bluuebunny/crossref_metadata_2025 huggingface dataset:
Decoding trans-saccadic prediction error
Authors: Barne Louise Catheryne , Giordano Jonathan , Collins Thérèse , Desantis Andrea
Published: March 2022

We are constantly sampling our environment by moving our eyes, but our subjective experience of the world is stable and constant. Stimulus displacement during or shortly after a saccade often goes unnoticed, a phenomenon called the saccadic suppression of displacement. Although we fail to notice such displacements, our oculomotor system computes the prediction errors and adequately adjusts the gaze and future saccadic execution, a phenomenon known as saccadic adaptation. In the present study, we aimed to find a brain signature of the trans-saccadic prediction error that informs the motor system but not explicit perception. We asked participants (either sex) to report whether a visual target was displaced during a saccade while recording electroencephalography (EEG). Using multivariate pattern analysis, we were able to differentiate displacements from no displacements, even when participants failed to report the displacement. In other words, we found that trans-saccadic prediction error is represented in the EEG signal 100 ms after the displacement presentation, mainly in occipital and parieto-occipital channels, even in the absence of explicit perception of the displacement.

Significance Statement

Stability in vision occurs even while performing saccades. One suggested mechanism for this counterintuitive visual phenomenon is that external displacement is suppressed during the retinal remapping caused by a saccade. Here, we shed light on the mechanisms of trans-saccadic stability by showing that displacement information is not entirely suppressed and specifically present in the early stages of visual processing. Such a signal is relevant and computed for oculomotor adjustment despite being neglected for perception.
The Phytophthora capsici RxLR effector CRISIS2 has roles in suppression of PTI and triggering cell death in host plant
Authors: Mang Hyunggon , Seo Ye-Eun , Lee Hye-Young , Kim Haeun , Jeon Hyelim , Yan Xin , Lee Subin , Park Sang A , Kim Myung-Shin , Segonzac Cecile , Choi Doil
Published: March 2022

Pathogen effectors can suppress various plant immune responses, suggesting their multiple targets in the host. To understand the mechanisms underlying plasma membrane-associated and effector-mediated immunity, we performed Phytophthora capsici CRISIS screening. In Nicotiana benthamiana, cell death induced by the RxLR effector CRISIS2 is inhibited by irreversible plasma membrane H+-ATPase (PMA) activator fusicoccin. Biochemical and gene silencing analyses revealed that CRISIS2 physically and functionally associates with PMAs and induces cell death independent of immune receptors. CRISIS2 induces apoplastic alkalization by suppressing PMA activity by association with the C-terminal regulatory domain of PMA. In planta expression of CRISIS2 significantly enhanced virulence of P. capsici, whereas host-induced gene silencing of CRISIS2 compromised disease symptom and biomass of P. capsici. Furthermore, co-immunoprecipitation assays revealed CRISIS2 associates with BAK1, the co-receptor of PRRs. CRISIS2 interferes with the FLS2-BAK1 complex induced by flagellin perception and impairs downstream signaling from PRR complex. Proteomics and gene silencing assays identified putative PRRs negatively regulate the virulence of P. capsici in N. benthamiana as interactors of CRISIS2 and BAK1. Our study identified a novel RxLR effector playing multiple roles in suppression of plant defense and induction of cell death to support the pathogen hemibiotrophic life cycle in the host plant.
An E3 ligase network engages GCN1 to promote elongation factor-1α degradation on stalled ribosomes
Authors: Oltion Keely , Carelli Jordan D. , Yang Tangpo , See Stephanie K. , Wang Hao-Yuan , Kampmann Martin , Taunton Jack
Published: March 2022

How cells monitor the status of translating ribosomes is a major question in gene regulation. Elongating ribosomes frequently stall during mRNA translation, resulting in context-dependent activation of quality control pathways. However, surveillance mechanisms that specifically respond to stalled ribosomes with an elongation factor occupying the GTPase center have not been identified. By employing ternatin-4, an allosteric elongation factor-1α (eEF1A) inhibitor, we unveil an E3 ligase network that triggers ubiquitination and degradation of eEF1A on stalled ribosomes. A CRISPRi screen revealed two E3 ligases of unknown function, RNF14 and RNF25, which are both essential for ternatin-induced eEF1A degradation. Based on quantitative proteomics analysis, we find that RNF14 and RNF25 promote ubiquitination of eEF1A and a discrete set of ribosomal proteins. By forming a complex with RNF14, the ribosome collision sensor GCN1 plays an essential role in eEF1A degradation. Our findings illuminate a translation elongation checkpoint that monitors the ribosomal GTPase center.
Using data science to identify unusual treatment choices in England: illustrative findings of uncommon antipsychotics Pericyazine and Promazine
Authors: MacKenna Brian , Curtis Helen J , Walker Alex J , Croker Richard , Macdonald Orla , Evans Stephen JW , Inglesby Peter , Evans Dave , Morley Jessica , Bacon Seb CJ , Goldacre Ben
Published: March 2022

Background

Data analysis can be used to identify signals suggestive of variation in treatment choice or clinical outcome. Analyses to date have generally focused on an hypothesis-driven approach.

Methods

Here we report an innovative hypothesis-blind approach (calculating chemical-class proportions for every chemical substance prescribed in each Clinical Commissioning Group and ranking chemicals by (a) their kurtosis and (b) a ratio between inter-centile differences) applied to England’s national prescribing data, and demonstrate how this identified unusual prescribing of two antipsychotics.

