse leads to different protein changes compared to single substance misuse.
PAM binding ensures orientational integration during Cas4-Cas1-Cas2 mediated CRISPR adaptation
Authors: Dhingra Yukti , Suresh Shravanti K. , Juneja Puneet , Sashital Dipali G.
Published: May 2022

Adaptation in CRISPR-Cas systems immunizes bacteria and archaea against mobile genetic elements. In many DNA-targeting systems, the Cas4-Cas1-Cas2 complex is required for selection and processing of DNA segments containing PAM sequences, prior to integration of these “prespacer” substrates as spacers in the CRISPR array. We determined cryo-EM structures of the Cas4-Cas1-Cas2 adaptation complex from the type I-C system that encodes standalone Cas1 and Cas4 proteins. The structures reveal how Cas4 specifically reads out bases within the PAM sequence and how interactions with both Cas1 and Cas2 activate Cas4 endonuclease activity. The Cas4-PAM interaction ensures tight binding between the adaptation complex and the prespacer, significantly enhancing integration of the non-PAM end into the CRISPR array and ensuring correct spacer orientation. Corroborated with our biochemical results, Cas4-Cas1-Cas2 structures with substrates representing various stages of CRISPR adaptation reveal a temporally resolved mechanism for maturation and integration of functional spacers into the CRISPR array.
Decoding imagined speech reveals speech planning and production mechanisms
Authors: Orpella Joan , Mantegna Francesco , Assaneo M. Florencia , Poeppel David
Published: May 2022

Speech imagery (the ability to generate internally quasi-perceptual experiences of speech) is a fundamental ability linked to cognitive functions such as inner speech, phonological working memory, and predictive processing. Speech imagery is also considered an ideal tool to test theories of overt speech. The study of speech imagery is challenging, primarily because of the absence of overt behavioral output as well as the difficulty in temporally aligning imagery events across trials and individuals. We used magnetoencephalography (MEG) paired with temporal-generalization-based neural decoding and a simple behavioral protocol to determine the processing stages underlying speech imagery. We monitored participants’ lip and jaw micromovements during mental imagery of syllable production using electromyography. Decoding participants’ imagined syllables revealed a sequence of task-elicited representations. Importantly, participants’ micromovements did not discriminate between syllables. The decoded sequence of neuronal patterns maps well onto the predictions of current computational models of overt speech motor control and provides evidence for hypothesized internal and external feedback loops for speech planning and production, respectively. Additionally, the results expose the compressed nature of representations during planning which contrasts with the natural rate at which internal productions unfold. We conjecture that the same sequence underlies the motor-based generation of sensory predictions that modulate speech perception as well as the hypothesized articulatory loop of phonological working memory. The results underscore the potential of speech imagery, based on new experimental approaches and analytical methods, and further pave the way for successful non-invasive brain-computer interfaces.
Elicitors of plant defense induce the accumulation of amino acids that suppress both bacterial virulence and growth
Authors: Zhang Xiaomu , Tubergen Phil , Agorsor Israel , Khadka Pramod , Tempe Connor , Collakova Eva , Pilot Guillaume , Danna Cristian H.
Published: May 2022

Plant immunity relies on the perception of Microbe-Associate Molecular Patterns (MAMPs) from invading microbes to induce defense responses that suppress attempted infections. It has been proposed that MAMP-triggered immunity (MTI) suppresses bacterial infections by suppressing the onset of bacterial virulence. However, the mechanisms by which plants exert this action are poorly understood. Here we uncover that MAMP-perception in Arabidopsis induces the accumulation of free amino acids (AA) in a salicylic acid (SA) dependent manner. When co-infiltrated with Glutamine and Serine, two of the MAMP-induced highly accumulating amino acids, Pseudomonas syringae pv. tomato DC3000 expressed low levels of virulence genes and failed to produce robust infections in otherwise susceptible plants. When applied exogenously, Glutamine and Serine suppressed bacterial virulence and bacterial growth directly without the need for MAMP-perception and SA-signaling, bypassing MAMP-elicited defense. In addition, an increased level of endogenous Glutamine in the leaf apoplast of a gain-of-function mutant of Glutamine Dumper-1 rescued the partially compromised bacterial virulence and growth suppressing phenotype of the SA-induced deficient-2 (sid2) mutant. Our data suggest that MTI suppresses bacterial infections by the direct suppressing effect of accumulating amino acids on the onset of bacterial virulence.
NeuroCI: Continuous Integration of Neuroimaging Results Across Software Pipelines and Datasets
Authors: Sanz-Robinson Jacob , Jahanpour Arman , Phillips Natalie , Glatard Tristan , Poline Jean-Baptiste
Published: May 2022

