bluuebunny/crossref_metadata_2025 huggingface dataset:
Is there a gender hiring gap in academic economics? Evidence from a network analysis
Authors: Orland Andreas , Padubrin Max
Published: February 2022

We collect a network dataset of tenured economics faculty in Austria, Germany and Switzerland. We rank the 100 institutions included with a minimum violation ranking. This ranking is positively and significantly correlated with the Times Higher Education ranking of economics institutions. According to the network ranking, individuals on average go down about 23 ranks from their doctoral institution to their employing institution. While the share of females in our dataset is only 15%, we do not observe a significant gender hiring gap (a difference in rank changes between male and female faculty). We conduct a robustness check with the Handelsblatt and the Times Higher Education ranking. According to these rankings, individuals on average go down only about two ranks. We do not observe a significant gender hiring gap using these two rankings (although the dataset underlying this analysis is small and these estimates are likely to be noisy). Finally, we discuss the limitations of the network ranking in our context.
The
Incubascope
: a simple, compact and large field of view microscope for long-term imaging inside an incubator
Authors: Badon A. , Andrique L. , Mombereau A. , Rivet L. , Boyreau A. , Nassoy P. , Recher G.
Published: February 2022

Optical imaging has rapidly evolved in the last decades. Sophisticated microscopes allowing optical sectioning for three-dimensional imaging or sub-diffraction resolution are available. Due to price and maintenance issues, these microscopes are often shared between users in facilities. Consequently, long-term access is often prohibited and does not allow to monitor slowly evolving biological systems or to validate new models like organoids. Preliminary coarse long-term data that do not require acquisition of terabytes of high-resolution images are important as a first step. By contrast with expensive all-in-one commercialized stations, standard microscopes equipped with incubator stages offer a more cost-effective solution despite imperfect long-run atmosphere and temperature control. Here, we present the
Incubascope
, a custom-made compact microscope that fits into a table-top incubator. It is cheap and simple to implement, user-friendly and yet provides high imaging performances. The system has a field of view of 5.5 × 8 mm
2
, a 3 μm resolution, a 10 frames per second acquisition rate, and is controlled with a Python-based graphical interface. We exemplify the capabilities of the
Incubascope
on biological applications such as the hatching of
Artemia salina
eggs, the growth of the slime mould
Physarum polycephalum
and of encapsulated spheroids of mammalian cells.
Comparison between the kinematics for kangaroo rat hopping on a solid versus sand surface
Authors: Hall Joseph K. , McGowan Craig P. , Lin David C.
Published: February 2022

In their natural habitats, animals move on a variety of substrates, ranging from solid surfaces to those that yield and flow (e.g. sand). These substrates impose different mechanical demands on the musculoskeletal system and may therefore elicit different locomotion patterns. The goal of this study is to compare bipedal hopping by desert kangaroo rats (
Dipodomys deserti)
on a solid versus granular substrate under speed-controlled conditions. To accomplish this goal, we developed a rotary treadmill, which is able to have different substrates or uneven surfaces. We video recorded six kangaroo rats hopping on a solid surface versus sand at the same speed (1.8 m s
−1
) and quantified the differences in the hopping kinematics between the two substrates. We found no significant differences in the hop period, hop length or duty cycle, showing that the gross kinematics on the two substrates were similar. This similarity was surprising given that sand is a substrate that absorbs mechanical energy. Measurements of the penetration resistance of the sand showed that the combination of the sand properties, toe-print area and kangaroo rat weight was probably the reason for the similarity.
Seasonality of coronavirus shedding in tropical bats
Authors: Joffrin Léa , Hoarau Axel O. G. , Lagadec Erwan , Torrontegi Olalla , Köster Marie , Le Minter Gildas , Dietrich Muriel , Mavingui Patrick , Lebarbenchon Camille
Published: February 2022

Anticipating cross-species transmission of zoonotic diseases requires an understanding of pathogen infection dynamics within natural reservoir hosts. Although bats might be a source of coronaviruses (CoVs) for humans, the drivers of infection dynamics in bat populations have received limited attention. We conducted a fine-scale 2-year longitudinal study of CoV infection dynamics in the largest colony of Reunion free-tailed bats (
Mormopterus francoismoutoui
), a tropical insectivorous species. Real-time PCR screening of 1080 fresh individual faeces samples collected during the two consecutive years revealed an extreme variation of the detection rate of bats shedding viruses over the birthing season (from 0% to 80%). Shedding pulses were repeatedly observed and occurred both during late pregnancy and within two months after parturition. An additional shedding pulse at the end of the second year suggests some inter-annual variations. We also detected viral RNA in bat guano up to three months after bats had left the cave. Our results highlight the importance of fine-scale longitudinal studies to capture the rapid change of bat CoV infection over months, and that CoV shedding pulses in bats may increase spillover risk.
A new pseudosuchian archosaur,Mambawakale ruhuhugen. et sp. nov., from the Middle Triassic Manda Beds of Tanzania
Authors: Butler Richard J. , Fernandez Vincent , Nesbitt Sterling J. , Leite João Vasco , Gower David J.
Published: February 2022

