bluuebunny/crossref_metadata_2025 huggingface dataset:
Resolving the mesoscopic missing link: Biophysical modeling of EEG from cortical columns in primates
Authors: Herrera Beatriz , Westerberg Jacob A. , Schall Michelle S. , Maier Alexander , Woodman Geoffrey F. , Schall Jeffrey D. , Riera Jorge J.
Published: March 2022

Event-related potentials (ERP) are among the most widely measured indices for studying human cognition. While their timing and magnitude provide valuable insights, their usefulness is limited by our understanding of their neural generators at the circuit level. Inverse source localization offers insights into such generators, but their solutions are not unique. To address this problem, scientists have assumed the source space generating such signals comprises a set of discrete equivalent current dipoles, representing the activity of small cortical regions. Based on this notion, theoretical studies have employed forward modeling of scalp potentials to understand how changes in circuit-level dynamics translate into macroscopic ERPs. However, experimental validation is lacking because it requires in vivo measurements of intracranial brain sources. Laminar local field potentials (LFP) offer a mechanism for estimating intracranial current sources. Yet, a theoretical link between LFPs and intracranial brain sources is missing. Here, we present a forward modeling approach for estimating mesoscopic intracranial brain sources from LFPs and predict their contribution to macroscopic ERPs. We evaluate the accuracy of this LFP-based representation of brain sources utilizing synthetic laminar neurophysiological measurements and then demonstrate the power of the approach in vivo to clarify the source of a representative cognitive ERP component. To that end, LFP was measured across the cortical layers of visual area V4 in macaque monkeys performing an attention demanding task. We show that area V4 generates dipoles through layer-specific transsynaptic currents that biophysically recapitulate the ERP component through the detailed forward modeling. The constraints imposed on EEG production by this method also revealed an important dissociation between computational and biophysical contributors. As such, this approach represents an important bridge from the mesoscopic activity of cortical columns to the patterns of EEG we measure at the scalp.

Highlights

Cognitive EEG production was accurately modeled from empirically measured cortical activity in awake macaques.

V4 laminar activity plausibly generates the attention-related signal indexed by the EEG.

Models demonstrate the importance of biophysical geometry in cognitive EEG production.
SciCV, the Swiss National Science Foundation’s new CV format
Authors: Strinzel Michaela , Kaltenbrunner Wolfgang , van der Weijden Inge , von Arx Martin , Hill Michael
Published: March 2022

Background

The Swiss National Science Foundation (SNSF) tested a new CV format called SciCV to encourage fair, DORA-compliant assessment of grant applicants. It was developed in close collaboration with the academic evaluation community and international experts, introduced through detailed change management and finally tested in its utility by an independent research team of the Center for Science and Technology Studies Leiden (CWTS).

Methods

We present the development of the SciCV pilot and its evaluation by the CWTS research group. The analysis comprised both quantitative and qualitative methods, with (i) surveys and semi-structured interviews with applicants and reviewers, (ii) text analysis of the narrative elements of SciCV, and (iii) participant observation in ten evaluation panel meetings.

Results

Narrative elements and the inclusion of the academic age were rated as most useful new CV elements, while the inclusion of two metrics, the h-index and the relative citation ratio, were received more critically. The omission of a full publication list had similar numbers of supporters and opponents among applicants and reviewers. Less experienced and junior applicants and reviewers rated the new format generally more positively than more senior applicants and reviewers. The text analysis of narrative elements yielded no significant gender specific differences. The participant observation revealed that the new elements in SciCV broadened the information base used in the evaluation of applicants but did not fundamentally alter traditional, publication-centred evaluation practices.

Conclusion

SciCV was a relevant and successful initiative for the SNSF, which showed that the implementation of a new, well-structured CV format is not only feasible but also something that many stakeholders welcome.The extensive experience and results obtained during the change process formed the basis for the development of SciCV 2.0 at the SNSF. It also offers a basis and guidance for other funding organisations planning similar initiatives.
New features of micro-RNA regulation of mRNA translation and stability revealed by expression of targeted or not targeted reporter genes
Authors: Hudy Dorota , Rzeszowska-Wolny Joanna
Published: March 2022

The existence of translation regulation by RNA-induced silencing complexes (RISCs) composed from Argonaute proteins and micro-RNAs is well established, however the mechanisms underlying specific cellular and miRNA effects and the way in which specific complexes arise are not completely clear.

Here we describe experiments withRenillaandFireflyluciferase reporter genes transfected on a PsiCheck2 plasmid into human cancer HCT116 or Me45 cells where only theRenillagene contained or not sequences targeted by micro RNAs (miRNAs) in the 3’UTR. The effects of targeting were miRNA-specific; miRNA-21 caused strong inhibition of translation whereas miRNA-24 or Let-7 caused no change or an increase in global reporterRenillaluciferase synthesis, and the mRNA-protein complexes formed by reporter transcripts in both cell types differed as shown by sucrose gradient sedimentation. In both cell types the presence of miRNA targets onRenillatranscripts affected expression of the co-transfected non-targetedFireflyluciferase, andRenillaandFireflytranscripts were found in the same sucrose gradient fractions. We also observed that specific anti-miRNA oligoribonucleotides influenced expression of theFireflyas well as of theRenillagene, suggesting modulation of non-targeted transcript expression by miRNAs. Our results indicate the existence of interactions between miRNA-regulated and -unregulated transcripts and suggest that the use of the latter as a normalizers in experiments may be biased. We also discuss some hypothetical mechanisms which could explain the observed miRNA-induced effects.
Mesembryanthemum crystallinum plasma membrane root aquaporins are regulated via clathrin-coated vesicles in response to salt stress
Authors: Gómez-Méndez María Fernanda , Vera-Estrella Rosario , Amezcua-Romero Julio César , Rosas-Santiago Paul , Hernández-Domínguez Eric Edmundo , de Luna-Valdez Luis Alberto , Pantoja Omar
Published: March 2022