Outcomes

We identified that, while promazine and pericyazine are barely used by most clinicians, they make up a substantial proportion of all antipsychotic prescribing in two small geographic regions in England.

Interpretation

Data-driven approaches can be effective at identifying unusual clinical choices. More widespread adoption of such approaches, combined with clinician and decision-maker engagement could lead to better optimised patient care.

Funding

NIHR Biomedical Research Centre, Oxford; Health Foundation; National Institute for Health Research (NIHR) School of Primary Care Research and Research for Patient Benefit

Research in context

Evidence before this study

Identifying variation in clinical activity typically employs a traditional approach whereby measures are prospectively defined, and adherence then assessed in data. We are aware of no prior work using data science techniques hypothesis-blind to systematically identify outliers for any given treatment choice or clinical outcome (numerators) as a proportion of automatically generated denominators.

Added value of this study

Here we report an innovative hypothesis-blind approach applied to England’s national prescribing data, to identify chemical substances with substantial prescribing patterns between organisations. As illustrative examples we show that promazine and pericyazine, while rarely used by most clinicians, made up a substantial proportion of all antipsychotic prescribing in two small geographic regions in England.

Implications of all the available evidence

The choice of antipsychotics between English regions could be further investigated using qualitative methods to explore the implications for patient care. More broadly, data-driven approaches can be effective at identifying unusual clinical choices. More widespread adoption of such approaches, combined with clinician and decision-maker engagement could lead to better optimised patient care.
Psychometric properties of upper limb kinematics during functional tasks in children and adolescents with dyskinetic cerebral palsy
Authors: Vanmechelen Inti , Bekteshi Saranda , Konings Marco , Feys Hilde , Desloovere Kaat , Aerts Jean-Marie , Monbaliu Elegast
Published: March 2022

Aim

Dyskinetic cerebral palsy (DCP) is characterised by involuntary movements, and the movement patterns of children with DCP have not been extensively studied during upper limb tasks. The aim of this study is to evaluate psychometric properties of upper limb kinematics in participants with DCP and typically developing (TD) participants.

Methods

Twenty TD participants and 20 participants with DCP performed three functional tasks: reaching forward, reach and grasp vertical and reach sideways during three-dimensional motion analysis. Joint angles at point of task achievement (PTA) and spatio-temporal parameters were evaluated within-and between sessions using intra-class correlation coefficients (ICC) and standard error of measurement (SEM). Independent t-tests/Mann-Whitney U tests were used to compare all parameters between groups.

Results

Within-session ICC values ranged from 0.55 to 0.99 for joint angles at PTA and spatio-temporal parameters for both groups during all tasks. Within-session SEM values ranged from 1.1° to 11.7° for TD participants and from 1.9° to 13.0° for participants with DCP. Eight within-session repetitions resulted in the smallest change in ICC and SEM values for both groups. Within-session variability was higher for participants with DCP in comparison with the TD group for the majority of the joint angles and spatio-temporal parameters. Intrinsic variability over time was small for all angles and spatio-temporal parameters, whereas extrinsic variability was higher for elbow pro/supination and scapula angles. Between-group differences revealed lower shoulder adduction and higher elbow flexion, pronation and wrist flexion, as well as higher trajectory deviation and a lower maximal velocity for participants with DCP.

Conclusion

This is the first study to assess the psychometric properties of upper limb kinematics in children and adolescents with DCP, showing that children with DCP show higher variability during task execution. However, their variable movement pattern can be reliably captured within- and between-sessions, if sufficient repetitions are taken into account within one session.
Effect of prior infection, vaccination, and hybrid immunity against symptomatic BA.1 and BA.2 Omicron infections and severe COVID-19 in Qatar
Authors: Altarawneh Heba N. , Chemaitelly Hiam , Ayoub Houssein , Tang Patrick , Hasan Mohammad R. , YASSINE HADI M. , Al-Khatib Hebah A. , Smatti Maria K. , Coyle Peter , Al-Kanaani Zaina , Al-Kuwari Einas , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Abdul-Rahim Hanan F. , Nasrallah Gheyath , Al-Kuwari Mohamed Ghaith , Butt Adeel A , Al-Romaihi Hamad Eid , Al-Thani Mohamed H. , Al-Khal Abdullatif , Bertollini Roberto , Abu-Raddad Laith J
Published: March 2022

BACKGROUND: Protection offered by five different forms of immunity, combining natural and vaccine immunity, was investigated against SARS-CoV-2 Omicron symptomatic BA.1 infection, symptomatic BA.2 infection, BA.1 hospitalization and death, and BA.2 hospitalization and death, in Qatar, between December 23, 2021 and February 21, 2022.
METHODS: Six national, matched, test-negative case-control studies were conducted to estimate effectiveness of BNT162b2 (Pfizer-BioNTech) vaccine, mRNA-1273 (Moderna) vaccine, natural immunity due to prior infection with pre-Omicron variants, and hybrid immunity from prior infection and vaccination.
RESULTS: Effectiveness of only prior infection against symptomatic BA.2 infection was 46.1% (95% CI: 39.5-51.9%). Effectiveness of only two-dose BNT162b2 vaccination was negligible at -1.1% (95% CI: -7.1-4.6), but nearly all individuals had received their second dose several months earlier. Effectiveness of only three-dose BNT162b2 vaccination was 52.2% (95% CI: 48.1-55.9%). Effectiveness of hybrid immunity of prior infection and two-dose BNT162b2 vaccination was 55.1% (95% CI: 50.9-58.9%). Effectiveness of hybrid immunity of prior infection and three-dose BNT162b2 vaccination was 77.3% (95% CI: 72.4-81.4%). Meanwhile, prior infection, BNT162b2 vaccination, and hybrid immunity all showed strong effectiveness >70% against any severe, critical, or fatal COVID-19 due to BA.2 infection. Similar levels and patterns of effectiveness were observed for BA.1 and for the mRNA-1273 vaccine.
CONCLUSIONS: There are no discernable differences in the effects of prior infection, vaccination, and hybrid immunity against BA.1 versus BA.2. Hybrid immunity resulting from prior infection and recent booster vaccination confers the strongest protection against either subvariant. Vaccination enhances protection of those with a prior infection.
Exploring patient experiences and concerns in the online Cochlear Implant community: a natural language processing approach
Authors: Williams Christopher Y.K. , Li Rosia X , Luo Michael Y , Bance Manohar
Published: March 2022