—Neuroimaging study results can vary significantly depending on the datasets and processing pipelines utilized by researchers to run their analyses, contributing to reproducibility issues. These issues are compounded by the fact that there are a large variety of seemingly equivalent tools and methodologies available to researchers for processing neuroimaging data. Here we present NeuroCI, a novel software framework that allows users to evaluate the variability of their results across multiple pipelines and datasets. NeuroCI makes use of Continuous Integration (CI), a software engineering technique, to facilitate the reproducibility of computational experiments by launching a series of automated tests when code or data is added to a repository. However, unlike regular CI services, our CI-based framework uses distributed computation and storage to meet the large memory and storage requirements of neuroimaging pipelines and datasets. Moreover, the framework’s modular design enables it to continuously ingest pipelines and datasets provided by the user, and to compute and visualize results across the multiple different pipelines and datasets. This allows researchers and practitioners to quantify the variability and reliability of results in their domain across a large range of computational methods.
Facultative winter accession ofCamelina sativa(L. Crantz) with early maturity contributes to understanding of the role ofFLOWERING LOCUS Cin camelina flowering
Authors: Ott Matthew A. , Chopra Ratan , Frels Katherine , Brusa Anthony , Gjesvold Eva Serena , Marks M. David , Anderson James A.
Published: May 2022

Camelina is being developed as a winter oilseed cover crop. Early flowering and maturity are desired traits in camelina to allow for relay planting or seeding of a summer annual following camelina harvest. Here we report that while all winter biotype accessions of camelina have a functional allele ofFLOWERING LOCUS C (FLC)on chromosome 20, there are also at least 20 previously characterized spring biotype accessions that have a functionalFLCallele at this locus. We observed this by analyzing 75 accessions (67 spring type, one facultative, and seven winter type) that were resequenced by Li et al., (2020) as well as 21 additional accessions for this analysis. This discovery will inform marker assisted selection efforts that are underway to increase genetic variation in the genetically narrow base of winter camelina germplasm. Furthermore, we optimized a KASP genotyping approach that effectively differentiates the presence of either the functional or subfunctionalFLCallele on chromosome 20. These analyses identified a facultative winter biotype accession of camelina (PI650163-1, winter hardy with subfunctional chromosome 20FLCallele) that has demonstrated two years of winter-hardiness and has flowered at least a week earlier than the common winter accession, ‘Joelle’. A bioinformatics approach to cytotype analysis in camelina also provided more precise categorizing of camelina accessions in the USDA-NPGS germplasm into 2n=38 and 2n=40 cytotypes. Early maturing winter-hardy camelina will reduce stress on a subsequent soybean crop and improve total cropping system yields when camelina and soybean are grown sequentially in the same season on the same land.
MEBOCOST: Metabolite-mediated Cell Communication Modeling by Single Cell Transcriptome
Authors: Zheng Rongbin , Zhang Yang , Tsuji Tadataka , Gao Xinlei , Wagner Allon , Yosef Nir , Chen Hong , Zhang Lili , Tseng Yu-Hua , Chen Kaifu
Published: May 2022

