bluuebunny/crossref_metadata_2025 huggingface dataset:
18F-PSMA-1007 Uptake in Pulmonary Lymphangitic Carcinomatosis Metastasis From Prostate Cancer
Authors: Liu Bo-Le , Hong Jun-Jie , Tang Kun , Lin Jie , Zheng Xiang-Wu
Published: March 2021

A 55-year-old man with cough, bone pain, and cervical lymphadenopathy underwent both 18F-FDG and 18F-PSMA-1007 PET/CT scans with clinical suspicion of malignant disease. Compared with 18F-FDG PET/CT, 18F-PSMA PET/CT showed intense tracer uptake in the prostate gland, lungs, osteogenic lesions, and multiple lymph nodes. Interestingly, we also found the high tracer concentration of pulmonary lymphangitic carcinomatosis, a very rare form of prostate cancer metastasis to the lung, on 18F-PSMA-1007 PET/CT images.
A Case of Solitary Laryngotracheal Lymphoma Evaluated by 18F-FDG PET/CT
Authors: Wang Qixin , Tang Wenxin , Yang Songsong , Chen Yue
Published: March 2021

Solitary non-Hodgkin lymphoma of the trachea is extremely rare. Herein, we reported a case of solitary laryngotracheal lymphoma in a 55-year-old man. He complained of cough, tachypnea, and dyspnea. 18F-FDG PET/CT showed a hypermetabolic lesion in the subglottic larynx and upper cervical trachea. The subsequent histology and immunohistochemistry of the laryngotracheal lesion tissue confirmed the diagnosis of non-Hodgkin lymphoma (mucosa-associated lymphatic tissue lymphoma).
Increased 68Ga-FAPI Uptake in Chronic Cholecystitis and Degenerative Osteophyte
Authors: Liu Huipan , Chen Zan , Yang Xiao , Fu Wenhui , Chen Yue
Published: March 2021

68Ga-FAPI PET/CT has been used in the evaluation of a variety of malignancies. An increasing number of case studies on FAPI uptake in nonmalignant diseases is also gaining support and enthusiasm. We present a case of asymptomatic chronic cholecystitis and degenerative osteophyte detected incidentally by 68Ga-FAPI PET/CT.
Cultural Considerations in Debriefing
Authors: Palaganas Janice C. , Chan Albert K. M. , Leighton Kim
Published: March 2021

Summary Statement

Culture influences how we communicate, teach, and learn. Debriefings are laden with cultural influences. Without attention to cultural considerations, accepted debriefing techniques might not reach the desired outcome and, in certain cultures, may even harm teacher-learner relationships. We explore cultural considerations in healthcare simulation debriefing and offer guidance for debriefers to gain awareness of potential cultural biases.
Personalized Training Schedules for Retention and Sustainment of Cardiopulmonary Resuscitation Skills
Authors: Oermann Marilyn H. , Krusmark Michael A. , Kardong-Edgren Suzan , Jastrzembski Tiffany S. , Gluck Kevin A.
Published: March 2021

Introduction

The study examined how the spacing of training during initial acquisition of cardiopulmonary resuscitation (CPR) skill affects longer-term retention and sustainment of these skills.

Methods

This was a multiphased, longitudinal study. Nursing students were randomly assigned to 2 initial acquisition conditions in which they completed 4 consecutive CPR training sessions spaced by shorter (1 or 7 days) or longer (30 or 90 days) training intervals. Students were additionally randomized to refresh skills for 1 year every 3 months, 6 months, or at a personalized interval prescribed by the Predictive Performance Optimizer (PPO), a cognitive tool that predicts learning and decay over time.

Results

At the end of the acquisition period, performance was better if training intervals were shorter. At 3 or 6 months after acquisition, performance was better if initial training intervals were longer. At 1 year after acquisition, compression and ventilation scores did not differ by initial training interval nor by 3-month or PPO-prescribed sustainment interval refreshers. However, 6-month interval refreshers were worse than the PPO for compressions and worse than 3 months for ventilations. At the final test session, participants in the personalized PPO condition had less variability in compression scores than either the 3- or 6-month groups.

Conclusions

Results suggest that CPR learning trajectories may be accelerated by first spacing training sessions by days and then expanding to longer intervals. Personalized scheduling may improve performance, minimize performance variability, and reduce overall training time.
Acquisition of Medicaid at the time of injury: An opportunity for sustainable insurance coverage
Authors: Jaramillo Joshua D. , Arnow Katherine , Trickey Amber W. , Dickerson Katherine , Wagner Todd H. , Harris Alex H.S. , Tran Linda D. , Bereknyei Sylvia , Morris Arden M. , Spain David A. , Knowlton Lisa Marie
Published: March 2021

INTRODUCTION

Uninsured trauma patients are at higher risk of mortality, limited access to postdischarge resources, and catastrophic health expenditure. Hospital Presumptive Eligibility (HPE), enacted with the 2014 Affordable Care Act, enables uninsured patients to be screened and acquired emergency Medicaid at the time of hospitalization. We sought to identify factors associated with successful acquisition of HPE insurance at the time of injury, hypothesizing that patients with higher Injury Severity Score (ISS) (ISS >15) would be more likely to be approved for HPE.