Importance: There is a paucity of research examining patient experiences of cochlear implants, with existing studies limited by small sample sizes and closed question-answer style formats.

Objective: To use natural language processing methods to explore patient experiences and concerns in the online cochlear implant (CI) community when in conversation with each other.

Design: Cross-sectional study of the online Reddit r/CochlearImplants forum. No date restrictions were imposed; data were retrieved on 11 November 2021 and analysed between November 2021 and March 2022. The following details were extracted for each post: 1) original post content, 2) post comments, and 3) metadata for the original post and user.

Setting: Online Reddit forum r/CochlearImplants.

Participants: Consecutive sample of all users posting on the r/CochlearImplants forum from 1 March 2015 to 11 November 2021.

Main Outcomes and Measures: Natural language processing using the BERTopic automated topic modelling technique was employed to cluster posts into semantically similar topics. Topic categorisation was manually validated by two independent reviewers and Cohen's Kappa calculated to determine inter-rater reliability between machine vs human and human vs human categorisation.

Results: We retrieved 987 posts from 588 unique Reddit users on the r/CochlearImplants forum. Posts were initially categorised by BERTopic into 16 different Topics, which were increased to 22 Topics following manual inspection. The most popular topics related to CI connectivity (n = 112),adults considering getting a CI (n=107), surgery-related posts (n = 89) and day-to-day living with a CI (n = 85). Topics with the most comments included Choosing cochlear implant brand (mean = 12.9 comments) and Adults considering getting a CI (mean = 12.2 comments). Cohen's kappa among all posts was 0.62 (machine vs human) and 0.72 (human vs human), and among categorised posts was 0.85 (machine vs human) and 0.84 (human vs human).

Conclusions and Relevance: This cross-sectional study of social media discussions amongst the online cochlear implant community identified common attitudes, experiences and concerns of patients living with, or seeking, a cochlear implant. Our validation of natural language processing methods to categorise topics shows that automated analysis of similar Otolaryngology-related content is a viable and accurate alternative to manual qualitative approaches.
Risk of SARS-CoV-2 transmission by fomites: a clinical observational study in highly infectious COVID-19 patients
Authors: Meister Toni Luise , Dreismeier Marielen , Blanco Elena Vidal , Brüggemann Yannick , Heinen Natalie , Kampf Günter , Todt Daniel , Nguyen Huu Phuc , Steinmann Jörg , Schmidt Wolfgang Ekkehard , Steinmann Eike , Quast Daniel Robert , Pfaender Stephanie
Published: March 2022

Background

The contribution of droplet-contaminated surfaces for virus transmission has been discussed controversially in the context of the current Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic. Importantly, the risk of fomite-based transmission has not been systematically addressed.

Methods

We initiated this single-center observational study to evaluate whether hospitalized COVID-19 patients can contaminate stainless steel carriers by coughing or intensive moistening with saliva and to assess the risk of SARS-CoV-2 transmission upon detection of viral loads and infectious virus in cell culture. Fifteen hospitalized patients with a high baseline viral load (CT value ≤ 25) shortly after admission were included. We documented clinical and laboratory parameters and used patient samples to perform virus culture, quantitative PCR and virus sequencing.

Results

Nasopharyngeal and oropharyngeal swabs of all patients were positive for viral RNA on the day of the study. Infectious SARS-CoV-2 could be isolated from 6 patient swabs (46.2 %). While after coughing, no infectious virus could be recovered, intensive moistening with saliva resulted in successful viral recovery from steel carriers of 5 patients (38.5 %).

Conclusions

Transmission of infectious SARS-CoV-2 via fomites is possible upon extensive moistening, but unlikely to occur in real-life scenarios and from droplet-contaminated fomites.
Environmental chemical-wide associations with immune biomarkers in the US: A cross-sectional analysis
Authors: Middleton Lauren Y. M. , Nguyen Vy K. , Dou John , Park Sung Kyun , Colacino Justin A. , Bakulski Kelly M.
Published: March 2022