The Manda Beds of southwest Tanzania have yielded key insights into the early evolutionary radiation of archosaurian reptiles. Many key archosaur specimens were collected from the Manda Beds in the 1930s and 1960s, but until recently, few of these had been formally published. Here, we describe an archosaur specimen collected in 1963 which has previously been referred to informally asPallisteria angustimentum. We recognize this specimen as the type of a new taxon,Mambawakale ruhuhugen. et sp. nov. The holotype and only known specimen ofM. ruhuhucomprises a partial skull of large size (greater than 75 cm inferred length), lower jaws and fragments of the postcranium, including three anterior cervical vertebrae and a nearly complete left manus.Mambawakale ruhuhuis characterized by several cranial autapomorphies that allow it to be distinguished with confidence from all other Manda Beds archosaurs, with the possible exception ofStagonosuchus nyassicusfor which comparisons are highly constrained due to very limited overlapping material. Phylogenetic analysis suggests thatM. ruhuhuis an early diverging pseudosuchian, but more precise resolution is hampered by missing data.Mambawakale ruhuhuis one of the largest known pseudosuchians recovered to date from the Middle Triassic.
High-pitch sounds small for domestic dogs: abstract crossmodal correspondences between auditory pitch and visual size
Authors: Korzeniowska A. T. , Simner J. , Root-Gutteridge H. , Reby D.
Published: February 2022

Humans possess intuitive associations linking certain non-redundant features of stimuli—e.g. high-pitched sounds with small object size (or similarly,low-pitched sounds withlargeobject size). This phenomenon, known as crossmodal correspondence, has been identified in humans across multiple different senses. There is some evidence that non-human animals also form crossmodal correspondences, but the known examples are mostly limited to the associations between the pitch of vocalizations and the size of callers. To investigate whether domestic dogs, like humans, show abstract pitch-size association, we first trained dogs to approach and touch an object after hearing a sound emanating from it. Subsequently, we repeated the task but presented dogs withtwoobjects differing in size, only one of which was playing a sound. The sound was either high or low pitched, thereby creating trials that were either congruent (high pitch from small object; low pitch from large objects) or incongruent (the reverse). We found that dogs reacted faster on congruent versus incongruent trials. Moreover, their accuracy was at chance on incongruent trials, but significantly above chance for congruent trials. Our results suggest that non-human animals show abstract pitch sound correspondences, indicating these correspondences may not be uniquely human but rather a sensory processing feature shared by other species.
Neutralization Of SARS-CoV-2 Variants By A Human Polyclonal Antibody Therapeutic (COVID-HIG, NP-028) With High Neutralizing Titers To SARS-CoV-2
Authors: Toth Derek
Published: February 2022

Since the start of the COVID-19 outbreak the World Health Organization (WHO) has classified multiple SARS-CoV-2 Variants-of-Concern and Variants-of-Interest (VOC/VOI) with mutations in their Spike protein that increase transmissibility and/or reduce the effectiveness of vaccines and monoclonal antibody therapeutics. The emergence of these variants represents a significant health risk and highlights the need for additional COVID-19 therapeutics that maintain the ability to neutralize current, as well as future variants.

COVID-HIG (NP-028) is a polyclonal Anti-SARS-CoV-2 human Immunoglobulin purified from source human plasma screened for high antibody titers to SARS-CoV-2 antigens. COVID-HIG was previously evaluated in INSIGHT 013 clinical trial [NCT04546581] which was an international, multi-center, adaptive, randomized, double-blind, placebo-controlled trial of the safety, tolerability and efficacy of a single dose infusion (up to 400 mL) of Anti-Coronavirus Hyperimmune Intravenous Immunoglobulin (hIVIG) for the treatment of adult recently hospitalized COVID-19 patients (N=593). COVID-HIG is currently being evaluated for clinical efficacy in a Phase 3 placebo-controlled study INSIGHT 012 (NCT04910269) to compare the safety and efficacy of a single infusion of anti-COVID-19 hyperimmune immunoglobulin (hIVIG) versus placebo among adults with recently diagnosed SARS-CoV-2 infection who do not require hospitalization.

In the present study, in-vitro pseudovirus and live virus neutralization assays were used to assess the impact of SARS-CoV-2 variant spike mutations on neutralizing potency of COVID-HIG. These assays are valuable tools for monitoring the potential impact of variant mutations on efficacy of antibody therapeutics as well as vaccines/natural immunity.

To date, COVID-HIG (NP-028) has been shown to retain neutralizing potency against 20 full spike protein sequence SARS-CoV-2 pseudovirus variants including all currently classified VOC/VOI (Alpha, Beta, Gamma, Delta/Delta+, Eta, Iota, Kappa, Lambda, Mu as of Sept 2021) as well as 4 live virus variants (Alpha, Beta, Gamma, and Iota).
Neuroaffective profiles are associated with e-cigarette use
Authors: Versace Francesco , Kypriotakis George
Published: February 2022

Introduction

Identifying the psychophysiological underpinnings of cue-induced compulsive nicotine use will provide new targets for relapse prevention treatments. We tested whether neuroaffective responses to motivationally relevant stimuli are associated with cue-induced nicotine self-administration. We hypothesized that smokers with stronger neuroaffective responses to nicotine-related cues than to pleasant stimuli (C>P) are more vulnerable to cue-induced nicotine self-administration than smokers with stronger neuroaffective responses to pleasant stimuli than to nicotine-related cues (P>C).