We developed MEBOCOST, a computational algorithm for quantitatively inferring metabolite-mediated intercellular communications using single cell RNA-seq data. The algorithm identifies cell-cell communications in which metabolites, such as lipids, are secreted by sender cells and traveled to interact with sensor proteins of receiver cells. The sensor proteins on receiver cell might be cell surface receptors, transporters across the cell membrane, or nuclear receptors. MEBOCOST relies on a comprehensive database of metabolite-sensor partners, which we manually curated from the literatures and other public sources. MEBOCOST defines sender and receiver cells for an extracellular metabolite based on the expression levels of the enzymes and sensors, respectively, thus identifies metabolite-sensor communications between the cells. Applying MEBOCOST to mouse brown adipose tissue (BAT) successfully recaptured known metabolite-mediated cell communications and further identified new communications. Additionally, MEBOCOST identified a set of BAT intercellular metabolite-sensor communications that was regulated by cold exposure of the mice. MEBOCOST will be useful to numerous researchers to investigate metabolite-mediated cell-cell communications in many biological and disease models. The MEBOCOST software is freely available athttps://github.com/zhengrongbin/MEBOCOST.
Computational multiphase characterization of perfusion trends inside biomimetic reduced-order dense tumors
Authors: Akash Mohammad Mehedi Hasan , Chakraborty Nilotpal , Mohammad Jiyan , Reindl Katie , Basu Saikat
Published: May 2022

Dense fibrous extracellular constitution of solid tumors exerts high resistance to diffusive transport into it; additionally, the scarcity of blood and lymphatic flows hinders convection. The complexity of fluidic transport mechanisms in such tumor environments still presents open questions with translational end goals. For example, clinical diagnosis and targeted drug delivery platforms for such dense tumors can ideally benefit from a quantitative framework on plasma uptake into the tumor. In this study, we present a computational model for physical parameters that may influence blood percolation and penetration into a simple biomimetic solid tumor geometry. The model implements 3-phase viscous laminar transient simulation to mimic the transport physics inside a tumor-adhering blood vessel and measures the constituent volume fractions of the three considered phases, viz. plasma, RBCs (Red Blood Cells, also known as “erythrocytes”), and WBCs (White Blood Cells, also known as “leukocytes”) at three different flow times, while simultaneously recording the plasma pressure and velocity at the entry point to the tumor’s extracellular space. Subsequently, to quantify plasma perfusion within the tumor zone, we have proposed a reduced-order 2D transport model for the tumor entry zone and its extracellular space for three different fenestra diameters: 0.1, 0.3, and 0.5 μm; the simulations were 2-phase viscous laminar transient. The findings support the hypothesis that plasma percolation into the tumor is proportional to the leakiness modulated by the fenestra openings, quantifiable through the opening sizes.
Genetic evidence for parthenogenesis in small carpenter bee, Ceratina dallatoreana in its native distribution area
Authors: Mikát Michael , Straka Jakub
Published: May 2022

Arrhenotoky is typical mode of reproduction for Hymenoptera – females originate from fertilized eggs, males from unfertilized eggs. However, some lineages of Hymenoptera have switched to thelytoky, where diploid females originate instead from unfertilized diploid eggs. In the contras with some other hymenopteran lineages, thelytoky is generally very rare in bees.

Here, we examined reproduction in the small carpenter bee Ceratina dallatoreana, which is assumed to be thelytokous. We compared genotype of microsatellite loci between mothers and their offspring. Offspring were genetically identical with mother in all cases. We did not detect any male offspring. Therefore, we conclude that parthenogeny is the prevailing, and perhaps obligate, mode of reproduction in C. dallatoreana. Offspring were clones of their mother with no observed decrease of heterozygosity. Thus the cytological mode of parthenogenesis is apomixis, or automimic with central fusion and extremely reduced or non-existing recombination.

Ceratina bees are originally facultatively eusocial, therefore thelytoky may influence social evolution by causing extremely high within-colony relatedness. However, to date no multifemale nests have been recorded in C. dallatoreana.
Aridity modulates biogeographic distribution and community assembly of cyanobacterial morphotypes in drylands
Authors: Guo Xiaoyu , Li Hua , Huo Da , Li Renhui , Zhang Silong , Hu Chunxiang , Yu Gongliang , Song Lirong
Published: May 2022