Exposure to environmental chemicals influence immune system functions, and humans are exposed to a wide range of chemicals, termed the chemical exposome. Thus, a comprehensive analysis of the effects across multiple chemical families with immune biomarkers is needed. In this study, we tested the associations between environmental chemicals and immune biomarkers. We analyzed the United States cross-sectional National Health and Nutrition Examination Survey (NHANES 1999-2018). Chemicals were measured in blood or urine (198 chemicals, 17 families). Immune biomarkers included percentages of lymphocytes, neutrophils, monocytes, basophils, and eosinophils, and counts of red blood cells, white blood cells, and mean corpuscular volume. We conducted survey-weighted, multivariable linear regressions of log2-transformed chemicals on immune measures, adjusted for age, sex, race/ethnicity, poverty-income ratio, waist circumference, cotinine concentration, creatinine for urinary chemicals, and survey cycle. We accounted for multiple comparisons using a false discovery rate (FDR). Among 45,528 adult participants, using survey weights, the mean age was 45.7 years, 51.4% were female, and 69.3% were Non-Hispanic White. There were 65 chemicals associated with white blood cell count. For example, a doubling in the concentration of blood lead was associated with a decrease of 61 white blood cells per µL (95% CI: 23–99; FDR=0.005). 122 (61.6%) chemicals were associated with at least one of the eight immune biomarkers. Chemicals in the Metals family were associated with all eight immune measures. Concentrations of a wide variety of biomarkers of exposure to chemicals such as metals and smoking-related compounds, were highly associated with immune system biomarkers, with implications for immune function and toxicology. This environmental chemical-wide association study identified chemicals from multiple families for further toxicological and epidemiological investigation.
Stage-specific gene and transcript dynamics in human male germ cells
Authors: Siebert-Kuss Lara Marie , Krenz Henrike , Tekath Tobias , Wöste Marius , Di Persio Sara , Terwort Nicole , Wyrwoll Margot J. , Cremers Jann-Frederik , Wistuba Joachim , Dugas Martin , Kliesch Sabine , Schlatt Stefan , Tüttelmann Frank , Gromoll Jörg , Neuhaus Nina , Laurentino Sandra
Published: March 2022

Cell differentiation processes are highly dependent on cell stage-specific gene expression, including timely production of alternatively spliced transcripts. One of the most transcriptionally rich tissues is the testis, where the process of spermatogenesis, or generation of male gametes, takes place. To date, germ cell-specific transcriptome dynamics remain understudied due to limited transcript information emerging from short-read sequencing technologies. To fully characterize the transcriptional profiles of human male germ cells and to understand how the human spermatogenic transcriptome is regulated, we compared whole transcriptomes of men with different types of germ cells missing from their testis. Specifically, we compared the transcriptomes of testis lacking germ cells (Sertoli cell-only phenotype; SCO; n=3), with an arrest at the stage of spermatogonia (SPG; n=4), spermatocytes (SPC; n=3), and round spermatids (SPD; n=3), with the transcriptomes of testis with normal and complete spermatogenesis (Normal; n=3). We found between 839 and 4,138 differentially expressed genes (DEGs, log2 fold change ≥ 1) per group comparison, with the most prevalent changes observed between SPG and SPC arrest samples, corresponding to the entry into meiosis. We detected highly germ cell-type specific marker genes among the topmost DEGs of each group comparison. Moreover, applying state-of-the-art bioinformatic analysis we were able to evaluate differential transcript usage (DTU) during human spermatogenesis and observed between 1,062 and 2,153 genes with alternatively spliced transcripts per group comparison. Intriguingly, DEGs and DTU genes showed minimal overlap (< 8%), suggesting that stage-specific splicing is an additional layer of gene regulation in the germline. By generating the most complete human testicular germ cell transcriptome to date, we unravel extensive dynamics in gene expression and alternative splicing during human spermatogenesis.
A self-amplifying RNA vaccine against COVID-19 with long-term room-temperature stability
Authors: Voigt Emily A. , Gerhardt Alana , Hanson Derek , Battisti Peter , Reed Sierra , Singh Jasneet , Mohamath Raodoh , Jennewein Madeleine F. , Bakken Julie , Beaver Samuel , Press Christopher , Soon-Shiong Patrick , Paddon Christopher J. , Fox Christopher B. , Casper Corey
Published: March 2022

mRNA vaccines were the first to be authorized for use against SARS-CoV-2 and have since demonstrated high efficacy against serious illness and death. However, limitations in these vaccines have been recognized due to their requirement for cold storage, short durability of protection, and lack of access in low-resource regions. We have developed an easily-manufactured, potent self-amplifying RNA (saRNA) vaccine against SARS-CoV-2 that is stable at room temperature. This saRNA vaccine is formulated with a nanostructured lipid carrier (NLC), providing enhanced stability, improved manufacturability, and protection against degradation. In preclinical studies, this saRNA/NLC vaccine induced strong humoral immunity, as demonstrated by high pseudovirus neutralization titers to the Alpha, Beta, and Delta variants of concern and induction of long-lived bone marrow-resident antibody secreting cells. Robust Th1-biased T-cell responses were also observed after prime or homologous prime-boost in mice. Notably, the saRNA/NLC platform demonstrated thermostability at room temperature for at least 6 months when lyophilized. Taken together, this saRNA delivered by NLC represents a potential improvement in RNA technology that could allow wider access to RNA vaccines for the current COVID-19 and future pandemics.
Macrophages only sense infectious SARS-CoV-2 when they express sufficient ACE2 to permit viral entry, where rapid cytokine responses then limit viral replication
Authors: Labzin Larisa I , Chew Keng Yih , Eschke Kathrin , Wang Xiaohui , Esposito Tyron , Stocks Claudia J , Rae James , Patrick Ralph , Mostafavi Helen , Hill Brittany , Yordanov Teodor E. , Holley Caroline L , Emming Stefan , Fritzlar Svenja , Mordant Francesca L. , Steinfort Daniel P. , Subbarao Kanta , Nefzger Christian M. , Lagendijk Anne K , Gordon Emma , Parton Robert , Short Kirsty R. , Londrigan Sarah L. , Schroder Kate
Published: March 2022