METHODS

We identified Medicaid and uninsured patients aged 18 to 64 years with a primary trauma diagnosis (International Classification of Diseases, Tenth Revision) in a large level I trauma center between 2015 and 2019. We combined trauma registry data with review of electronic medical records, to determine our primary outcome, HPE acquisition. Descriptive and multivariate analyses were performed.

RESULTS

Among 2,320 trauma patients, 1,374 (59%) were already enrolled in Medicaid at the time of hospitalization. Among those uninsured at arrival, 386 (40.8%) acquired HPE before discharge, and 560 (59.2%) remained uninsured. Hospital Presumptive Eligibility patients had higher ISS (ISS >15, 14.8% vs. 5.7%; p < 0.001), longer median length of stay (2 days [interquartile range, 0–5 days] vs. 0 [0–1] days, p < 0.001), were more frequently admitted as inpatients (64.5% vs. 33.6%, p < 0.001), and discharged to postacute services (11.9% vs. 0.9%, p < 0.001). Patient, hospital, and policy factors contributed to HPE nonapproval. In adjusted analyses, Hispanic ethnicity (vs. non-Hispanic Whites: aOR, 1.58; p = 0.02) and increasing ISS (p ≤ 0.001) were associated with increased likelihood of HPE approval.

CONCLUSION

The time of hospitalization due to injury is an underused opportunity for intervention, whereby uninsured patients can acquire sustainable insurance coverage. Opportunities to increase HPE acquisition merit further study nationally across trauma centers. As administrative and trauma registries do not capture information to compare HPE and traditional Medicaid patients, prospective insurance data collection would help to identify targets for intervention.

LEVEL OF EVIDENCE

Economic, level IV.
Strategies for successful implementation of resuscitative endovascular balloon occlusion of the aorta in an urban Level I trauma center
Authors: Hadley Jamie B. , Coleman Julia R. , Moore Ernest E. , Lawless Ryan , Burlew Clay C. , Platnick Barry , Pieracci Fredric M. , Hoehn Melanie R. , Coleman Jamie J. , Campion Eric M. , Cohen Mitchell J. , Cralley Alexis , Eitel Andrew P. , Bartley Matthew , Vigneshwar Navin , Sauaia Angela , Fox Charles J.
Published: March 2021

Background

The rationale for resuscitative endovascular balloon occlusion of the aorta (REBOA) is to control life-threatening subdiaphragmatic bleeding and facilitate resuscitation; however, incorporating this into the resuscitative practices of a trauma service remains challenging. The objective of this study is to describe the process of successful implementation of REBOA use in an academic urban Level I trauma center. All REBOA procedures from April 2014 through December 2019 were evaluated; REBOA was implemented after surgical faculty attended a required and internally developed Advanced Endovascular Strategies for Trauma Surgeons course. Success was defined by sustained early adoption rates.

Methods

An institutional protocol was published, and a REBOA supply cart was placed in the emergency department with posters attached to depict technical and procedural details. A focused professional practice evaluation was utilized for the first three REBOA procedures performed by each faculty member, leading to internal privileging.

Results

Resuscitative endovascular balloon occlusion of the aorta was performed in 97 patients by nine trauma surgeons, which is 1% of the total trauma admissions during this time. Each surgeon performed a median of 12 REBOAs (interquartile range, 5–14). Blunt (77/97, 81%) or penetrating abdominopelvic injuries (15/97, 15%) comprised the main injury mechanisms; 4% were placed for other reasons (4/97), including ruptured abdominal aortic aneurysms (n = 3) and preoperatively for a surgical oncologic resection (n = 1). Overall survival was 65% (63/97) with a steady early adoption trend that resulted in participation in a Department of Defense multicenter trial.

Conclusion

Strategies for how departments adopt new procedures require clinical guidelines, a training program focused on competence, and a hospital education and privileging process for those acquiring new skills.

LEVEL OF EVIDENCE

Therapeutic, level V.
Phase separation of RNA-binding protein promotes polymerase engagement and transcription
Authors: Shao Wen , Bi Xianju , Gao Boyang , Wu Jun , Pan Yixuan , Yin Yafei , Liu Zhimin , Zhang Wenhao , Jiang Xu , Ren Wenlin , Xu Yanhui , Wu Zhongyang , Wang Kaili , Zhan Ge , Lu J. Yuyang , Han Xue , Li Tong , Wang Jianlong , Li Guohong , Deng Haiteng , Li Bing , Shen Xiaohua
Published: March 2021

An RNA-involved phase-separation model has been proposed for transcription control. Yet, the molecular links that connect RNA binding to the transcription machinery remain missing. Here we find RNA-binding proteins (RBPs) constitute half of the chromatin proteome in embryonic stem cells (ESCs), and some are colocalized with RNA polymerase (Pol) II at promoters and enhancers. Biochemical analyses of representative RBPs—such as PSPC1 and PTBP1—show that the paraspeckle protein PSPC1 not only prevents the RNA-induced premature release of Pol II, and also makes use of RNA as multivalent molecules to promote Pol II engagement and activity, by enhancing the phase separation and subsequent phosphorylation and release of polymerase condensates. In ESCs, auxin-induced acute degradation of PSPC1 leads to genome-wide defects in Pol II phosphorylation and chromatin-binding and nascent transcription. We propose that the synergistic interplay of RBPs and RNA aids in the rate-limiting step of polymerase condensate formation to promote active transcription.
COVID-19 dominant D614G mutation in the SARS-CoV-2 spike protein desensitizes its temperature-dependent denaturation
Authors: Yang Tzu-Jing , Yu Pei-Yu , Chang Yuan-Chih , Kuo Chu-Wei , Khoo Kay-Hooi , Danny Hsu Shang-Te
Published: March 2021