The patterns of biogeographical distribution and assembly processes of microbiota are of vital importance for understanding ecological adaptation and functioning maintenance that microorganisms provide. Although the assembly of microbial communities was increasingly inspected, the role of their morphological characteristics is still poorly ascertained. Here, by integrating high-throughput sequencing and traditional trait-based classification, we investigated taxonomic and phylogenetic turnovers of different morphotypes of terrestrial cyanobacteria in biocrusts, as a model system, to evaluate the contributions of deterministic and stochastic processes across a large scale in drylands. The results showed that the bundle-forming category dominated in arid ecosystems with high tolerance against environmental fluctuations. Despite strong distance-decay relationships ofβ-diversity in all categories, both spatial composition and phylogenetic turnover rates of bundle-forming cyanobacteria were significantly lower than unicellular/colonial, heterocystous, and other non-heterocyst filamentous cyanobacteria. Null model analysis of phylogenetic signals and abundance-based neutral model found that stochastic processes prevailed in the assembly, while aridity mediated the balance between determinism and stochasticity and prompted a shifting threshold among morphotypes. Our findings provide a unique perspective to understand the role of microbial morphology, highlighting the differentiation of biogeographic distribution, environmental response, and species preference between morphotypes with consideration of potential functional consequences, and therefore facilitated the prediction of biodiversity loss under climate change.
Genetic structure and differentiation of the endemic Bolle’s Laurel Pigeon (Columba bollii) in the Canary Islands
Authors: Marrero Patricia , Fregel Rosa , Richardson David S.
Published: May 2022

Island archipelagos are global biodiversity hotspots since they often foster high concentrations of diverse lineages and endemic species. Here, we examine the population genetics of the endemic Bolle’s Laurel PigeonColumba bollii, a frugivorous bird inhabiting subtropical laurel forests. We genotyped ten microsatellite loci using DNA obtained from moulted tail feathers collected at eight sampling sites on the four western islands of the Canarian archipelago. Analyses including F-statistics, Bayesian clustering approaches, isolation by distance tests and population graph topologies, were used to infer the genetic diversity and the population differentiation within and among insular populations. Additionally, we evaluated the effect of null alleles on data analysis. Low genetic diversity was found in all populations of Bolle’s Laurel Pigeon, with no significant differences in diversity among them. However, significant genetic differentiation was detected among all populations, with pigeons from La Palma and El Hierro exhibiting the closest affinity. Bayesian clustering supported population separation between islands, and also detected fine-scale structure within the Tenerife and La Gomera populations. Present-day pigeon movements appear to occur between islands, however, this has not been sufficient to remove the signature of genetic divergence among the populations of Bolle’s Laurel Pigeon, which was moderately linked to geographical distance. According to metapopulation structure, this study suggests that the evolutionary history ofC. bolliiis closely related to the geological past of these oceanic islands and the distribution range of its habitat, the laurel forest. Finally, conservation implications for the species are discussed.
Semantic Surprise Predicts the N400 Brain Potential
Authors: Lindborg Alma , Musiolek Lea , Ostwald Dirk , Rabovsky Milena
Published: May 2022

Language is central to human life; however, how our brains derive meaning from language is still not well understood. A commonly studied electrophysiological measure of on-line meaning related processing is the N400 component, the computational basis of which is still actively debated. Here, we test one of the recently proposed, computationally explicit hypotheses on the N400 – namely, that it reflects surprise with respect to a probabilistic representation of the semantic features of the current stimulus in a given context. We devise a Bayesian sequential learner model to derive trial-by-trial semantic surprise in a semantic oddball like roving paradigm experiment, where single nouns from different semantic categories are presented in sequences. Using experimental data from 40 subjects, we show that model-derived semantic surprise significantly predicts the N400 amplitude, substantially outperforming a non-probabilistic baseline model. Investigating the temporal signature of the effect, we find that the effect of semantic surprise on the EEG is restricted to the time window of the N400. Moreover, comparing the topography of the semantic surprise effect to a conventional ERP analysis of predicted vs. unpredicted words, we find that the semantic surprise closely replicates the N400 topography. Our results make a strong case for the role of probabilistic semantic representations in eliciting the N400, and in language comprehension in general.