Macrophages are key cellular contributors to COVID-19 pathogenesis. Whether SARS-CoV-2 can enter macrophages, replicate and release new viral progeny remains controversial. Similarly, whether macrophages need to sense replicating virus to drive cytokine release is also unclear. Macrophages are heterogeneous cells poised to respond to their local microenvironment, and accordingly, the SARS-CoV-2 entry receptor ACE2 is only present on a subset of macrophages at sites of human infection. Here, we use in vitro approaches to investigate how SARS-CoV-2 interacts with ACE2-negative and ACE2-positive human macrophages and determine how these macrophage populations sense and respond to SARS-CoV-2. We show that SARS-CoV-2 does not replicate within ACE2-negative human macrophages and does not induce pro-inflammatory cytokine expression. By contrast, ACE2 expression in human macrophages permits SARS-CoV-2 entry, replication, and virion release. ACE2-expressing macrophages sense replicating virus to trigger pro-inflammatory and anti-viral programs that limit virus release. These combined findings resolve several controversies regarding macrophage-SARS-CoV-2 interactions and identify a signaling circuit by which macrophages sense SARS-CoV-2 cell entry and respond by restricting viral replication.

One sentence summary

Lack of macrophage ACE2 expression precludes SARS-CoV-2 entry and sensing, while ACE2-expressing macrophages sense intramacrophage SARS-CoV-2 replication to induce rapid anti-viral responses that limit new virion release.
Humanized mice for sustained Plasmodium vivax blood-stage infection and transmission
Authors: Luiza-Batista Camilla , Thiberge Sabine , Serra-Hassoun Malika , Garcia Sylvie , Nardella Flore , Claes Aurelie , Nicolete Vanessa C. , Commere Pierre-Henri , Silva-Mancio Liliana , Ferreira Marcelo U. , Scherf Artur , Garcia Sylvie
Published: March 2022

Plasmodium vivax is the most widespread human malaria parasite. The presence of extravascular reservoirs, the early circulation of infective stages (gametocytes), and relapsing infections arising from dormant liver stages render this parasite particularly difficult to control and eliminate. Experimental research is limited by the lack of a continuous culture in vitro system that fulfills the parasite needs, namely its tropism for immature CD71+ red blood cells (RBCs). Here, we report a humanized mice model, which upon engraftment of human hematopoietic progenitor and stem cells (HPSCs), exhibits efficient human erythropoiesis. Humanized HIS-HEry mice inoculated with cryopreserved P. vivax samples sustain long-lasting asexual parasite multiplication within CD71+ human RBCs and differentiation into mature gametocytes that can be efficiently transmitted to Anopheles mosquitoes, leading to formation salivary-gland sporozoites. Blood stages can be sequentially transferred to uninfected humanized mice by injection of fresh or frozen infected bone marrow cells, providing a unique murine model for the long-term maintenance of P. vivax isolates. This work offers a novel experimental platform to investigate the biology of RBC invasion and intraerythrocytic P. vivax development in vivo and evaluate new interventions against this elusive human parasite.
Using protein-per-mRNA differences among human tissues in codon optimization
Authors: Hernandez-Alias Xavier , Benisty Hannah , Serrano Luis , Schaefer Martin H
Published: March 2022

Codon usage and nucleotide composition of coding sequences have profound effects on protein expression. However, while it is recognized that different tissues have distinct tRNA profiles and codon usages in their transcriptomes, the effect of tissue-specific codon optimality on protein synthesis remains elusive. Here, we leverage existing state-of-the-art transcriptomics and proteomics datasets from the GTEx project and the Human Protein Atlas to compute the protein-to-mRNA ratios of 36 human tissues. Using this as a proxy of translational efficiency, we build a machine learning model that identifies codons enriched or depleted in specific tissues. In particular, we detect two clusters of tissues with an opposite pattern of codon preferences. We then use the identified patterns for the development of CUSTOM, a codon optimizer algorithm which suggests a synonymous codon design in order to optimize protein production in a tissue-specific manner. In a human cell model, we provide evidence that codon optimization should indeed take into account particularities of the translational machinery of the tissues in which the target proteins are expressed and that our approach can design genes with tissue-optimized expression profiles. Altogether, CUSTOM could benefit biological and biotechnological research, such as the design of tissue-targeted therapies and vaccines.
Parallel processing, hierarchical transformations, and sensorimotor associations along the ‘where’ pathway
Authors: Doudlah Raymond , Chang Ting-Yu , Thompson Lowell W , Kim Byounghoon , Sunkara Adhira , Rosenberg Ari
Published: March 2022

Visually guided behaviors require the brain to transform ambiguous retinal images into object-level spatial representations and implement sensorimotor transformations. These processes are supported by the dorsal ‘where’ pathway. However, the specific functional contributions of areas along this pathway remain elusive due in part to methodological differences across studies. We previously showed that macaque caudal intraparietal (CIP) area neurons possess robust three-dimensional (3D) visual representations, carry choice-related and presaccadic activity, and exhibit experience-dependent sensorimotor associations (Chang et al., 2020b). Here, we used a common experimental design to reveal parallel processing, hierarchical transformations, and the formation of sensorimotor associations along the ‘where’ pathway by extending the investigation to V3A, a major feedforward input to CIP. Higher-level 3D representations and choice-related activity were more prevalent in CIP than V3A. Both areas contained presaccadic activity that predicted the direction/timing of eye movements. Intriguingly, the time-course of presaccadic activity in CIP aligned with the temporally integrated V3A output. Sensorimotor associations between 3D orientation and saccade direction preferences were strongest in CIP and moderated by choice signals in both areas. Together, the results explicate parallel representations, hierarchical transformations, and functional associations of visual and presaccadic signals at a key juncture in the ‘where’ pathway.
Methylene Blue Is a Nonspecific Protein-Protein Interaction Inhibitor with Potential for Repurposing as an Antiviral for COVID-19
Authors: Chuang Sung-Ting , Papp Henrietta , Kuczmog Anett , Eells Rebecca , Condor Capcha Jose Manuel , Shehadeh Lina A. , Jakab Ferenc , Buchwald Peter
Published: March 2022