Methods

Smokers (N=36) looked at pleasant, unpleasant, neutral, and nicotine-related images signaling that an electronic nicotine delivery system (ENDS) was immediately available for use. We measured event-related potentials (a direct measure of cortical activity) and computed the amplitude of the late positive potential, a robust index of motivational salience. We used k-means cluster analysis to identify individuals characterized by the C>P or the P>C neuroaffective profile. We compared the ENDS use frequency in the two groups using quantile regression for counts.

Results

Cluster analysis assigned 18 smokers to the C>P profile and 18 smokers to the P>C profile. Smokers with the C>P neuroaffective profile used the ENDS significantly more often than smokers with the P>C profile. Significant differences in the number of puffs persisted across different quantiles.

Conclusions

These results support the hypothesis that individual differences in the tendency to attribute motivational salience to drug-related cues underlie vulnerability to cue-induced drug self-administration.

Implications

By linking brain reactivity profiles to nicotine self-administration, we identified a neuroaffective biomarker that could guide the development of personalized treatments to prevent smoking relapse.
A Nile Grass Rat Transcriptomic Landscape Across 22 Organs By Ultra-deep Sequencing and Comparative RNA-seq pipeline (CRSP)
Authors: Toh Huishi , Bagheri Atefeh , Dewey Colin , Stewart Ron , Yan Lili , Clegg Dennis , Thomson James A. , Jiang Peng
Published: February 2022

RNA sequencing (RNA-seq) has been a widely used high-throughput method to characterize transcriptomic dynamics spatiotemporally. However, typical RNA-seq data analysis pipelines depend on either a sequenced genome or corresponding reference transcripts or them both. This restriction makes the use of RNA-seq for species lacking both of sequenced genomes and corresponding reference transcripts challenging. Nile grass rat (Arvicanthis niloticus) is a diurnal rodent species with several unique characteristics making it as a useful model to study diet-induced type 2 diabetes and other physiological or behavioral processes due to its diurnal nature. However, there is neither a high-quality annotated Nile grass rat genome nor a reference transcript sets available so far, making it technically challenging to perform large-scale RNA-seq based transcriptomic studies. Although we are working on the first draft of Nile grass rat genome, a well annotated genome typically requires several rounds of manually reviewing curated transcripts and can take years to achieve. To solve this problem, we developed a Comparative RNA-Seq Pipeline (CRSP), integrating a comparative species strategy but not depending on a specific sequenced genome or species-matched reference transcripts. Benchmarking suggests the CRSP tool can achieve high accuracy to quantify gene expression levels. In this study, we generated the first ultra-deep (2.3 billion × 2 paired-end) Nile grass rat RNA-seq data from 59 biopsy samples representing 22 major organs, providing a unique resource and spatial gene expression reference for using Nile grass rat as a model to study human diseases. To facilitate a general use of CRSP, we also characterized the number of RNA-seq reads required for accurate estimation via simulation studies. CRSP and documents are available at: https://github.com/pjiang1105/CRSP.

Highlights

CRSP is a novel software tool which can quantify gene expression levels from RNA-seq data for species lacking both a sequenced genome and corresponding reference transcripts.

Nile grass rat is a unique diurnal rodent species (day active but not night active) with several unique characteristics making it as a useful model to study diet-induced type 2 diabetes and other physiological or behavioral processes due to its diurnal nature.

We generated the first ultra-deep (2.3 billion × 2 paired-end reads) Nile grass rat RNA-seq data from 59 biopsy samples representing 22 major organs, providing a unique resource and spatial transcriptomic reference (e.g., tissue gene expression baseline) for using Nile grass rat as a model to study human diseases.
Spatial and temporal epidemiology of SARS-CoV-2 virus lineages in Teesside, UK, in 2020: effects of socio-economic deprivation, weather, and lockdown on lineage dynamics
Authors: Moss E.D. , Rushton S.P. , Baker P. , Bashton M. , Crown M.R. , dos Santos R.N. , Nelson A. , O’Brien S.J. , Richards Z. , Sanderson R.A. , Yew W.C. , Young G.R. , McCann C.M. , Smith D.L.
Published: February 2022

Background

SARS-CoV-2 emerged in the UK in January 2020. The UK government introduced control measures including national ‘lockdowns’ and local ‘tiers’ in England to control virus transmission. As the outbreak continued, new variants were detected through two national monitoring programmes that conducted genomic sequencing. This study aimed to determine the effects of weather, demographic features, and national and local COVID-19 restrictions on positive PCR tests at a sub-regional scale.

Methods

We examined the spatial and temporal patterns of COVID-19 in the Teesside sub-region of the UK, from January to December 2020, capturing the first two waves of the epidemic. We used a combination of disease mapping and mixed-effect modelling to analyse the total positive tests, and those of the eight most common virus lineages, in response to potential infection risk factors: socio-economic deprivation, population size, temperature, rainfall, government interventions, and a government restaurant subsidy (“Eat Out to Help Out”).