The D614G mutation in the spike protein of SARS-CoV-2 alters the fitness of the virus, making it the dominant form in the COVID-19 pandemic. Here we demonstrated by cryo-electron microscopy that the D614G mutation does not significantly perturb the structure of the spike protein, but multiple receptor binding domains are in an upward conformation poised for host receptor binding. The impact of the mutation lies in its ability to eliminate the unusual cold-induced unfolding characteristics, and to significantly increase the thermal stability under physiological pH. Our findings shed light on how the D614G mutation enhances the infectivity of SARS-CoV-2 through a stabilizing mutation, and suggest an approach for better design of spike-protein based conjugates for vaccine development.
Intergenerational metabolic priming by sperm piRNAs
Authors: Lempradl Adelheid , Kugelberg Unn , Iconomou Mary , Beddows Ian , Nätt Daniel , Casas Eduard , Örkenby Lovisa , Enders Lennart , Martinez Alejandro Gutierrez , Lushchak Oleh , Boonen Erica , Rückert Tamina , Sabev Martin , Roth Marie G.L. , Pettinga Dean , Vavouri Tanya , Öst Anita , Pospisilik J. Andrew
Published: March 2021

Preconception parental environment can reproducibly program offspring phenotype without altering the DNA sequence, yet the mechanisms underpinning this ‘epigenetic inheritance’ remains elusive. Here, we demonstrate the existence of an intact piRNA-pathway in mature Drosophila sperm and show that pathway modulation alters offspring gene transcription in a sequence-specific manner. We map a dynamic small RNA content in developing sperm and find that the mature sperm carry a highly distinct small RNA cargo. By biochemical pulldown, we identify a small RNA subset bound directly to piwi protein. And, we show that piRNA-pathway controlled sperm small RNAs are linked to target gene repression in offspring. Critically, we find that full piRNA-pathway dosage is necessary for the intergenerational metabolic and transcriptional reprogramming events triggered by high paternal dietary sugar. These data provide a direct link between regulation of endogenous mature sperm small RNAs and transcriptional programming of complementary sequences in offspring. Thus, we identify a novel mediator of paternal intergenerational epigenetic inheritance.
Combining experiments and in silico modeling to infer the role of adhesion and proliferation on the collective dynamics of cells
Authors: Melo Hygor P. M. , Maia F. Raquel , Nunes André S. , Reis Rui L. , Oliveira Joaquim M. , Araújo Nuno A. M.
Published: March 2021

The collective dynamics of cells on surfaces and interfaces poses technological and theoretical challenges in the study of morphogenesis, tissue engineering, and cancer. Different mechanisms are at play, including, cell-cell adhesion, cell motility, and proliferation. However, the relative importance of each one is elusive. Here, experiments with a culture of glioblastoma multiforme cells on a substrate are combined with in silico modeling to infer the rate of each mechanism. By parametrizing these rates, the time-dependence of the spatial correlation observed experimentally is reproduced. The obtained results suggest a reduction in cell-cell adhesion with the density of cells. The reason for such reduction and possible implications for the collective dynamics of cancer cells are discussed.
Coupling between cerebrovascular oscillations and CSF flow fluctuation during wakefulness: An fMRI study
Authors: Yang Ho-Ching (Shawn) , Inglis Ben , Talavage Thomas M. , Nair Vidhya Vijayakrishnan , Yao Jinxia (Fiona) , Fitzgerald Bradley , Schwichtenberg Amy J. , Tong Yunjie
Published: March 2021

Cerebrospinal fluid (CSF) plays an important role in the clearance of metabolic waste products from the brain, yet the driving forces of CSF movement are not fully understood. It is commonly believed that CSF movement is facilitated by blood vessel wall movements (i.e., hemodynamic oscillations) in the brain. A coherent pattern of low frequency hemodynamic oscillations and CSF movement was recently found during non-rapid eye movement (NREM) sleep via functional MRI. However, questions remain regarding 1) the explanation of coupling between hemodynamic oscillations and CSF movement from fMRI signals; 2) the existence of the coupling during wakefulness; 3) the direction of CSF movement. In this resting state fMRI study, we proposed a mechanical model to explain the coupling between hemodynamics and CSF movement through the lens of fMRI. We found that the observed delays between hemodynamics and CSF movement match those predicted by the model. Moreover, by conducting separate fMRI scans of the brain and neck, we confirmed the low frequency CSF movement at the fourth ventricle is bidirectional. Our finding also demonstrates that CSF movement is facilitated by hemodynamic oscillations mainly in the low frequency range, even when the individual is awake.
Oxytocin receptor activation does not mediate associative fear deficits in a Williams Syndrome model
Authors: Nygaard Kayla R. , Swift Raylynn G. , Glick Rebecca M. , Wagner Rachael E. , Maloney Susan E. , Gould Georgianna G. , Dougherty Joseph D.
Published: March 2021