The regulation of PIP-type aquaporins in the roots of plants has been identified as an important aspect in salinity tolerance. However, the molecular and cellular details underlying this process in halophytes remain unclear. Using free flow electrophoresis and label-free proteomics, we report that the increased abundance of PIPs at the plasma membrane of Mesembryanthemum crystallinum roots under salinity conditions is regulated by clathrin-coated vesicles (CCVs). To understand this regulation, we analyzed several components of the M. crystallinum CCVs complexes: clathrin light chain (McCLC) and subunits μ1 and μ2 of the adaptor complex (McAP1μ and McAP2μ). Co-localization analyses revealed the association between McPIP1;4 and McAP2μ and between McPIP2;1 and McAP1μ, observations corroborated by mbSUS assays, suggesting that aquaporin abundance at the PM is under the control of CCVs. The ability of McPIP1;4 and McPIP2;1 to form homo- and hetero-oligomers was tested and confirmed, as well as their activity as water channels. Also, we found increased phosphorylation of McPIP2;1 only at plasma membrane in response to salt stress. Our results prompt how root PIPs from halophytes are regulated through CCVs trafficking and phosphorylation, impacting their localization, transport activity and abundance under salinity conditions.

One-sentence summary

Abundance of plasma membrane aquaporins in M. crystallinum roots increases in response to salinity via a clathrin-coated vesicle-dependent mechanism.
Hiplot: a comprehensive and easy-to-use web service boosting publication-ready biomedical data visualization
Authors: Li Jianfeng , Miao Benben , Wang Shixiang , Dong Wei , Xu Houshi , Si Chenchen , Wang Wei , Duan Songqi , Lou Jiacheng , Bao Zhiwei , Zeng Hailuan , Yang Zengzeng , Cheng Wenyan , Zhao Fei , Zeng Jianming , Liu Xue-Song , Wu Renxie , Shen Yang , Chen Zhu , Chen Saijuan , Wang Mingjie ,   Hiplot Consortium
Published: March 2022

Modern web techniques provide an unprecedented opportunity for leveraging complex biomedical data generating in clinical, omics, and mechanism experiments. Currently, the functions for carrying out publication-ready biomedical data visualization represent primary technical hurdles in the state-of-art omics-based web services, whereas the demand for visualization-based interactive data mining is ever-growing. Here, we propose an easy-to-use web service, Hiplot (https://hiplot.com.cn), equipping with comprehensive and interactive biomedical data visualization functions (230+) including basic statistics, multi-omics, regression, clustering, dimensional reduction, meta-analysis, survival analysis, risk modeling, etc. We used the demo and real datasets to demonstrate the usage workflow and the core functions of Hiplot. It permits users to conveniently and interactively complete a few specialized visualization tasks that previously could only be done by senior bioinformatics or biostatistics researchers. A modern web client with efficient user interfaces and interaction methods has been implemented based on the custom components library and the extensible plugin system. The versatile output can also be produced in different environments via using the cross-platform portable command-line interface (CLI) program, Hctl. A switchable view between the editable data table and the file uploader/path selection could facilitate data importing, previewing, and exporting, while the plumber-based response strategy significantly reduced the time costs for generating basic scientific graphics. Diversified layouts, themes/styles, and color palettes in this website allow users to create high-quality and publication-ready graphics. Researchers devoted to both life and data science may benefit from the emerging web service.
Assessing performance and clinical usefulness in prediction models with survival outcomes: practical guidance for Cox proportional hazards models
Authors: McLernon David J , Giardiello Daniele , Van Calster Ben , Wynants Laure , van Geloven Nan , van Smeden Maarten , Therneau Terry , Steyerberg Ewout W
Published: March 2022

Risk prediction models need thorough validation to assess their performance. Validation of models for survival outcomes poses challenges due to the censoring of observations and the varying time horizon at which predictions can be made. We aim to give a description of measures to evaluate predictions and the potential improvement in decision making from survival models based on Cox proportional hazards regression.

As a motivating case study, we consider the prediction of the composite outcome of recurrence and death (the ‘event’) in breast cancer patients following surgery. We develop a Cox regression model with three predictors as in the Nottingham Prognostic Index in 2982 women (1275 events within 5 years of follow-up) and externally validate this model in 686 women (285 events within 5 years). The improvement in performance was assessed following the addition of circulating progesterone as a prognostic biomarker.

The model predictions can be evaluated across the full range of observed follow up times or for the event occurring by a fixed time horizon of interest. We first discuss recommended statistical measures that evaluate model performance in terms of discrimination, calibration, or overall performance. Further, we evaluate the potential clinical utility of the model to support clinical decision making. SAS and R code is provided to illustrate apparent, internal, and external validation, both for the three predictor model and when adding progesterone.