Results

Total positive tests of SARS-CoV-2 were decreased by temperature and the first national lockdown (the only one to include school closures), while deprivation, population, the second national lockdown, and the local tiered interventions were associated with increased cases. The restaurant subsidy and rainfall had no apparent effect. The relationships between positive tests and covariates varied greatly between lineages, likely due to the strong heterogeneity in their spatial and temporal distributions. Cases during the second wave appeared to be higher in areas that recorded fewer first-wave cases, however, an additional model showed the number of first-wave cases was not predictive of second-wave cases.

Discussion

National and local government interventions appeared to be ineffective at the sub-regional level if they did not include school closures. Examination of viral lineages at the sub-regional scale was less useful in terms of investigating covariate associations but may be more useful for tracking spread within communities. Our study highlights the importance of understanding the effects of government interventions in local and regional contexts, and the importance of applying local restrictions appropriately within such settings.
TNF signaling is required for castration-induced vascular damage preceding prostate cancer regression
Authors: Krolewski John J. , Singh Shalini , Sha Kai , Agrawal Neha Jaiswal , Turowski Steven G. , Pan Chunliu , Rich Laurie J. , Seshadri Mukund , Nastiuk Kent L.
Published: February 2022

The mainstay treatment for locally advanced, recurrent, or metastatic prostate cancer (PrCa) is androgen deprivation therapy (ADT). ADT causes prostate cancers to shrink in volume, or regress, by inducing epithelial tumor cell apoptosis. In normal, non-neoplastic murine prostate, androgen deprivation via castration induces prostate gland regression that is dependent on TNF signaling. Besides this direct mechanism of action, castration has also been implicated in an indirect mechanism of prostate epithelial cell death which has been described as vascular regression. The initiating event is endothelial cell apoptosis and/or increased vascular permeability. This subsequently leads to reduced blood flow and perfusion, and then hypoxia, which may enhance epithelial cell apoptosis. Castration-induced vascular regression has been observed in both normal and neoplastic prostate. We used photoacoustic, power Doppler, and contrast-enhanced ultrasound imaging, and CD31 immunohistochemical staining of the microvasculature to assess vascular integrity in the period immediately following castration, enabling us to test the role of TNF signaling in vascular regression. In two mouse models of androgen-responsive prostate cancer, TNF signaling blockade using a soluble TNFR2 ligand trap reversed the functional aspects of vascular regression as well as structural changes in the microvasculature, including reduced vessel wall thickness, cross-sectional area and vessel perimeter length. These results demonstrate that TNF signaling is required for vascular regression, most likely inducing endothelial cell apoptosis and increasing vessel permeability. Since TNF is also the critical death receptor ligand for prostate epithelial cells, we propose that TNF is a multi-purpose, comprehensive signal within the prostate cancer micro-environment mediating prostate cancer regression following androgen deprivation.

SIGNIFICANCE

These studies define TNF as the mediator of androgen deprivation therapy-induced functional and structural vascular damage in prostate tumors.
A wearable platform for closed-loop stimulation and recording of single-neuron and local field potential activity in freely-moving humans
Authors: Topalovic Uros , Barclay Sam , Ling Chenkai , Alzuhair Ahmed , Yu Wenhao , Hokhikyan Vahagn , Chandrakumar Hariprasad , Rozgic Dejan , Jiang Wenlong , Basir-Kazeruni Sina , Maoz Sabrina L. , Inman Cory S. , Gill Jay , Bari Ausaf , Fallah Aria , Eliashiv Dawn , Pouratian Nader , Fried Itzhak , Suthana Nanthia , Markovic Dejan
Published: February 2022

Advances in technologies that can record and stimulate deep-brain activity in humans have led to impactful discoveries within the field of neuroscience and contributed to the development of novel therapies for neurological and psychiatric disorders. Further progress, however, has been hindered by device limitations in that recording of single-neuron activity during freely-moving behaviors in humans has not been possible. Additionally, implantable neurostimulation devices, currently approved for human use, have limited stimulation programmability and lack full-duplex bi-directional capability. Here, we developed a wearable bi-directional closed-loop neuromodulation system (Neuro-stack) and used it to record single-neuron and local field potential activity during stationary and ambulatory behavior in humans. Together with a highly flexible and customizable stimulation capability, the Neuro-stack provides an opportunity to investigate the neurophysiological basis of disease, develop improved responsive neuromodulation therapies, explore brain function during naturalistic behaviors in humans, and consequently, bridge decades of neuroscientific findings across species.
Belayer: Modeling discrete and continuous spatial variation in gene expression from spatially resolved transcriptomics
Authors: Ma Cong , Chitra Uthsav , Zhang Shirley , Raphael Benjamin J.
Published: February 2022