Williams Syndrome is caused by a deletion of 26-28 genes on chromosome 7q11.23. Patients with this disorder have distinct behavioral phenotypes including learning deficits, anxiety, increased phobias, and hypersociability. Some studies also suggest elevated blood oxytocin and altered oxytocin receptor expression, and this oxytocin dysregulation is hypothesized to be involved in the underlying mechanisms driving a subset of these phenotypes. A ‘Complete Deletion’ mouse, modeling the hemizygous critical region deletion in Williams Syndrome, recapitulates many of the phenotypes present in humans. These Complete Deletion mice also exhibited impaired fear responses in the conditioned fear task. Here, we address whether oxytocin dysregulation is responsible for this impaired associative fear memory response. We show direct delivery of an oxytocin receptor antagonist to the central nervous system did not rescue the attenuated contextual or cued fear memory responses in Complete Deletion mice. Thus, increased oxytocin signaling is not acutely responsible for this phenotype. We also evaluated oxytocin receptor and serotonin transporter availability in regions related to fear learning, memory, and sociability using autoradiography in wild type and Complete Deletion mice. While we identified trends in lowered oxytocin receptor expression in the lateral septal nucleus, and trends towards lowered serotonin transporter availability in the striatum and orbitofrontal cortex, we found no significant differences after correction. Together, these data suggest the fear conditioning anomalies in the Williams Syndrome mouse model are independent of any alterations in the oxytocinergic system caused by deletion of the Williams locus.
SpeciesRax: A tool for maximum likelihood species tree inference from gene family trees under duplication, transfer, and loss
Authors: Morel Benoit , Schade Paul , Lutteropp Sarah , Williams Tom A. , Szöllősi Gergely J. , Stamatakis Alexandros
Published: March 2021

Species tree inference from gene family trees is becoming increasingly popular because it can account for discordance between the species tree and the corresponding gene family trees. In particular, methods that can account for multiple-copy gene families exhibit potential to leverage paralogy as informative signal. At present, there does not exist any widely adopted inference method for this purpose. Here, we present SpeciesRax, the first maximum likelihood method that can infer a rooted species tree from a set of gene family trees and can account for gene duplication, loss, and transfer events. By explicitly modelling events by which gene trees can depart from the species tree, SpeciesRax leverages the phylogenetic rooting signal in gene trees. SpeciesRax infers species tree branch lengths in units of expected substitutions per site and branch support values via paralogy-aware quartets extracted from the gene family trees. Using both empirical and simulated datasets we show that SpeciesRax is at least as accurate as the best competing methods while being one order of magnitude faster on large datasets at the same time. We used SpeciesRax to infer a biologically plausible rooted phylogeny of the vertebrates comprising 188 species from 31612 gene families in one hour using 40 cores. SpeciesRax is available under GNU GPL athttps://github.com/BenoitMorel/GeneRaxand on BioConda.
A cryo-ET study of microtubules in axons
Authors: Foster H E , Ventura Santos C , Carter A P
Published: March 2021

The microtubule cytoskeleton in axons plays key roles in intracellular transport and in defining cell shape. Despite many years of study of microtubules, many questions regarding their native architecture remain unanswered. Here, we performed cryo-electron tomography of mouse dorsal root ganglion (DRG) andDrosophila melanogaster(Dm) neurons and examined their microtubule ultrastructurein situ. We found that the microtubule minus and plus ends in DRG axons are structurally similar and frequently contact nearby components. The microtubules in DRG axons maintained a 13 protofilament (pf) architecture, even close to lattice break sites. In contrast, microtubules in Dm neurons had 12 or 13 pfs and we detected sites of pf number transition. The microtubule lumen in DRG axons is filled with globular microtubule inner proteins (MIPs). Our data suggest these have a defined structure, which is surprising given they are thought to contain the disordered protein MAP6. In summary, we reveal novel morphological and structural features of microtubules in their native environment.
An 18S V4 rDNA metabarcoding dataset of protist diversity in the Atlantic inflow to the Arctic Ocean, through the year and down to 1000 m depth
Authors: Egge Elianne , Elferink Stephanie , Vaulot Daniel , John Uwe , Bratbak Gunnar , Larsen Aud , Edvardsen Bente
Published: March 2021

Arctic marine protist communities have been understudied due to challenging sampling conditions, in particular during winter and in deep waters. The aim of this study was to improve our knowledge on Arctic protist diversity through the year, both in the epipelagic (< 200 m depth) and mesopelagic zones (200-1000 m depth). Sampling campaigns were performed in 2014, during five different months, to capture the various phases of the Arctic primary production: January (winter), March (pre-bloom), May (spring bloom), August (post-bloom) and November (early winter). The cruises were undertaken west and north of the Svalbard archipelago, where warmer Atlantic waters from the West Spitsbergen Current meets cold Arctic waters from the Arctic Ocean. From each cruise, station, and depth, 50 L of sea water were collected and the plankton was size-fractionated by serial filtration into four size fractions between 0.45-200 µm, representing the picoplankton, nanoplankton and microplankton. In addition vertical net hauls were taken from 50 m depth to the surface at selected stations. From the plankton samples DNA was extracted, the V4 region of the 18S rRNA-gene was amplified by PCR with universal eukaryote primers and the amplicons were sequenced by Illumina high-throughput sequencing. Sequences were clustered into Amplicon Sequence Variants (ASVs), representing protist genotypes, with the dada2 pipeline. Taxonomic classification was made against the curated Protist Ribosomal Reference database (PR2). Altogether 6,536 protist ASVs were obtained (including 54 fungal ASVs). Both ASV richness and taxonomic composition were strongly dependent on size-fraction, season, and depth. ASV richness was generally higher in the smaller fractions, and higher in winter and the mesopelagic samples than in samples from the well-lit epipelagic zone during summer. During spring and summer, the phytoplankton groups diatoms, chlorophytes and haptophytes dominated in the epipelagic zone. Parasitic and heterotrophic groups such as Syndiniales and certain dinoflagel-lates dominated in the mesopelagic zone all year, as well as in the epipelagic zone during the winter. The dataset is available at https://doi.org/10.17882/79823, (Egge et al., 2014).
Identifying and correcting for misspecifications in GWAS summary statistics and polygenic scores
Authors: Privé Florian , Arbel Julyan , Aschard Hugues , Vilhjálmsson Bjarni J.
Published: March 2021