We recommend the proposed set of performance measures for transparent reporting of the validity of predictions from survival models.
Founder effect contributes to the unique pattern of SARS-CoV-2 variant B.1.1.519 emergence in Alaska
Authors: Haan Tracie J. , Smith Lisa K. , DeRonde Stephanie , House Elva , Zidek Jacob , Puhak Diana , Redlinger Matthew , Parker Jayme , Barnes Brian M. , Burkhead Jason L. , Knall Cindy , Bortz Eric , Chen Jack , Drown Devin M.
Published: March 2022

Alaska is the largest geographic state in the United States with the lowest population density and a mix of urban centers and isolated rural communities. The differences in population dynamics in Alaska from the contiguous United States may have contributed to a unique pattern of emergence and spread of SARS-CoV-2 variants observed in early 2021. Here we examined 2,323 virus genomes from Alaska and 278,635 virus genomes from the contiguous United States collected between the first week of December 2020 through the last week of June 2021. We focused on this timeframe because of the notable emergence and spread of the SARS-CoV-2 lineage B.1.1.519 observed in Alaska. We found that this variant was consistently detected in Alaska from the end of January through June of 2021 with a peak prevalence in April of 77.9% unlike the rest of the United States with a peak prevalence of 4.6%. In Alaska, the earlier emergence of B.1.1.519 coincided with a later peak of Alpha (B.1.1.7) when compared to the rest of the United States. We also observed differences in the composition of lineages and variants over time between the two most populated regions of Alaska. Although there was a modest increase in COVID-19 cases during the peak incidence of B.1.1.519, it is difficult to disentangle how social dynamics conflated changes in COVID-19 during this time. We suggest that the viral characteristics, such as amino acid substitutions in the spike protein, and a founder effect likely contributed to the unique spread of B.1.1.519 in Alaska.
SARS-CoV-2 virus dynamics in recently infected people – data from a household transmission study
Authors: Mellis Alexandra M. , Meece Jennifer K , Halasa Natasha B. , Chappell James D. , McLean Huong Q. , Grijalva Carlos G. , Hanson Kayla E. , Zhu Yuwei , Kim Ahra , Deyoe Jessica , Ivacic Lynn C. , Reed Carrie , Talbot H. Keipp , Rolfes Melissa A.
Published: March 2022

We used daily real-time reverse-transcription polymerase chain reaction (rRT-PCR) results from 67 cases of SARS-CoV-2 infection in a household transmission study to examine the trajectory of cycle threshold (Ct) values, an inverse correlate of viral RNA concentration, from nasal specimens collected between April 2020 and May 2021. Ct values varied over the course of infection, across RT-PCR platforms, and by participant age. Specimens collected from children and adolescents showed higher Ct values and adults aged ≥50 years showed lower Ct values than adults aged 18-49 years. Ct values were lower on days when participants reported experiencing symptoms.
From Delta to Omicron SARS-CoV-2 variant: switch to saliva sampling for higher detection rate
Authors: Cornette Margot , Decaesteker Bieke , Martens Geert Antoine , Vandecandelaere Patricia , Jonckheere Stijn
Published: March 2022

Background

Real-time polymerase chain reaction (RT-PCR) testing on a nasopharyngeal swab is the current standard for SARS-CoV-2 virus detection. Since collection of this sample type is experienced uncomfortable by patients, saliva- and oropharyngeal swab collections should be considered as alternative specimens.

Objectives

Evaluation of the relative performance of oropharyngeal swab, nasopharyngeal swab and saliva for the RT-PCR based SARS-CoV-2 Delta (B.1.617.2) and Omicron (B.1.1.529) variant detection.

Study design

Nasopharyngeal swab, oropharyngeal swab and saliva were collected from 246 adult patients who presented for SARS-CoV-2 testing at the screening centre in Ypres (Belgium). RT-PCR SARS-CoV-2 detection was performed on all three sample types separately. Variant type was determined for each positive patient using whole genome sequencing or Allplex SARS-CoV-2 variants I and II Assay.

Results and conclusions

Saliva is superior compared to nasopharyngeal swab for the detection of the Omicron variant. For the detection of the Delta variant, nasopharyngeal swab and saliva can be considered equivalent specimens. Oropharyngeal swab is the least sensitive sample type and shows little added value when collected in addition to a single nasopharyngeal swab.

Highlights

Saliva is the preferred sample type for Omicron variant (B.1.1.529) detection

Nasopharyngeal swab and saliva are equivalent for Delta variant (B.1.617.2) detection

Oropharyngeal swab is the least preferred sample type for SARS-CoV-2 detection
Updated population-level estimates of child restraint practices among children aged 0-12 years in Australia, ten years after introduction of age-appropriate restraint use legislation
Authors: Brown Julie , Albanese Bianca , Ho Catherine , Elkington Jane , Koppel Sjaan , Charlton Judith L. , Olivier Jake , Keay Lisa , Bilston Lynne E
Published: March 2022

Objective

To determine child restraint practices approximately 10 years after introduction of legislation requiring correct use of age-appropriate restraints for all children aged up to 7 years.

Methods

A stratified cluster sample was constructed to collect observational data from children aged 0-12 years across the Greater Sydney region of NSW. Methods replicated those used in a similar 2008 study. Population weighted estimates for restraint practices were generated, and logistic regression used to examine associations between restraint type, and child age with correct use accounting for the complex sample.