Spatially resolved transcriptomics (SRT) technologies measure gene expression at known locations in a tissue slice, enabling the identification of spatially varying genes or cell types. Current approaches for these tasks assume either that gene expression varies continuously across a tissue or that a slice contains a small number of regions with distinct cellular composition. We propose a model for SRT data that includes both continuous and discrete spatial variation in expression, and an algorithm, Belayer, to estimate the parameters of this model from layered tissues. Belayer models gene expression as a piecewise linear function of the relative depth of a tissue layer with possible discontinuities at layer boundaries. We use conformal maps to model relative depth and derive a dynamic programming algorithm to infer layer boundaries and gene expression functions. Belayer accurately identifies tissue layers and infers biologically meaningful spatially varying genes in SRT data from brain and skin tissue samples.
Heterologous SARS-CoV-2 IgA neutralising antibody responses in convalescent plasma
Authors: Davis Samantha K , Selva Kevin John , Lopez Ester , Haycroft Ebene R , Lee Wen Shi , Wheatley Adam K , Juno Jennifer A , Adair Amy , Pymm Phillip , Redmond Samuel J , Gherardin Nicholas A , Godfrey Dale I , Tham Wai-Hong , Kent Stephen J , Chung Amy W
Published: February 2022

Following infection with SARS-CoV-2, virus-specific antibodies are generated which can both neutralise virions and clear infection via Fc effector functions. The importance of IgG antibodies for protection and control of SARS-CoV-2 has been extensively reported. In comparison, other antibody isotypes including IgA have been poorly characterized. Here we characterized plasma IgA from 41 early convalescent COVID-19 subjects for neutralisation and Fc effector functions. We find that convalescent plasma IgA from >60% of the cohort have the capacity to inhibit the interaction between wild-type RBD and ACE2. Furthermore, a third of the cohort induced stronger IgA-mediated inhibition of RBD binding to ACE2 than IgG, when tested at equivalent concentrations. Plasma IgA and IgG from the cohort, broadly recognize similar RBD epitopes and showed similar ability to inhibit ACE2 from binding 22 of 23 different prevalent RBD proteins with single amino acid mutations. Plasma IgA was largely incapable of mediating antibody-dependent phagocytosis in comparison to plasma IgG. Overall, convalescent plasma IgA contributes to neutralisation towards wild-type RBD and various RBD single mutants in most subjects, although this response is heterogeneous and less potent than IgG.
An AI-assisted Tool For Efficient Prostate Cancer Diagnosis
Authors: Oner Mustafa Umit , Ng Mei Ying , Giron Danilo Medina , Xi Cecilia Ee Chen , Xiang Louis Ang Yuan , Singh Malay , Yu Weimiao , Sung Wing-Kin , Wong Chin Fong , Lee Hwee Kuan
Published: February 2022

Pathologists diagnose prostate cancer by core needle biopsy. For low-grade and low-volume cases, the pathologists look for the few malignant glands out of hundreds within a core. They may miss the few malignant glands, resulting in repeat biopsies or missed therapeutic opportunities. This study developed a multi-resolution deep learning pipeline detecting malignant glands in core needle biopsies to help pathologists effectively and accurately diagnose prostate cancer in low-grade and low-volume cases. The pipeline consisted of two stages: the gland segmentation model detected the glands within the sections and the multi-resolution model classified each detected gland into benign vs. malignant. Analyzing a gland at multiple resolutions provided the classification model to exploit both morphology information (of nuclei and glands) and neighborhood information (for architectural patterns), important in prostate gland classification. We developed and tested our pipeline on the slides of a local cohort of 99 patients in Singapore. The images were made publicly available, becoming the first digital histopathology dataset of prostatic carcinoma patients of Asian ancestry. Our pipeline successfully classified the core needle biopsy parts (81 parts: 50 benign and 31 malignant) into benign vs. malignant. It achieved an AUROC value of 0.997 (95% CI: 0.987 - 1.000). Moreover, it produced heatmaps highlighting the malignancy of each gland in core needle biopsies. Hence, our pipeline can effectively assist pathologists in core needle biopsy analysis.
Glypican-3 (GPC3) is associated with MCPyV-negative status and impaired outcome in Merkel Cell Carcinoma
Authors: Muralidharan Sujatha , Kervarrec Thibault , Weiss Glen J. , Samimi Mahtab
Published: February 2022

Background

Merkel cell carcinoma (MCC) is an aggressive skin cancer, related to the Merkel Cell Polyomavirus (MCPyV) in 80% of cases. Immune checkpoint inhibitors provide sustained benefit in about half of MCC patients with advanced disease. Glypican-3 (GPC3) is an oncofetal tumor antigen that is an attractive target for chimeric antigen receptor T cell therapy due to its highly restricted expression on normal tissue and high prevalence in several solid tumors. GPC3 was previously found to be expressed in MCC but its association with tumor characteristics or prognosis has not been reported.

Objectives

To investigate the expression of GPC3 in MCC by immunohistochemistry (IHC) and its association with tumor characteristics, MCPyV status, and patient outcome.

Methods

The GC33 antibody clone was validated for GPC3 IHC staining of tumor specimens in comparison to an established GPC3 IHC antibody. A tissue microarray of tumors collected from an ongoing cohort of MCC patients was stained for GPC3 by IHC using GC33 antibody. Association of GPC3 positivity with baseline characteristics, MCPyV status (quantitative PCR) and outcome (death from MCC, recurrence) were assessed by Fisher’s exact tests and Cox regression analysis.

Results

Among 62 tumors from 59 patients, 42 samples (67.7%) were GPC3-positive. GPC3 expression was more frequently observed in females (p=0.048) and MCPyV-negative tumors (p=0.021). In the multivariate analysis, GPC3 expression was associated with increased death from disease (CSS) (hazard ratio [HR] 4.05, 95% CI 1.06-15.43), together with advanced age (HR 4.85, 95% CI 1.39-16.9) and male gender (HR 4.64, 95% CI 1.31-16.41).