Publicly available genome-wide association studies (GWAS) summary statistics exhibit uneven quality, which can impact the validity of follow-up analyses. First, we present an overview of possible misspecifications that come with GWAS summary statistics. Then, in both simulations and real data analyses, we show that additional information such as imputation INFO scores, allele frequencies, and per-variant sample sizes in GWAS summary statistics can be used to detect possible issues and correct for misspecifications in the GWAS summary statistics. One important motivation for us is to improve the predictive performance of polygenic scores built from these summary statistics. Unfortunately, due to the lack of reporting standards for GWAS summary statistics, this additional information is not systematically reported. We also show that using well-matched LD references can improve model fit and translate into more accurate prediction. Finally, we discuss how to make polygenic score methods such as lassosum and LDpred2 more robust to these misspecifications to improve their predictive power.
Enrichment of SARS-CoV-2 entry factors and interacting intracellular genes in peripheral immune cells
Authors: Devaprasad Abhinandan , Pandit Aridaman
Published: March 2021

SARS-CoV-2 uses ACE2 and TMPRSS2 to gain entry into the cell. However, recent studies have shown that SARS-CoV-2 may use additional host factors that are required for the viral lifecycle. Here we used publicly available datasets, CoV associated genes and machine learning algorithms to explore the SARS-CoV-2 interaction landscape in different tissues. We find that in general a small fraction of cells expresses ACE2 in the different tissues including nasal, bronchi and lungs. We show that a small fraction of immune cells (including T-cells, macrophages, dendritic cells) found in tissues also express ACE2. We show that healthy circulating immune cells do not express ACE2 and TMPRSS2. However, a small fraction of circulating immune cells (including dendritic cells, monocytes, T-cells) in the PBMC of COVID-19 patients express ACE2 and TMPRSS2. Additionally, we found that a large spectrum of cells (in circulation and periphery) in both healthy and COVID-19 positive patients were significantly enriched for SARS-CoV-2 factors. Thus, we propose that further research is needed to explore if SARS-CoV-2 can directly infect peripheral immune cells to better understand the virus’ mechanism of action.
Detection of pathogenic splicing events from RNA-sequencing data using dasper
Authors: Zhang David , Reynolds Regina H. , Garcia-Ruiz Sonia , Gustavsson Emil K , Sethi Sid , Aguti Sara , Barbosa Ines A. , Collier Jack J. , Houlden Henry , McFarland Robert , Muntoni Francesco , Oláhová Monika , Poulton Joanna , Simpson Michael , Pitceathly Robert D.S. , Taylor Robert W. , Zhou Haiyan , Deshpande Charu , Botia Juan A. , Collado-Torres Leonardo , Ryten Mina
Published: March 2021

Although next-generation sequencing technologies have accelerated the discovery of novel gene-to-disease associations, many patients with suspected Mendelian diseases still leave the clinic without a genetic diagnosis. An estimated one third of these patients will have disorders caused by mutations impacting splicing. RNA-sequencing has been shown to be a promising diagnostic tool, however few methods have been developed to integrate RNA-sequencing data into the diagnostic pipeline. Here, we introducedasper, an R/Bioconductor package that improves upon existing tools for detecting aberrant splicing by using machine learning to incorporate disruptions in exon-exon junction counts as well as coverage.dasperis designed for diagnostics, providing a rank-based report of how aberrant each splicing event looks, as well as including visualization functionality to facilitate interpretation. We validatedasperusing 16 patient-derived fibroblast cell lines harbouring pathogenic variants known to impact splicing. We find thatdasperis able to detect pathogenic splicing events with greater accuracy than existingLeafCutterMDor z-score approaches. Furthermore, by only applying a broad OMIM gene filter (without any variant-level filters),dasperis able to detect pathogenic splicing events within the top 10 most aberrant identified for each patient. Since using publicly available control data minimises costs associated with incorporating RNA-sequencing into diagnostic pipelines, we also investigate the use of 504 GTEx fibroblast samples as controls. We find thatdasperleverages publicly available data effectively, ranking pathogenic splicing events in the top 25. Thus, we believedaspercan increase diagnostic yield for a pathogenic splicing variants and enable the efficient implementation of RNA-sequencing for diagnostics in clinical laboratories.
A variable-gain stochastic pooling motif mediates information transfer from receptor assemblies into NF-κB
Authors: Cruz J. Agustin , Mokashi Chaitanya S. , Kowalczyk Gabriel J. , Guo Yue , Zhang Qiuhong , Gupta Sanjana , Schipper David L. , Lee Robin E. C.
Published: March 2021

A myriad of inflammatory cytokines regulate signaling pathways to maintain cellular homeostasis. The IKK complex is an integration hub for cytokines that govern NF-κB signaling. In response to inflammation, IKK is activated through recruitment to receptor-associated protein assemblies. How and what information IKK complexes transmit about the milieu are open questions. Here we track dynamics of IKK complexes and nuclear NF-κB to identify upstream signaling features that determine same-cell responses. Experiments and modeling of single complexes reveals their size, number, and timing relays cytokine-specific information with feedback control that is independent of transcription. Our results provide evidence for variable-gain stochastic pooling, a noise-reducing motif that enables parsimonious and cytokine-specific information transfer. We propose that emergent properties of stochastic pooling are general principles of receptor signaling.