We have previously identified methylene blue, a tricyclic phenothiazine dye approved for clinical use for the treatment of methemoglobinemia and used for other medical applications, as a small-molecule inhibitor of the protein-protein interaction (PPI) between the spike protein of the SARS-CoV-2 coronavirus and ACE2, the first critical step of the attachment and entry of this coronavirus responsible for the COVID-19 pandemic. Here, we show that methylene blue concentration-dependently inhibits this PPI for the spike protein of the original strain as well as for those of variants of concerns such as the D614G mutant and delta (B.1.617.2) with IC50 in the low micromolar range (1-5 μM). Methylene blue also showed promiscuous activity and inhibited several other PPIs of viral proteins (e.g., HCoV-NL63 - ACE2, hepatitis C virus E - CD81) as well as others (e.g., IL-2 - IL-2Rα) with similar potency. This non-specificity notwithstanding, methylene blue inhibited the entry of pseudoviruses bearing the spike protein of SARS-CoV-2 in hACE2-expressing host cells both for the original strain and the delta variant. It also blocked SARS-CoV-2 (B.1.5) virus replication in Vero E6 cells with an IC50 in the low micromolar range (1.7 μM) when assayed using quantitative PCR of the viral RNA. Thus, while it seems to be a promiscuous PPI inhibitor with low micromolar activity and it has a relatively narrow therapeutic index, methylene blue inhibits entry and replication of SARS-CoV-2, including several of its mutant variants, and has potential as a possible inexpensive, broad-spectrum, orally bioactive small-molecule antiviral for the prevention and treatment of COVID-19.
A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification
Authors: Edginton-White B. , Maytum A , Kellaway S.G. , Goode D.K. , Keane P. , Pagnuco I. , Assi S.A. , Ames L. , Clarke M , Cockerill P.N. , Göttgens B. , Cazier J.B. , Bonifer C.
Published: March 2022

Developmental control of gene expression critically depends on distal cis-regulatory elements including enhancers which interact with promoters to activate gene expression. To date no global experiments have been conducted that identify their cell type and cell stage-specific transcription stimulatory activity within one developmental pathway and in a chromatin context. Here, we describe a high-throughput method that identifies thousands of differentially active cis-elements able to stimulate a minimal promoter at five stages of hematopoietic progenitor development from embryonic stem cells, which can be adapted to any ES cell derived cell type. Exploring this new resource, we show that blood cell-specific gene expression is controlled by the concerted action of thousands of differentiation stage-specific sets of cis-elements which respond to cytokine signals that terminate at signalling responsive transcription factors. Our work presents a major advance in our understanding of developmental gene expression control in the hematopoietic system and beyond.
Simultaneous profiling of spatial gene expression and chromatin accessibility for mouse brain development
Authors: Jiang Fuqing , Zhou Xin , Qian Yingying , Zhu Miao , Wang Li , Li Zhuxia , Shen Qingmei , Qu Fangfang , Cui Guizhong , Chen Kai , Peng Guangdun
Published: March 2022

Brain are complex biological tissues which function relies on coordinated anatomical and molecular structure comprised by a large number of specialized cells. The spatial architecture of brain which is key to the understanding of its physiological and pathological significance is formed during embryo development. However, the molecular basis for discrete neuroanatomical domains particularly in the context of spatial organization of the brain is inadequate. Here, we introduced microfluidic indexing based spatial ATAC and RNA sequencing (MISAR-seq), a method for joint profiling of chromatin accessibility and gene expression with spatial information retained in the developing mouse brain. Our study has established a direct means to spatially determine the coordination between chromatin accessibility and transcriptome, identified the chromatin potential to define cell fate determination of brain organization, and uncovered spatiotemporal regulatory principles during mammalian brain development.
The wheat multi-pathogen resistance gene, Lr67res, confers a novel gain-of-function phenotype involving anion fluxes
Authors: Milne Ricky J , Dibley Katherine E , Bose Jay , Riaz Adnan , Zhang Jianping , Schnippenkoetter Wendelin Heribert , Ashton Anthony R. , Ryan Peter R , Tyerman Stephen D , Lagudah Evans
Published: March 2022

Partial resistance to multiple biotrophic fungal pathogens in wheat (Triticum aestivum L.) is conferred by the Lr67 gene, which encodes a Sugar Transport Protein 13 (STP13) family hexose-proton symporter variant. Two mutations (G144R, V387L) differentiate the resistant and susceptible protein variants (Lr67res and Lr67sus). The molecular function of the Lr67res protein is not well understood. We functionally characterized the wheat Lr67res protein variant using two heterologous expression systems - Xenopus laevis oocytes and Saccharomyces cerevisiae yeast. Wheat and barley (Hordeum vulgare) were used to verify disease resistance capability of Lr67/STP13 variants. The Lr67res allele, but not Lr67sus, induced large sugar-independent, anion-dominated currents in oocytes and an increased sensitivity to ions in yeast, implicating a novel gain-of-function. We demonstrate that the single mutant variant, Lr67susG144R, confers disease resistance in wheat and that transgenic barley (Hordeum vulgare L.) plants expressing the orthologous HvSTP13 gene carrying the equivalent mutations present in Lr67res exhibited increased resistance to Puccinia hordei. NaCl treatment was found to induce leaf tip necrosis in Lr67res wheat. An Lr67res-like gain-of-function can be introduced into orthologous plant hexose transporters via single amino acid mutation, highlighting the possibility of generating disease resistance in other crop species, especially with gene editing.
Inhalable polymer nanoparticles for versatile mRNA delivery and mucosal vaccination
Authors: Suberi Alexandra , Grun Molly K. , Mao Tianyang , Israelow Benjamin , Reschke Melanie , Grundler Julian , Akhtar Laiba , Lee Teresa , Shin Kwangsoo , Piotrowski-Daspit Alexandra S. , Homer Robert J. , Iwasaki Akiko , Suh Hee Won , Saltzman W. Mark
Published: March 2022