Conclusions

GPC3 expression is frequently expressed in MCC tumors, especially MCPyV-negative cases, and is associated with increased risk of death. The high prevalence of surface GPC3 makes it a putative drug target.
Stability Criterion for the Assembly of Hybrid Lipid-Polymer-Nucleic Acid Nanoparticles
Authors: Paris Juan L. , Gaspar Ricardo , Coelho Filipe , De Beule Pieter A. A. , Silva Bruno F. B.
Published: February 2022

Hybrid lipid-polymer-nucleic acid nanoparticles (LPNPs) provide unique delivery strategies for nonviral gene therapy. Since LPNPs consist of multiple components that can undergo different pairwise interactions between them, LPNPs are difficult to prepare and characterize. Here we demonstrate that the interaction between the polycation (polylysine) and DNA is robust through an innovative implementation of fluorescence cross-correlation spectroscopy, implying that the polycation is not displaced by cationic liposomes in the formation process. Hence, the polycation-DNA cores (polyplexes) and liposome shells must be oppositely charged to associate. Furthermore, we prove that the liposome:polyplex number ratio (ρN) is the primary critical parameter to predict stable LPNP formation. We establish thatρN≥ 1 is required to ensure that every polyplex is enveloped by a liposome, avoiding the coexistence of oppositely charged species and thereby inhibiting aggregation. We expect our observations to be valid for the formation of many other LPNPs and composite nanomaterials.
An atlas of gene expression variation across the Caenorhabditis elegans species
Authors: Zhang Gaotian , Roberto Nicole M. , Lee Daehan , Hahnel Steffen R. , Andersen Erik C.
Published: February 2022

Phenotypic variation in diverse organism-level traits have been studied in Caenorhabditis elegans wild strains, but differences in gene expression and the underlying variation in regulatory mechanisms are largely unknown. Here, we use natural variation in gene expression to connect genetic variants to differences in organismal- level traits, including drug and toxicant responses. We performed transcriptomic analysis on 207 genetically distinct C. elegans wild strains to study natural regulatory variation of gene expression. Using this massive dataset, we performed genome-wide association mappings to investigate the genetic basis underlying gene expression variation and revealed complex genetic architectures. We found a large collection of hotspots enriched for expression quantitative trait loci across the genome. We further used mediation analysis to understand how gene expression variation could underlie organism-level phenotypic variation for a variety of complex traits. These results reveal the natural diversity in gene expression and possible regulatory mechanisms in this keystone model organism, highlighting the promise of gene expression variation in shaping phenotypic diversity.
A “step too far” or “perfect sense”? A qualitative study of British adults’ views on mandating COVID-19 vaccination and vaccine passports
Authors: Stead Martine , Ford Allison , Eadie Douglas , Biggs Hannah , Elliott Claire , Ussher Michael , Bedford Helen , Angus Kathryn , Hunt Kate , MacKintosh Anne Marie , Jessop Curtis , MacGregor Andy
Published: February 2022

Background

Debate is ongoing about mandating COVID-19 vaccination to maximise uptake. Policymakers must consider whether to mandate, for how long, and in which contexts, taking into account not only legal and ethical questions but also public opinion. Implementing mandates among populations who oppose them could be counterproductive.

Methods

Qualitative telephone interviews (Feb-May 2021) with British adults explored views on vaccine passports and mandatory vaccination. Participants (n=50) were purposively selected from respondents to a probability-based national survey of attitudes to COVID-19 vaccination, to include those expressing vaccine-hesitancy. Data were analysed thematically.

Findings

Six themes were identified in participants’ narratives concerning mandates: (i) mandates are a necessary and proportionate response for some occupations to protect the vulnerable and facilitate the resumption of free movement; (ii) mandates undermine autonomy and choice; (iii) mandates represent an over-reach of state power; (iv) mandates could potentially create ‘vaccine apartheid’; (v) the importance of context and framing; and (vi) mandates present considerable feasibility challenges. Those refusing vaccination tended to argue strongly against mandates. However, those in favour of vaccination also expressed concerns about freedom of choice, state coercion and social divisiveness.

Discussion

To our knowledge, this is the first in-depth UK study of public views on COVID-19 vaccine mandates. It does not assess support for different mandates but explores emotions, principles and reasoning underpinning views. Our data suggest that debate around mandates can arouse strong concerns and could entrench scepticism. Policymakers should proceed with caution. While surveys can provide snapshots of opinion on mandates, views are complex and further consultation is needed regarding specific scenarios.
Robust Determinants of Neurocognitive Development in Children: Evidence from the Pune Maternal Nutrition Study (PMNS)
Authors: Yajnik Chittaranjan S. , Tan Chih Ming , Bhate Vidya , Bandyopadhyay Souvik , Sankar Ashwini , Behere Rishikesh V.
Published: February 2022