One Sentence Summary

A variable-gain stochastic pooling motif mediates robust and tunable information transmission from the extracellular milieu into the cell.
Fasciola hepaticafatty acid binding protein (Fh12) induces apoptosis and tolerogenic properties in murine bone marrow derived dendritic cells
Authors: Ruiz-Jiménez Caleb , Celias Daiana P. , Valdés Bianca , Ramos-Pérez Willy D. , Cervi Laura , Espino Ana M.
Published: March 2021

In a previous study we demonstrated thatFasciola hepaticafatty acid binding protein (Fh12) significantly suppress macrophage function by inhibiting IL-6, IL-1B, tumor necrosis factor (TNF) and IL-12 production in TLR4-stimulated murine macrophages, an effect mediated through the signaling of CD14 co-receptor without affecting the viability of these cells. Given that dendritic cells (DCs) are immune cells that play a central role in the initiation of primary immune responses and that are the only antigen-presenting cells capable of stimulating naive T-cells, in the present study we investigated the effect of Fh12 on DCs. We found that Fh12 exerts a strong suppressive effect on activation and function of DCs. However, in contrast to the effect observed on macrophages, Fh12 induces early and late apoptosis of DCs being this phenomenon dose-dependent and CD14-coreceptor independent. At low concentration Fh12 modulates the LPS-induced DCs maturation status by suppressing the MHC-II, and co-stimulatory molecules CD40 and CD80 surface expression together with the pro-inflammatory cytokines IL-12p70 and IL-6 production whereas increase the IL-10 levels. Besides, Fh12 decreased the ability of LPS-activated DCs to induce IFNg production against allogeneic splenocytes, while increasing IL-4 production. We have described for the first time the ability of Fh12 to modify selectively the viability of DCs by apoptosis induction. The selective diminution in DCs survival could be aF. hepaticastrategy in order to prevent a host immune response during the earliest phases of infection.
The trade-off between color and size in lizards’ conspicuous tails
Authors: Guidi Raiane dos Santos , São-Pedro Vinicius de Avelar , da Silva Holda Ramos , Costa Gabriel Correa , Pessoa Daniel Marques Almeida
Published: March 2021

A tail of conspicuous coloration is hypothesized to be an advantageous trait for many species of lizards. Predator attacks would be directed to a non-vital, and autotomizable, body part, increasing the chance of survival. However, as body size increases it also increases the signaling area that could attract predators from greater distances, increasing the overall chance of predation. Here, we test the hypothesis that there is a trade-off between tail color and size, affecting predation probabilities. We used plasticine replicas of lizards to study the predation patterns of small and large lizards with red and blue tails. In a natural environment, we exposed six hundred replicas subjected to the attack of free-ranging predators. Large red-tailed models were attacked more quickly, and more intensely, by birds. Mammals and unidentified predators showed no preference for any size or colors. The attacks were not primarily directed to conspicuous tails when compared to the body or the head of our replicas. Our study suggests that red color signals in large lizards could enhance their detection by visually oriented predators (i.e., birds). The efficacy of conspicuous tails as a decoy may rely on associated behavioral displays, which are hard to test with static replicas.

Highlights

The roles of blue and red tails as decoys were not corroborated.

Tail color and size interact while influencing predation rates.

Larger red-tailed lizards are more prone to be attacked by birds.

The benefit of having conspicuous tails appears to decrease as body size increases.
Cis-regulatory elements of the cholinergic gene locus in the silkwormBombyx mori
Authors: Banzai Kota , Izumi Susumu
Published: March 2021

Genes ofcholine acetyltransferase(ChAT) andvesicular acetylcholine transporter(VAChT) are encoded in the same gene locus, called the cholinergic gene locus. They are essential in cholinergic neurons to maintain their functional phenotype. The genomic structure of the cholinergic gene locus is conserved among invertebrates to mammals. However, it is still inconclusive how cholinergic genes express only in cholinergic neurons in insects. In this study, we analyzed the upstream sequence of cholinergic gene locus in the silkwormBombyx morito identify specificcis-regulatory regions. We found multiple enhancer regions that are localized within 1 kb upstream of the cholinergic gene locus. The combination of promoter assays using small deletions and bioinformatic analysis among insect species illuminates two conserved sequences in thecis-regulatory region: TGACGTA and CCAAT, which are known as the cAMP response element and CAAT box, respectively. We found that dibutyryl-cAMP, an analog of cAMP, influences the expression ofChAT. Tissue-specific expression analysis of transcriptional factors showed potential candidates that control the cholinergic gene locus expression. Our investigation provides new insight into the regulation mechanism of cholinergic neuron-specific gene machinery in this lepidopteran insect.
DISTEMA: distance map-based estimation of single protein model accuracy with attentive 2D convolutional neural network
Authors: Chen Xiao , Cheng Jianling
Published: March 2021

Background

Estimation of the accuracy (quality) of protein structural models is important for both prediction and use of protein structural models. Deep learning methods have been used to integrate protein structure features to predict the quality of protein models. Inter-residue distances are key information for predicting protein’s tertiary structures and therefore have good potentials to predict the quality of protein structural models. However, few methods have been developed to fully take advantage of predicted inter-residue distance maps to estimate the accuracy of a single protein structural model.