Results

Almost all children were appropriately restrained (99.3%, 95% CI 98.4-100). However, less than half were correctly restrained (No error = 27.3%, 95% CI 10.8-43.8, No serious error = 43.8%, 95% CI 35.0-52.7). Forany error, the odds of error decreased by 39% per year of age (OR 0.61, 95% 0.46-0.81), and for serious error by 25% per year (OR 0.75 95% CI 0.60-0.93).

Conclusion

The findings demonstrate a substantial increase in appropriate child restraint, but no real change in correct use.

Implications for Public Health

Given the negative impact incorrect use has on crash protection, continuing high rates of incorrect use may reduce effectiveness of legislative change on injury reduction.
Maintaining hypoxia environment of subchondral bone alleviates osteoarthritis progression
Authors: Zhang Hao , Wang Lipeng , Cui Jin , Wang Sicheng , Han Yafei , Shao Hongda , Wang Cheng , Hu Yan , Li Xiaoqun , Zhou Qirong , Guo Jiawei , Zhuang Xinchen , Sheng Shihao , Zhang Tao , Zhou Dongyang , Chen Jiao , Wang Fuxiao , Gao Qianmin , Jing Yingying , Chen Xiao , Su Jiacan
Published: March 2022

Abnormal subchondral bone remodeling featured by over-activated osteoclastogenesis leads to articular cartilage degeneration and osteoarthritis (OA) progression, but the mechanism is still unclear. In this study, we used lymphocyte cytosolic protein 1 (Lcp1) knock-out mice to suppress subchondral osteoclast formation in mice OA model with anterior cruciate ligament transection (ACLT) and Lcp1-/- mice showed decreased bone remodeling and sensory innervation in subchondral bone accompanied by retarded cartilage degeneration. For mechanisms, in wildtype mice with ACLT the activated osteoclasts in subchondral bone induced type-H vessels and elevated oxygen concentration which ubiquitylated hypoxia-inducible factor 1α (HIF-1α), vital for maintaining chondrocyte homeostasis in articular chondrocytes and led to cartilage degeneration. Deletion of Lcp1 impeded osteoclast-mediated angiogenesis, which maintained the low levels of oxygen partial pressure (pO2) in subchondral bone as well as the whole joint and delayed the OA progression. Stabilization of HIF-1α delayed cartilage degeneration and knockdown of Hif1a abolished the protective effects of Lcp1 knockout. Notably, we identified a novel subgroup of hypertrophic chondrocytes highly associated with OA by single cell sequencing analysis of human articular chondrocytes. Lastly, we showed that Oroxylin A, an Lcp1-encoded protein L-plastin (LPL) inhibitor, could alleviate OA progression. In conclusion, maintaining hypoxic environment in subchondral bone is an attractive strategy for OA treatment.

Teaser

Inhibiting subchondral osteoclastogenesis alleviates OA progression via maintaining joint hypoxia environment.
DUF581-9 (At2g44670; FLZ3) negatively regulates SnRK1 activity by interference with T-loop phosphorylation
Authors: Bortlik Jennifer , Lühle Jost , Alseekh Saleh , Weiste Christoph , Fernie Alisdair R. , Dröge-Laser Wolfgang , Börnke Frederik
Published: March 2022

In plants, SUCROSE NON-FERMENTING RELATED KINASE 1 (SnRK1) is a key energy-sensor that orchestrates large-scale transcriptional reprogramming to maintain cellular homeostasis under energy deficit. SnRK1 activity is under tight negative control, although the exact mechanisms leading to its activation are far from being understood. We show that the Arabidopsis DOMAIN OF UNKNOWN FUNCTION (DUF581) protein DUF581-9/FLZ3 binds to the catalytic SnRK1α subunit KIN10 to inhibit its activation by GRIK-dependent T-loop phosphorylation. Overexpression of DUF581-9 in Arabidopsis dampens SnRK1 signalling and interferes with adaptation to dark-induced starvation. The presence of DUF581-9 significantly reduced SnRK1 activity in protoplasts and in vitro. This was accompanied by a reduction in T175 T-loop phosphorylation and also diminished KIN10 auto-phosphorylation. Furthermore, DUF581-9 reduced binding of the up-stream activating kinase GRIK2 to KIN10, explaining the reduced KIN10 T-loop phosphorylation. Ectopically expressed DUF581-9 protein was rapidly turned over by the proteasome when Arabidopsis plants were subjected to starvation treatment, likely releasing its inhibitory activity on the SnRK1 complex. Taken together, our results support a model in which DUF581-9 negatively regulates SnRK1 activity under energy sufficient conditions. Turnover over of the protein provides a rapid way for SnRK1 activation under energy deficit without the need of de-novo protein synthesis.
Establishment of an efficient transformation and CRISPR/Cas9-mediated gene editing system in Chinese local planting cassava (Manihot esculenta Crantz) cultivar SC8
Authors: Wang Yajie , Lu Xiaohua , Zhen Xinghou , Yang Hui , Che Yannian , Hou Jingyi , Li Ruimei , Liu Jiao , Geng Mengting , Hu Xinwen , Yao Yuan , Guo Jianchun
Published: March 2022