Neurocognitive development is a dynamic process over the life course and is influenced by intrauterine factors as well as later life environment. Using data from the Pune Maternal Nutrition Study (PMNS) from 1994 to 2008, we investigate the association of in-utero, birth, and childhood conditions with offspring neurocognitive development in 686 participants of the cohort, at age 12 years. The life course exposure variables in the analysis include maternal pre-pregnancy size and nutrition during pregnancy, offspring birth measurements, nutrition and physical growth at age 12 years along with parental education and socio-economic status. We used the novel Bayesian Model Averaging (BMA) approach; which has been shown to have better predictive performance over traditional tests of associations. Our study employs 8 standard neurocognitive tests that measure intelligence, working memory, visuo-conceptual and verbal learning, and decision-making/attention at 12 years of age. We control for nutritional-metabolic information based on blood measurements from the pregnant mothers and the children at 12 years of age. Our findings highlight the critical role of parental education and socioeconomic background in determining child neurocognitive performance. Maternal characteristics (pre-pregnancy BMI, fasting insulin during pregnancy) and child height at 12 years were also robust predictors on the BMA. A range of early factors – such as maternal folate and ferritin concentrations during pregnancy, and child’s head circumference at birth – remained important determinants of some dimensions of child’s neurocognitive development, but their associations were not robust once we account for model uncertainty. Our results suggest that intrauterine influences on long term neurocognitive outcomes may be potentially reversible by post birth remediation. In addition to the current nutritional interventions, public health policy should also consider social interventions in children born into families with low socio-economic status to improve human capital.
Deep tissue infection by an invasive human fungal pathogen requires novel lipid-based suppression of the IL-17 response
Authors: Basso P. , Dang E.V. , Urisman A. , Cowen L.E. , Madhani H. D. , Noble S. M.
Published: February 2022

Candida albicans is the most common cause of human fungal infection, but the mechanisms of invasive pathogenesis remain poorly defined. Here we identify an unexpected mechanism: lipid-mediated immunosuppression. Through forward genetics, we found that C. albicans secretes a lipase, Lip2, that is critical for invasive disease. Murine infection with C. albicans strains that lack Lip2 display an exaggerated host IL-17 response that leads to fungal clearance from solid organs and host survival. IL-17 signaling is required for Lip2 action. The lipase activity of Lip2 inhibits IL-17 production indirectly through suppression of IL-23 production by tissue resident dendritic cells. We conclude that C. albicans suppresses antifungal IL-17 defense in solid organs by altering the tissue lipid milieu.
Salp blooms increase carbon export 5-fold in the Southern Ocean
Authors: Décima Moira , Stukel Michael R. , Nodder Scott D. , Gutiérrez-Rodríguez Andrés , Selph Karen E. , dos Santos Adriana Lopes , Safi Karl , Kelly Thomas B. , Deans Fenella , Morales Sergio E. , Baltar Federico , Latasa Mikel , Gorbunov Maxim Y. , Pinkerton Matt
Published: February 2022

The Southern Ocean (SO) contributes substantially to the global biological carbon pump (BCP). Salps in the SO, in particularSalpa thompsoni, are keystone grazers that produce large, fast-sinking fecal pellets with high export potential. In a first study of this kind, we conducted Lagrangian experiments to quantify the salp bloom impacts on export pathways by contrasting locations differing in salp bloom presence/absence. We show that blooms increased particle export by ~5-fold, and exported up to 46% of net primary production out of the euphotic zone. BCP efficiency increased from 5% in non-salp areas to up to 28% in salp areas, which is among the highest recorded in the global ocean. Using SO salp abundances from KRILLBASE, we estimate they can consume ~ 13% of regional production, mediating 13-40% of the SO BCP. Consideration in models forecasting the SO BCP is recommended considering long-term increases in SO salp abundances.
De novo mass spectrometry peptide sequencing with a transformer model
Authors: Yilmaz Melih , Fondrie William E. , Bittremieux Wout , Oh Sewoong , Noble William Stafford
Published: February 2022

Tandem mass spectrometry is the only high-throughput method for analyzing the protein content of complex biological samples and is thus the primary technology driving the growth of the field of proteomics. A key outstanding challenge in this field involves identifying the sequence of amino acids—the peptide—responsible for generating each observed spectrum, without making use of prior knowledge in the form of a peptide sequence database. Although various machine learning methods have been developed to address this de novo sequencing problem, challenges that arise when modeling tandem mass spectra have led to complex models that combine multiple neural networks and post-processing steps. We propose a simple yet powerful method for de novo peptide sequencing, Casanovo, that uses a transformer framework to map directly from a sequence of observed peaks (a mass spectrum) to a sequence of amino acids (a peptide). Our experiments show that Casanovo achieves state-of-the-art performance on a benchmark dataset using a standard cross-species evaluation framework which involves testing with spectra with never-before-seen peptide labels. Casanovo not only achieves superior performance but does so at a fraction of the model complexity and inference time required by other methods.
Proteomics profiling reveals regulation of immune response to Salmonella Typhimurium infection in mice
Authors: Huang He , Even Zachary , Erickson Alyssa , Li Ling , Golovko Mikhail , Golovko Svetlana , Mathur Ramkumar , Wang Xusheng
Published: February 2022