Result

We developed an attentive 2D convolutional neural network (CNN) with channel-wise attention to take only a raw difference map between the inter-residue distance map calculated from a single protein model and the distance map predicted from the protein sequence as input to predict the quality of the model. The network comprises multiple convolutional layers, batch normalization layers, dense layers, and Squeeze-and-Excitation blocks with attention to automatically extract features relevant to protein model quality from the raw input without using any expert-curated features. We evaluated DISTEMA’s capability of selecting the best models for CASP13 targets in terms of ranking loss of GDT-TS score. The ranking loss of DISTEMA is 0.079, lower than several state-of-the-art single-model quality assessment methods. The work demonstrates that using raw inter-residue distance information alone with deep learning can predict the quality of protein structural models reasonably well.
Tbx1, a 22q11.2-encoded gene, is a link between alterations in fimbria myelination and cognitive speed in mice
Authors: Hiramoto Takeshi , Sumiyoshi Akira , Yamauchi Takahira , Tanigaki Kenji , Shi Qian , Kang Gina , Ryoke Rie , Nonaka Hiroi , Enomoto Shingo , Izumi Takeshi , Bhat Manzoor A. , Kawashima Ryuta , Hiroi Noboru
Published: March 2021

Copy number variants (CNVs) have provided a reliable entry point to identify structural correlates of atypical cognitive development. Hemizygous deletion of human chromosome 22q11.2 is associated with impaired cognitive function; however, the mechanisms by which numerous genes encoded in this CNV contribute to cognitive deficits via diverse structural alterations in the brain remain unclear. This study aimed to determine the cellular basis of the link between alterations in brain structure and cognitive functions in a mouse model. The heterozygosity ofTbx1, a22q11.2 gene, altered the composition of myelinated axons in the fimbria, reduced oligodendrocyte production capacity, and slowed the acquisition of spatial memory and cognitive flexibility. Our findings provide a cellular basis for specific cognitive dysfunctions that occur in patients with loss-of-functionTBX1variants and 22q11.2 hemizygous deletion.

Teaser

A risk gene for autism alters myelin composition in the hippocampal connection and slows cognitive speed.
A T-cell independent universal cellular therapy strategy through antigen depletion
Authors: Li Dan , Wang Wenbing , Xie Shufeng , Ge Maolin , Wang Ruiheng , Xu Qiongyu , Sun Yan , Zhu Jiang , Liu Han
Published: March 2021

CD19-targeting chimeric antigen receptor (CAR) T-cell therapeutics is a revolutionary, novel and successful treatment for B-cell malignancies. However, while CD19-CAR-T therapy can obtain high rates of complete responses in these patients, a significant fraction of patients may experience CD19-negative relapse. Moreover, the dependency on T-cell mediated cytotoxicity restricts CAR-T therapy as a patient-specific individualized therapy with severe side effects such as cytokine-release syndrome (CRS). Whether CAR-T therapy can be substituted by a non-T-cell based universal cellular therapy is largely unknown. Surprisingly, we have demonstrated here that T-lymphocytic cells, as well as non-lymphocytic cells, can cause CD19 internalization and subsequent depletion when they are armed with a CD19-recognizing moiety. This CD19 antigen depletion can efficiently induce T-cell independent apoptosis in target cancer cells whose survival is dependent upon CD19 expression, suggesting that CD19 antigen depletion constitutes a crucial tumor destroying mechanism for CD19-CAR-T, especially for its long-term efficacy. We therefore proposed a universal strategy for CRS-free cellular therapeutics, utilizing artificial antigen-recognizing cells (AARC), which can be manufactured universally and standardly as “off-the-shelf” mesenchymal stromal cells (MSCs) or other types of non-autologous cell expressing anergic CARs. Our results not only uncovered an unrecognized mechanism for CAR-T cytotoxicity and antigen loss, but also shed new insight into a shift in cellular therapeutics from unique patient-specific autologous therapeutics, to universal and standardized allogeneic treatment.
Reproducible Coactivation Patterns of Functional Brain Networks Reveal the Aberrant Dynamic State Transition in Schizophrenia
Authors: Yang Hang , Zhang Hong , Di Xin , Wang Shuai , Meng Chun , Tian Lin , Biswal Bharat
Published: March 2021

It is well documented that massive dynamic information is contained in the resting-state fMRI. Recent studies have identified recurring states dominated by similar coactivation patterns (CAP) and revealed their temporal dynamics. However, the reproducibility and generalizability of the CAP analysis is unclear. To address this question, the effects of methodological pipelines on CAP are comprehensively evaluated in this study, including preprocessing, network construction, cluster number and three independent cohorts. The CAP state dynamics are characterized by fraction of time, persistence, counts, and transition probability. Results demonstrate six reliable CAP states and their dynamic characteristics are also reproducible. The state transition probability is found to be positively associated with the spatial similarity. Furthermore, the aberrant CAP in schizophrenia has been investigated by using the reproducible method on three cohorts. Schizophrenia patients spend less time in CAP states that involve the fronto-parietal network, but more time in CAP states that involve the default mode and salience network. The aberrant dynamic characteristics of CAP are correlated with the symptom severity. These results reveal the reproducibility and generalizability of the CAP analysis, which can provide novel insights into the neuropathological mechanism associated with aberrant brain network dynamics of schizophrenia.