Cassava starch is a widely used raw material for industrial production. South Chinese cassava cultivar 8 (Manihot esculenta Crantz cv. SC8) is one of the main locally planted cultivars. In this study, an efficient transformation system for cassava SC8 mediated with Agrobacterium strain LBA4404 was presented for the first time, in which the factors of Agrobacterium strain cell infection (density OD600 = 0.65), 250 µM acetosyringone induction, and agro-cultivation with wet friable embryogenic callus (FEC) for 3 days in dark conditions were found to increase the transformation efficiency through the binary vector pCAMBIA1304 harboring GUS- and GFP-fused genes driven by the CaMV35S promoter. Based on the optimized transformation protocol, approximately 120-140 independent transgenic lines per mL settled FEC cell volume (SCV) by gene transformation in approximately five months, and 45.83% homozygous mono-allelic mutations of the MePDS gene with a YAO promoter-driven CRISPR/Cas9 system were generated. This study will open a more functional avenue for the genetic improvement of cassava SC8.
Maternal H3K36 and H3K27 HMTs protect germline immortality via regulation of the transcription factor LIN-15B
Authors: Cockrum Chad , Strome Susan
Published: March 2022

Maternally synthesized products play critical roles in development of offspring. A premier example is the C. elegans H3K36 methyltransferase MES-4, which is essential for germline survival and development in offspring. How maternal MES-4 protects germline immortality is not well understood, but its role in H3K36 methylation hinted that it may regulate gene expression in Primordial Germ Cells (PGCs). We tested this hypothesis by profiling transcripts from single pairs of PGCs dissected from wild-type and mes-4 mutant (lacking maternal and zygotic MES-4) newly hatched larvae. We found that mes-4 PGCs display normal turn-on of most germline genes and normal repression of somatic genes, but dramatically up-regulate hundreds of genes on the X chromosome. We demonstrated that X mis-expression is the cause of germline death by generating and analyzing mes-4 mutants that inherited different endowments of X chromosome(s). Intriguingly, removal of the THAP transcription factor LIN-15B from mes-4 mutants reduced X mis-expression and prevented germline death. lin-15B is X-linked and mis-expressed in mes-4 PGCs, identifying it as a critical target for MES-4 repression. The above findings extend to the H3K27 methyltransferase MES-2/3/6, the C. elegans version of Polycomb Repressive Complex 2. We propose that maternal MES-4 and PRC2 cooperate to protect germline survival by preventing synthesis of germline-toxic products encoded by genes on the X chromosome, including the key transcription factor LIN-15B.
Structure and functional mapping of the KRAB-KAP1 repressor complex
Authors: Stoll Guido A. , Pandiloski Ninoslav , Douse Christopher H. , Modis Yorgo
Published: March 2022

Transposable elements (TEs) are a genetic reservoir from which new genes and regulatory elements can emerge. Expression of TEs can be pathogenic, however, and is tightly regulated. KRAB domain-containing zinc finger proteins (KRAB-ZFPs) recruit co-repressor KRAB-associated protein 1 (KAP1/TRIM28) to regulate many TEs but how KRAB-ZFPs and KAP1 interact remains unclear. Here, we report the crystal structure of the KAP1 tripartite motif (TRIM) in complex with the KRAB domain from a human KRAB-ZFP, ZNF93. Structure-guided mutations in the KAP1-KRAB binding interface abolished repressive activity in an epigenetic TE silencing assay. Deposition of H3K9me3 over thousands of loci is lost genome-wide in cells expressing a KAP1 variant with mutations that abolish KRAB binding. Our work identifies and functionally validates the KRAB-KAP1 molecular interface, which forms the nexus of a transcriptional control axis vital to vertebrates and underpins programmable gene repression by CRISPRi.
The faecal microbiome of the wild European badger Meles meles; a comparison against other wild omnivorous mammals from across the globe
Authors: Scott-Baumann James , Friedersdorff Jessica C A , Villarreal-Ramos Bernardo , King Jonathan , Hopkins Beverley , Pizzey Richard , Rooke David , Hewinson Glyn , Mur Luis A. J.
Published: March 2022

Here we investigate the faecal microbiome of wild European badgers Meles meles using samples collected at post-mortem as part of the All Wales Badger Found Dead study based on sequencing the V3-V4 region of the 16S rRNA gene. This is the first published characterisation of the badger microbiome. We initially undertook a sex-matched age comparison between the adult and cub microbiomes. Analysis used the QIIME 2 pipeline utilising DADA2 and the Silva database for taxonomy assignment. Fusobacteria appeared to be more abundant in the microbiomes of the cubs than the adults although no significant difference was seen in alpha or beta diversity between the adult and cub badger microbiomes. Comparisons were also made against other wild, omnivorous, mammals’ faecal microbiomes using publicly available data. Significant differences were seen in both alpha and beta diversity between the microbiomes from different species. As a wildlife species of interest to the disease bovine tuberculosis, knowledge of the faecal microbiome could assist in identification of infected badgers. Our work here suggests that if comparisons were made between the faeces of bTB infected and non-infected badgers, its possible age may not have a significant impact on the microbiome.
Distinguishing fine structure and summary representation of sound textures from neural activity
Authors: Berto Martina , Ricciardi Emiliano , Pietrini Pietro , Weisz Nathan , Bottari Davide
Published: March 2022