An inhalable platform for mRNA therapeutics would enable minimally invasive and lung targeted delivery for a host of pulmonary diseases. Development of lung targeted mRNA therapeutics has been limited by poor transfection efficiency and risk of vehicle-induced pathology. Here we report an inhalable polymer-based vehicle for delivery of therapeutic mRNAs to the lung. We optimized biodegradable poly(amine-co-ester) polyplexes for mRNA delivery using end group modifications and polyethylene glycol. Our polyplexes achieved high transfection of mRNA throughout the lung, particularly in epithelial and antigen-presenting cells. We applied this technology to develop a mucosal vaccine for SARS-CoV-2. Intranasal vaccination with spike protein mRNA polyplexes induced potent cellular and humoral adaptive immunity and protected K18-hACE2 mice from lethal viral challenge.

One-sentence summary

Inhaled polymer nanoparticles (NPs) achieve high mRNA expression in the lung and induce protective immunity against SARS-CoV-2.
Hypertension perspectives and health behaviors of African youth: The effect of health education and employment
Authors: Mhlaba M , Mpondo F , Ware LJ
Published: March 2022

In South Africa between 1998 and 2016, hypertension rates in young adults (15-34 years) more than doubled calling for preventive interventions. However, with many youth unemployed, young adults struggle to prioritize health or implement healthy behaviors. We conducted six focus group discussions comparing hypertension-related beliefs and behaviors between NEET youth (n=20; not in employment, education or training) and previously NEET youth on a health-focused learnership (n=20). While all youth viewed hypertension as life threatening leading to cardiovascular disease or death, especially if left untreated, only youth undertaking health education felt empowered to implement healthy behaviors for disease prevention. In contrast, NEET youth felt hypertension was inevitable and described negative experiences at clinics and fear of lifelong medication use if diagnosed as reasons not to be screened. Our results suggest that engaging NEET youth in culturally appropriate health education programs can motivate preventive health behavior for chronic diseases such as hypertension.
Calcium Channel Blockers: clinical outcome associations with reported pharmacogenetics variants in 32,000 patients
Authors: Türkmen Deniz , Masoli Jane A.H. , Delgado João , Kuo Chia-Ling , Bowden Jack , Melzer David , Pilling Luke C.
Published: March 2022

Background

Dihydropiridine calcium channel blockers (dCCB) (e.g. amlodipine) are widely used for treating hypertension. Pharmacogenetic variants impact treatment efficacy, yet evidence on clinical outcomes in routine primary care is limited. We aimed to estimate associations between reported pharmacogenetic variants and incident adverse events in a community-based cohort prescribed dCCB, including in high-risk subgroups.

Methods

We analysed up to 32,360 UK Biobank European-ancestry participants prescribed dCCB in primary care electronic health records (from UK General Practices, 1990 to 2017). We investigated 23 genetic variants in 16 genes reported in PharmGKB, including CYP3A5 and RYR3. Outcomes were incident diagnosis of coronary heart disease (CHD), heart failure (HF), chronic kidney disease (CKD), edema, and switching antihypertensive medication. Secondary analysis in patients with history of heart disease was also performed.

Results

Participants were aged 40 to 79 years at first dihydropyridine prescription (treatment duration 1 month to 40 years, mean 5.9 years). Carriers of rs877087 T allele in the ryanodine receptor 3 (RYR3) had increased risk of HF (Hazard Ratio 1.13: 95% Confidence Intervals 1.02 to 1.25, p=0.02). We estimated that if rs877087 T allele carriers were prescribed an alternative treatment the incidence of HF in patients prescribed dCCB would reduce by 9.2% (95%CI 3.1 to 15.4). In patients with a history of heart disease when first prescribed dCCB (N=2,296), RYR3 rs877087 homozygotes had increased risk of new CHD or HF compared to CC variant (HR 1.25, 95%CI 1.09 to 1.44, p=0.002). Two variants increased likelihood of switching to an alternate antihypertensive medication (rs10898815 in gene NUMA1 HR 1.16: 95%CI 1.07 to 1,27, p=0.0009; rs776746 in CYP3A5 HR 1.59: 95%CI 1.09 to 2.32, p=0.02). rs776746 in CYP3A5 also increased CKD risk (HR 2.12, p=0.002). The remaining previously reported variants were not strongly or consistently associated with the studied clinical outcomes.