Highlights

Three coactivation patterns (CAPs) pairs with opposite coactivation profiles were identified, and the between-state transition probability was positively correlated with their spatial similarity.

Good spatial and temporal reproducibility and generalizability of CAPs were achieved under varied analytic methods and independent cohorts.

Schizophrenia patients showed altered temporal dynamics not only within the triple-network but also other primary and higher-order networks.
NRF1 Association with AUTS2-Polycomb Mediates Specific Gene Activation in the Brain
Authors: Liu Sanxiong , Aldinger Kimberly A , Cheng Chi Vicky , Kiyama Takae , Dave Mitali , McNamara Hanna K. , Caraffi Stefano G , Ivanovski Ivan , Errichiello Edoardo , Zweier Christiane , Zuffardi Orsetta , Schneider Michael , Papavasiliou Antigone S. , Perry M. Scott , Cho Megan T , Weber Astrid , Swale Andrew , Badea Tudor C. , Mao Chai-An , Garavelli Livia , Dobyns William B , Reinberg Danny
Published: March 2021

The heterogeneous complexes comprising the family of Polycomb Repressive Complex 1 (PRC1) are instrumental to establishing facultative heterochromatin that is repressive to transcription. Yet, two PRC1 species, PRC1.3 and PRC1.5, are known to comprise novel components, AUTS2, P300, and CK2 that convert this repressive function to that of transcription activation. Here, we report that patients harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mostly associated with a heterozygous pathogenic variant inCREBBP/EP300. As well, the absence of AUTS2 gives rise to a mis-regulation of a subset of developmental genes and curtails motor neuron differentiation from embryonic stem cells in the context of a well-defined system. Moreover, the transcription factor, Nuclear Respiratory Factor 1 (NRF1) exhibits a novel and integral role in this aspect of the neurodevelopmental process, being required for PRC1.3 recruitment to chromatin.
Don’t Stress, It’s Under Control: Neural Correlates of Stressor Controllability in Humans
Authors: Meine Laura E. , Meier Jana , Meyer Benjamin , Wessa Michèle
Published: March 2021

Animal research has repeatedly shown that experience of control over an aversive event can protect against the negative consequences of later uncontrollable stress. Neurobiologically, this effect is assumed to correspond to persistent changes in the pathway linking the ventromedial prefrontal cortex (vmPFC) and the dorsal raphe nucleus. However, it remains unclear to what extent these findings translate to humans. During functional magnetic resonance imaging, we subjected participants to controllable and uncontrollable aversive but non-painful electric stimuli, as well as to a control condition without aversive stimulation. In each trial, a symbol signalled whether participants could terminate the stressor through correct performance in a button-matching task or whether the stressor would be randomly terminated, i.e., uncontrollable. Along with neural responses, we assessed participants’ accuracy, reaction times, and heart rate. To relate neural activations and subjective experience, we asked participants to rate perceived control, helplessness, and stress. Results were largely in line with our hypotheses. The vmPFC was generally deactivated by stress, but this effect was attenuated when participants could terminate the stressor compared to when their responses had no effect. Furthermore, activation in stress-responsive regions, including the bilateral insula, was reduced during controllable trials. Under uncontrollable stress, greater vmPFC recruitment was linked to reduced feelings of helplessness. An investigation of condition-dependent differences in vmPFC connectivity yielded no significant results. Our findings further corroborate animal research and emphasise the role of the vmPFC in controllability-dependent regulation of stress responses. Based on the results, we discuss future directions in the context of resilience research and mental health promotion.
Dynamical processing of orientation precision in the primary visual cortex
Authors: Ladret Hugo J. , Cortes Nelson , Ikan Lamyae , Chavane Frédéric , Casanova Christian , Perrinet Laurent U.
Published: March 2021

In our daily visual environment, the primary visual cortex (V1) processes distributions of oriented features as the basis of our visual computations. Changes of the global, median orientation of such inputs form the basis of our canonical knowledge about V1. However, another overlooked but defining characteristic of these sensory variables is their precision, which characterizes the level of variance in the input to V1. Such variability is an intrinsic part of natural images, yet it remains unclear if and how V1 accounts for the changes in orientation precision to achieve its robust orientation recognition performances. Here, we used naturalistic stimuli to characterize the response of V1 neurons to quantified variations of orientation precision. We found that about thirty percent of the recorded neurons showed a form of invariant responses to input precision. While feedforward mechanisms failed to account for the existence of these resilient neurons, neuronal competition within V1 explained the extent to which a neuron is invariant to precision. Using a decoding algorithm, we showed that the existence of such neurons in the population response of V1 can serve to encode both the orientation and its precision in the V1 population activity, which improves the robustness of the overall neural code. These precision-specific neurons operate with slow recurrent cortical dynamics, which supports the notion of predictive precisionweighted processes in V1.