The auditory system relies on both local and summary representations; acoustic local features exceeding system constraints are compacted into a set of summary statistics. Such compression is pivotal for sound-object recognition. Here, we assessed whether computations subtending local and statistical representations of sounds could be distinguished at the neural level. A computational auditory model was employed to extract auditory statistics from natural sound textures (i.e., fire, rain) and to generate synthetic exemplars where local and statistical properties were controlled. Twenty-four human participants were passively exposed to auditory streams while the EEG was recorded. Each stream could consist of short, medium, or long sounds to vary the amount of acoustic information. Short and long sounds were expected to engage local or summary statistics representations, respectively. Data revealed a clear dissociation. Compared to summary-based ones, auditory-evoked responses based on local information were selectively greater in magnitude in short sounds. Opposite patterns emerged for longer sounds. Neural oscillations revealed that local features and summary statistics rely on neural activity occurring at different temporal scales, faster (beta) or slower (theta-alpha). These dissociations emerged automatically without explicit engagement in a discrimination task. Overall, this study demonstrates that the auditory system developed distinct coding mechanisms to discriminate changes in the acoustic environment based on fine structure and summary representations.

SIGNIFICANCE STATEMENT

Prior to this study, it was unknown whether we could measure auditory discrimination based on local temporal features or spectrotemporal statistics properties of sounds from brain responses. Results show that the two auditory modes of sound discrimination (local and summary statistics) are automatically attuned to the temporal resolution (high or low) at which a change has occurred. In line with the temporal resolutions of auditory statistics, faster or slower neural oscillations (temporal scales) code sound changes based on local or summary representations. These findings expand our knowledge of some fundamental mechanisms underlying the function of the auditory system.
High-resolution secretory timeline from vesicle formation at the Golgi to fusion at the plasma membrane in S. cerevisiae
Authors: Gingras Robert M. , Sulpizio Abigail M. , Park Joelle , Bretscher Anthony
Published: March 2022

Most of the components in the yeast secretory pathway have been studied, yet a high resolution temporal timeline of their participation is lacking. Here we define the order of acquisition, lifetime, and release of critical components involved in late secretion from the Golgi to the plasma membrane. Of particular interest is the timing of the many reported effectors of the secretory vesicle Rab protein Sec4, including the myosin-V Myo2, the exocyst complex, the lgl homolog Sro7, and the small yeast-specific protein Mso1. At the trans-Golgi network (TGN) Sec4’s GEF, Sec2, is recruited to Ypt31-positive compartments, quickly followed by Sec4 and Myo2 and vesicle formation. While transported to the bud tip, the entire exocyst complex, including Sec3, is assembled on to the vesicle. Before fusion, vesicles tether for 5s, during which the vesicle retains the exocyst complex and stimulates lateral recruitment of Rho3 on the plasma membrane. Sec2 and Myo2 are rapidly lost, followed by recruitment of cytosolic Sro7, and finally the SM protein Sec1, which appears for just 2 seconds prior to fusion. Perturbation experiments reveal an ordered and robust series of events during tethering that provide insights into the function of Sec4 and effector exchange.
Transcriptional control of the lacZ promoter is under directional and diversifying selection
Authors: Vlková Markéta , Silander Olin K.
Published: March 2022

Bacterial cells often respond to changes in the environment by modifying protein expression. This can be achieved through changes in transcriptional or translational activity, or both. Recent research has shed some light on how natural selection shapes overall protein expression. Still, little is known about how selection acts on transcription or translation individually. To address part of this question, we implement an experimental system which allows us to measure how genetic changes affect transcription only, excluding the effects on translation. We use this system to quantify changes in three regulatory phenotypes of the lacZ promoter: transcriptional activity, plasticity, and cell-to-cell variability. We compare these phenotypes from segregating variants that have been subject to natural selection, and random variants that have never been subjected to natural selection. We show that natural selection filters out mutations causing large changes in transcriptional levels from the lacZ promoter. Further, we detect directional selection acting on transcriptional plasticity in combinations of glucose, galactose and lactose environments. Focusing on cell-to-cell variability in transcription, we describe both directional and diversifying selection acting on this phenotype depending on the environment used. We also observe a link between the phylogeny of the environmental E. coli strains and high and low transcriptional noise levels in glucose which are mediated by just one or two SNPs. Our results thus provide new insight into how one of the most well-characterized bacterial promoters is shaped in nature by selection.
Effects of different environmental intervention durations on the intestinal mucosal barrier and the brain-gut axis in rats with colorectal cancer
Authors: Dun Liu , Mei-Jing Chen , Si-Ting Huang , Xin-Yuan Yu , Yu-Xuan Wu
Published: March 2022

Objectives

Enriched environment (EE) is a promising strategy to protect the intestinal mucosal barrier and regulate brain-gut peptide expression. However, the optimal enriched environment intervention duration is unknown. Here, different EE intervention durations were applied to assess the optimal intervention duration in rats with colorectal cancer.

Methods

We used a rat model of 1,2-dimethylhydrazine-induced colorectal cancer. Rats were housed in an EE for 0, 2, 4 or 8 weeks. The intestinal mucosa and serum TNF-α, IL-6, IL-10, DAO, ATP, CRF, and occludin levels and bacterial translocation (BT) were measured, and the intestinal mucosa morphology was evaluated.

Results

Eight-week EE intervention was more beneficial to the intestinal mucosal mechanical barrier than 2-week or 4-week intervention (P<0.05). There was a significant different between the 4-week and 8-week groups on BT (P=0.049). However, which intervention duration had the greatest advantages in intestinal mucosa and serum inflammatory factor regulation was not determined. There were no significant differences in the effects of different EE intervention durations on BT or brain intestinal peptide levels among the other groups (P>0.05).