Conclusions

In this large primary care cohort, patients with common genetic variants in NUMA1, CYP3A5 and RYR3 had increased adverse clinical outcomes. Work is needed to establish whether outcomes of dCCB prescribing could be improved by prior knowledge of such pharmacogenetics variants supported by clinical evidence of association with adverse events.
The contribution of malaria and sickle cell disease to anaemia among children aged 6 to 59 months in Nigeria: A secondary analysis using data from the 2018 Demographic and Health Survey
Authors: Chao Dennis L. , Oron Assaf P. , Chabot-Couture Guillaume , Sopekan Alayo , Nnebe-Agumadu Uche , Bates Imelda , Piel Frédéric B. , Nnodu Obiageli E.
Published: March 2022

Introduction

Anaemia is a major cause of morbidity and mortality among children in sub-Saharan Africa. Anaemia has many aetiologies best addressed by different treatments, so regional studies of the aetiology of anaemia may be required.

Methods

We analysed data from Nigeria’s 2018 Demographic and Health Survey (DHS) to study predictors of anaemia among children ages 6-59m. We computed the fraction of anaemia at different degrees of severity attributable to malaria and sickle cell disease (SCD) using a regression model adjusting for demographic and socioeconomic risk factors. We also estimated the contribution of the risk factors to haemoglobin concentration.

Results

We found that 63.7% (95% CI: 58.3-69.4) of semi-severe anaemia (<80 g/L) was attributable to malaria compared to 12.4% (95% CI: 11.1-13.7) of mild-to-severe (adjusted haemoglobin concentration <110 g/L) and 29.6% (95% CI: 29.6-31.8) of moderate-to-severe (<100 g/L) anaemia and that SCD contributed 0.6% (95%CI: 0.4-0.9), 1.3% (95% CI: 1.0-1.7), and 7.3% (95%CI: 5.3-9.4) mild-to-severe, moderate-to-severe, and semi-severe anaemia, respectively. Sickle trait was protective against anaemia and was associated with higher haemoglobin concentration compared to children with normal haemoglobin (HbAA) among malaria-positive but not malaria-negative children.

Conclusion

This approach used offers a new tool to estimate the contribution of malaria to anaemia in many settings using widely available DHS data. The fraction of anaemia among young children in Nigeria attributable to malaria and SCD is higher at more severe levels of anaemia. Prevention of malaria and SCD and timely treatment of affected individuals would reduce cases of severe anaemia.
The relationship between wild-type transthyretin amyloid load and ligamentum flavum thickness in lumbar stenosis patients
Authors: Wang Andy Y. , Saini Harleen , Tingen Joseph N. , Sharma Vaishnavi , Flores Alexandra , Liu Diang , Olmos Michelle , McPhail Ellen D. , Safain Mina G. , Kryzanski James , Arkun Knarik , Riesenburger Ron I.
Published: March 2022

Background

One key contributor to lumbar stenosis is thickening of the ligamentum flavum (LF), a process still poorly understood. Wild-type transthyretin amyloid (ATTRwt) has been found in the LF of patients undergoing decompression surgery, suggesting that amyloid may play a role. However, it is unclear whether within patients harboring ATTRwt, the amount of amyloid is associated with LF thickness.

Methods

From an initial cohort of 324 consecutive lumbar stenosis patients whose LF specimens from decompression surgery were sent for analysis (2018-2019), 33 patients met the following criteria: (1) Congo red-positive amyloid in the LF; (2) ATTRwt by mass spectrometry-based proteomics; and (3) an available preoperative MRI. Histological specimens were digitized, and amyloid load quantified through Trainable Weka Segmentation (TWS) machine learning. LF thicknesses were manually measured on axial T2-weighted preoperative MRI scans at each lumbar level, L1-S1. The sum of thicknesses at every lumbar LF level (L1-S1) equals “lumbar LF burden.”

Results

Patients had a mean age of 72.7 years (range 59-87), were mostly male (61%) and white (82%); and predominantly had surgery at L4-L5 levels (73%). Amyloid load was positively correlated with LF thickness (R=0.345, p=0.0492) at the levels of surgical decompression. Furthermore, amyloid load was positively correlated with lumbar LF burden (R=0.383, p=0.0279).

Conclusions

Amyloid load is positively correlated with LF thickness and lumbar LF burden across all lumbar levels, in a dose-dependent manner. Further studies are needed to validate these findings, uncover the underlying pathophysiology, and pave the way towards using therapies that slow LF thickening.
Ubiquitin ligase TRAIP plays an essential role during the S-phase of unperturbed cell cycle in the resolution of DNA replication – transcription conflicts
Authors: Scaramuzza Shaun , Sadurni Martina Muste , Poovathumkadavil Divyasree , Natsume Toyoaki , Rojas Patricia , Kanemaki Masato T. , Saponaro Marco , Gambus Agnieszka
Published: March 2022

Cell division is the basis for the propagation of life and requires accurate duplication of all genetic information. DNA damage created during replication (replication stress) is a major cause of cancer, premature aging and a spectrum of other human disorders. Over the years, TRAIP E3 ubiquitin ligase has been shown to play a role in various cellular processes that govern genome integrity and faultless segregation. TRAIP is essential for cell viability, and mutations in TRAIP ubiquitin ligase activity lead to primordial dwarfism in patients. Here, for the first time, we have determined the mechanism of inhibition of cell proliferation in TRAIP-depleted cells. We have taken advantage of the auxin induced degron system to rapidly degrade TRAIP within cells and to dissect the importance of various functions of TRAIP in different stages of the cell cycle. We find that upon rapid TRAIP degradation, specifically in S-phase, cells cease to proliferate, arrest in G2 stage of the cell cycle and undergo senescence. Our findings reveal that TRAIP works in S-phase to prevent DNA damage at transcription start sites, caused by replication-transcription conflicts.