Significance Statement

When we read or listen to a sentence, our brain continuously analyses its meaning and updates its understanding of it. The N400 brain potential, measured with electrophysiology, is modulated by on-line, meaning related processing. However, its computational underpinnings are still under debate. Inspired by studies of mismatch potentials in perception, here we test the hypothesis that the N400 indexes the surprise of a Bayesian observer of semantic features. We show that semantic surprise predicts the N400 amplitude to single nouns in an oddball like roving paradigm with nouns from different semantic categories. Moreover, the semantic surprise predicts the N400 to a much larger extent than a non-probabilistic baseline model. Our results thus yield further support to the Bayesian brain hypothesis.
Shallow nanopore RNA sequencing enables transcriptome profiling for precision cancer medicine
Authors: Mock Andreas , Braun Melissa , Scholl Claudia , Fröhling Stefan , Erkut Cihan
Published: May 2022

Transcriptome profiling is a mainstay of translational cancer research and is increasingly finding its way into precision oncology. While bulk RNA sequencing (RNA-seq) is widely available, high costs and long data return time are limiting factors for clinical applications. We investigated a portable nanopore long-read sequencing device (MinION, Oxford Nanopore Technologies) for transcriptome profiling of tumors. In particular, we investigated the impact of lower coverage than that of larger sequencing devices by comparing shallow nanopore RNA-seq data with short-read RNA-seq data generated using reversible dye terminator technology (Illumina) for ten samples representing four cancer types. Coupled with ShaNTi (Shallow Nanopore Sequencing for Transcriptomics), a newly developed data processing pipeline, a turnaround time of five days was achieved. The correlation of normalized gene-level counts between nanopore and Illumina RNA-seq was high for MinION but not for very low-throughput Flongle flow cells (r = 0.89 and r = 0.24, respectively). A cost-saving approach based on multiplexing of four samples per MinION flow cell maintained a high correlation with Illumina data (r = 0.56 – 0.86). In addition, we compared the utility of nanopore and Illumina RNA-seq data for analysis tools commonly applied in translational oncology: (i) Shallow nanopore and Illumina RNA-seq were equally useful for inferring signaling pathway activities with PROGENy. (ii) Highly expressed genes encoding kinases targeted by clinically approved small-molecule inhibitors were reliably identified by shallow nanopore RNA-seq. (iii) In tumor microenvironment composition analysis, quanTIseq performed better than CIBERSORT, likely due to higher average expression of the gene set used for deconvolution. (iv) Shallow nanopore RNA-seq was successfully applied to validate known gene fusions by breakpoint analysis. These findings suggest that shallow nanopore RNA-seq enables rapid, cost-effective, and biologically meaningful transcriptome profiling of tumors and warrants further exploration in precision cancer medicine studies.
P176S polymorphism in Maspin rewires electrostatic interaction that alters Maspin functionality
Authors: Anwar Muhammad Ayaz , Haseeb Muhammad , Choi Sangdun , Kwong-Pyo Kim
Published: May 2022

Maspin has been known to regress tumors by inhibiting angiogenesis, however, its roles have been reported to be context and sequence-dependent. There are various proteins and cofactors that bind with maspin possibly explaining the conflicting roles of maspin. Moreover, maspin polymorphic forms have also been linked to tumor regression or survival, for instance, maspin with Ser at 176 (maspin-S176) promotes tumor while maspin with Pro at 176 (maspin-Pro176) has opposing roles in cancer pathogenesis. With the help of long molecular dynamic simulation, a possible link between polymorphic forms and tumor progression has been established. First, the maspin is dynamically stable with either amino acid at 176 position, secondly, differential contacts have been observed among various regions, thirdly, these contacts have significantly altered the electrostatic energetics of various residues, and finally, these altered electrostatics of maspin-S176 and maspin-P176 rewired the polar contacts that abolished the allosteric control in protein. By combining these factors, the altered electrostatics can substantially affect the localization, and the preference of maspin binding partners, thus, culminating in a different maspin-protein (cofactor)-interaction landscape that could have been manifested with conflicting reports in previous studies. Here, the underlying reason has been highlighted and discussed that could be helpful for better therapeutic manipulations.

Significance

Protein altered functions in response to mutations are well documented, however, a slight perturbation in structure can lead to dramatic effects that are being felt at longer distances are rare. Here, we have reported that the substitution of Pro to Ser at 176th position in Maspin can substantially alter the protein electrostatic interactions that can hamper the allosteric control. This could lead to different binding partners, localization preferences, and altered cytoplasmic retention duration resulting in functions that are not associated with normal protein. Moreover, the electrostatic attraction/repulsion can immensely affect the allosteric cohesion of protein resulting in unexpected outcomes.