Conclusions

The effect of an 8-week environmental intervention duration on the intestinal mucosal barrier was better than that of 2-week and 4-week durations overall, but the effect of different environmental intervention durations on brain-gut peptide levels was not obvious. In the future, we can further explore the molecular biological mechanism of the effect of different EE intervention durations on the intestinal mucosal barrier and analyze the effect of an EE on other brain-gut peptides.
Medical Evaluation of Unanticipated Monogenic Disease Risks Identified through Newborn Genomic Screening: Findings from the BabySeq Project
Authors: Green Robert C. , Shah Nidhi , Genetti Casie A. , Yu Timothy , Zettler Bethany , Schwartz Talia S. , Uveges Melissa K. , Ceyhan-Birsoy Ozge , Lebo Matthew S. , Pereira Stacey , Agrawal Pankaj B. , Parad Richard B. , McGuire Amy L. , Christensen Kurt , Rehm Heidi L. , Holm Ingrid A. , Beggs Alan H. ,   the BabySeq Project
Published: March 2022

Genomic sequencing of healthy newborns to screen for medically important genetic information has long been anticipated but data around downstream medical consequences are lacking. Among 159 infants randomized to the sequencing arm in the BabySeq Project, an unanticipated monogenic disease risk (uMDR) was discovered in 18 (11.3%). We assessed uMDR actionability by visualizing scores from a modified ClinGen Actionability SemiQuantitative Metric and tracked medical outcomes in these infants for 3-5 years. All uMDRs scored as highly actionable (mean 9, range: 7-11 on a 0-12 scale) and had readily available clinical interventions. In 4 cases, uMDRs revealed unsuspected genetic etiologies for existing phenotypes, and in the remaining 14 cases provided risk stratification for future surveillance. In 8 cases, uMDRs prompted screening for multiple at-risk family members. These results suggest that actionable uMDRs are more common than previously thought and support ongoing efforts to evaluate population-based newborn genomic screening.
SARS-CoV-2 Omicron potently neutralized by a novel antibody with unique Spike binding properties
Authors: Fenwick Craig , Turelli Priscilla , Ni Dongchun , Perez Laurent , Lau Kelvin , Lana Erica , Pellaton Céline , Raclot Charlène , Esteves-Leuenberger Line , Campos Jérémy , Farina Alex , Fiscalini Flurin , Herate Cécile , Marlin Romain , Abdelnabi Rana , Foo Caroline S. , Neyts Johan , Leyssen Pieter , LeGrand Roger , Lévy Yves , Pojer Florence , Stahlberg Henning , Trono Didier , Pantaleo Giuseppe
Published: March 2022

The SARS-CoV-2 Omicron variant exhibits very high levels of transmission, pronounced resistance to authorized therapeutic human monoclonal antibodies and reduced sensitivity to vaccine-induced immunity. Here we describe P2G3, a human monoclonal antibody (mAb) isolated from a previously infected and vaccinated donor, which displays picomolar-range neutralizing activity against Omicron BA.1, BA.1.1, BA.2 and all other current variants, and is thus markedly more potent than all authorized or clinically advanced anti-SARS-CoV-2 mAbs. Structural characterization of P2G3 Fab in complex with the Omicron Spike demonstrates unique binding properties to both down and up spike trimer conformations at an epitope that partially overlaps with the receptor-binding domain (RBD), yet is distinct from those bound by all other characterized mAbs. This distinct epitope and angle of attack allows P2G3 to overcome all the Omicron mutations abolishing or impairing neutralization by other anti-SARS-COV-2 mAbs, and P2G3 accordingly confers complete prophylactic protection in the SARS-CoV-2 Omicron monkey challenge model. Finally, although we could isolate in vitro SARS-CoV2 mutants escaping neutralization by P2G3 or by P5C3, a previously described broadly active Class 1 mAb, we found these viruses to be lowly infectious and their key mutations extremely rare in the wild, and we could demonstrate that P2G3/P5C3 efficiently cross-neutralized one another’s escapees. We conclude that this combination of mAbs has great prospects in both the prophylactic and therapeutic settings to protect from Omicron and other VOCs.
Alpha-mannosidase-2 modulates arbovirus infection in a pathogen- and Wolbachia-specific manner in Aedes aegypti mosquitoes
Authors: Urakova Nadya , Joseph Renuka E. , Huntsinger Allyn , Macias Vanessa M. , Jones Matthew J. , Sigle Leah T. , Li Ming , Akbari Omar S. , Xi Zhiyong , Lymperopoulos Konstantinos , Sayre Richard T , McGraw Elisabeth A. , Rasgon Jason L.
Published: March 2022

Multiple Wolbachia strains can block pathogen infection, replication, and/or transmission in Aedes aegypti mosquitoes under both laboratory and field conditions. However, Wolbachia effects on pathogens can be highly variable across systems and the factors governing this variability are not well understood. It is increasingly clear that the mosquito host is not a passive player in which Wolbachia governs pathogen transmission phenotypes; rather, the genetics of the host can significantly modulate Wolbachia-mediated pathogen blocking. Specifically, previous work linked variation in Wolbachia pathogen blocking to polymorphisms in the mosquito alpha-mannosidase 2 (αMan2) gene. Here we use CRISPR-Cas9 mutagenesis to functionally test this association. We developed αMan2 knockouts and examined effects on both Wolbachia and virus levels, using both dengue virus (DENV; Flaviviridae) and Mayaro virus (MAYV; Togaviridae). Wolbachia titers were significantly elevated in αMan2 knockout (KO) mosquitoes, but there were complex interactions with virus infection and replication. In Wolbachia-uninfected mosquitoes, the αMan2 KO mutation was associated with decreased DENV titers, but in a Wolbachia-infected background, the αMan2 KO mutation significantly modulated virus blocking. In contrast, the αMan2 KO mutation significantly increased MAYV replication in Wolbachia-uninfected mosquitoes and did not affect Wolbachia-mediated virus blocking. These results demonstrate that αMan2 modulates arbovirus infection in Ae. aegypti mosquitoes in a pathogen- and Wolbachia-specific manner, and that Wolbachia-mediated pathogen blocking is a complex phenotype dependent on the mosquito host genotype and the pathogen. These results have significant impact for the design and use of Wolbachia-based strategies to control vector-borne pathogens.
Impact of Maternal Protein Restriction on Hypoxia-Inducible Factor (HIF) Expression in Male Fetal Kidney Development
Authors: Gomes Júlia Sevá , de Barros Sene Letícia , Lamana Gabriela Leme , Boer Patricia Aline , Gontijo José Antônio Rocha
Published: March 2022

Background

The kidney ontogenesis is the most structurally affected by gestational protein restriction, reducing close to 30% of their functional units. The reduced nephron number is predictive of hypertension and cardiovascular dysfunctions generally observed in the adult age of most fetal programming models. We demonstrate HIF-1 predicts molecular pathway changes may be associated with the decreased nephron numbers in the 17 gestational days (17GD) low protein (LP) intake male fetal kidney compared to regular protein (NP) progeny intake. Here, we evaluated the predicted targets and related pathways in the fetal kidneys of 17-GD LP offspring to elucidate the molecular modulations during nephrogenesis.

Methods

Pregnant Wistar rats were allocated into two groups: NP (regular protein diet −17%) or LP (diet-6%). Taking into account miRNA transcriptome sequencing previous study (miRNA-Seq) in 17-GD male offspring kidneys using previously described methods, was investigated predicted target genes and proteins, in particular, related to HIF-1 pathway by RT-qPCR and immunohistochemistry.

Results and conclusions

The current study data supported that nephron onset impairment in the 17-DG fetus’s kidney, programmed by gestational low-protein intake, is, at least in part, related to alterations in the HIF-1α signaling pathway. Factors that facilitate the transposition of HIF-1α to the mesenchymal cell’s nucleus, such as NOS, Ep300, and HSP90, may have an essential role in this regulatory process. This alteration leads to the inhibition of adaptive responses to the adverse environment, secondary to an increase in ungraded HIF-1α, possibly associated with a reduction in the transcription factor elF-4 and proteins of their respective signaling pathways. Consequently, we may suggest an early maturation process of renal cells, inhibition of nephron progenitor cell division, and reduction of renal functional units in the offspring of rats submitted to severe gestational protein restriction.
Biocompatible polymers for scalable production of human neural organoids
Authors: Narazaki Genta , Miura Yuki , Pavlov Sergey D. , Thete Mayuri Vijay , Roth Julien G. , Shin Sungchul , Heilshorn Sarah C. , Pașca Sergiu P.
Published: March 2022

The generation of neural organoids from human pluripotent stem cells holds great promise in modeling disease and screenings drugs, but current approaches are difficult to scale due to undesired organoid fusion. Here, we develop a scalable neural organoid platform by screening biocompatible polymers that prevent fusion of organoids cultured in suspension. We show that addition of one inexpensive polysaccharide enables straightforward screening of 298 FDA-approved drugs and teratogens for growth defects using over 2,400 cortical organoids.
Perceptions of users and non-users of an early contact tracing mobile application to fight COVID-19 spread: a value-based empirical investigation
Authors: Cocosila Mihail , Farrelly Glen , Trabelsi Houda
Published: March 2022

Purpose

The purpose of this study is to describe a comparative study of the perceptions of users and non-users of an early contact tracing application helping to prevent the spread of the COVID-19 pandemic. The unprecedented incidence of this disease warrants investigating theoretically the use of mobile contact tracing applications as a promising approach to curtail its transmission.

Design/methodology/approach

A consumption value-based model of the adoption and use of a contact tracing mobile application was built and tested through a cross-sectional survey conducted with 2 samples (of 309 already users and 306 non-users) in the Province of Alberta, Canada.

Findings

Utilitarian and social values together with health information seeking and perceived critical mass drive the use of the application while perceived privacy risk is an obstacle to usage for both users and non-users.

Research limitations/implications

Study participants self-assessed their risk category of potential exposure to the COVID-19 virus, and this was a subjective measure including an emotional component.

Practical implications

No major differences in the approaches targeting users and non-users of a mobile contact tracing application to encourage its adoption and use are necessary.

Social implications

Additional efforts are required to convey to people information on the benefits and current rate of use of such an application and to mitigate privacy risk concerns.

Originality/value

Overall, the study offers theoretical and practical contributions that may help improve the adoption and usage of contact tracing applications addressing the COVID-19 pandemic or other possible public health crises.