Regulation of the immune response to Salmonella typhimurium (S. Typhimurium) infection is a complex process, influenced by genetic and environmental factors. Different inbred mouse strains show distinct levels of resistance to S. Typhimurium infection, ranging from susceptible (e.g., C57BL/6J) to resistant (e.g., DBA/2J) strains. However, the underlying molecular mechanisms contributing to the host response remain elusive. In this study, we present a comprehensive proteomics profiling of the spleen tissue from C57BL/6J and DBA/2J strains with different doses of S. Typhimurium infection by tandem tag mass coupled with two-dimensional liquid chromatography-tandem mass spectrometry. We identified and quantified 3,986 proteins, resulting in 475 differentially expressed proteins between C57BL/6J and DBA/2J strains. Functional enrichment analysis revealed that the mechanisms of innate immune responses to S. Typhimurium infection are associated with several signaling pathways, including the interferon signaling pathway. Our proteomic data also discovered a plausible gene in a genomic region that control different levels of resistance to S. Typhimurium infection. We further revealed the roles of macrophage cells and pro-inflammatory cytokines in the mechanisms under the natural resistance to S. Typhimurium. In summary, our results provide new insights into the genetic regulation of the immune response to S. Typhimurium infection in mice.

Author Summary

Salmonella infection (salmonellosis) is a common zoonotic disease that mainly propagates through contaminated food and drink. Various mouse strains display prominent disparities in responses to Salmonella invasion. Elucidating the heterogeneous immune reactions between different mouse strains can shed light on the fundamental molecular mechanisms of the innate immune system. Here, we employed a combination of proteomics and systems biology approaches to provide an unprecedented panorama of the inextricably interlaced immune signaling pathways in response to Salmonella infection in mice. Our results revealed the dynamics of cell signaling molecules elicited by inflammation and established new connections among them. We also identified a new candidate gene involved in the combat with pathogens. Our proteomic data and results contribute to understanding the intricate interactions of immune responses to Salmonella infection from molecular to systemic levels.
MCMBP promotes the assembly of the MCM2-7 hetero-hexamer to ensure robust DNA replication in human cells
Authors: Saito Yuichiro , Santosa Venny , Ishiguro Kei-ichiro , Kanemaki Masato T.
Published: February 2022

The MCM2-7 hetero-hexamer is the replicative DNA helicase that plays a central role in eukaryotic DNA replication. In proliferating cells, the expression level of the MCM2-7 hexamer is kept high, which safeguards the integrity of the genome. However, how the MCM2-7 hexamer is assembled in living cells remains unknown. Here, we revealed that the MCM-binding protein (MCMBP) plays a critical role in the assembly of this hexamer in human cells. MCMBP associates with MCM3 which is essential for maintaining the level of the MCM2-7 hexamer. Acute depletion of MCMBP demonstrated that it contributes to MCM2-7 assembly using nascent MCM3. Cells depleted of MCMBP gradually ceased to proliferate because of reduced replication licensing. Under this condition, p53-positive cells exhibited arrest in the G1 phase, whereas p53-null cells entered the S phase and lost their viability because of the accumulation of DNA damage, suggesting that MCMBP is a potential target for killing p53-deficient cancers.
Relative enrichment – a density-based colocalization measure for single-molecule localization microscopy
Authors: Ejdrup Aske L. , Lycas Matthew D. , Lorenzen Niels , Konomi Ainoa , Herborg Freja , Madsen Kenneth L. , Gether Ulrik
Published: February 2022

Dual-color single-molecule localization microscopy (SMLM) provides unprecedented possibilities for detailed studies of colocalization of different molecular species in a cell. However, the informational richness of the data is not fully exploited by current analysis tools that often reduce colocalization to a single value. Here, we describe a new tool specifically designed for determination of co-localization in both 2D and 3D from SMLM data. The approach uses a novel function that describes the relative enrichment of one molecular species on the density distribution of a reference species. The function reframes the question of colocalization by providing a density-context relevant to multiple biological questions. Moreover, the function visualize enrichment (i.e. colocalization) directly in the images for easy interpretation. We demonstrate the approach’s functionality on both simulated data and cultured neurons, and compare it to current alternative measures. The method is available in a Python function for easy and parameter-free implementation.
Multi-excitation Raman Spectroscopy Complements Whole Genome Sequencing for Rapid Detection of Bacterial Infection and Resistance in WHO Priority Pathogens
Authors: Lister Adam , Avershina Ekaterina , Ali Jawad , Devitt George , Hanrahan Niall , Highmore Callum , Webb Jeremy , Muller Fredrik , Mahajan Sumeet , Ahmad Rafi
Published: February 2022

Current methods for diagnosing acute and complex infections mostly rely on culture-based methods and, for biofilms, fluorescencein-situhybridization. These techniques are labor-intensive and can take 2-4 days to return a test result, especially considering an extra culturing step required for the antibiotic susceptibility testing (AST). This places a significant burden on healthcare providers, delaying treatment and leading to adverse patient outcomes. Here, we report the complementary use of our newly developed multi-excitation Raman spectroscopy (ME-RS) method with whole-genome sequencing (WGS). Four WHO priority pathogens are AST phenotyped and their antimicrobial resistance (AMR) profile determined by WGS. On application of ME-RS method we find high correlation with the WGS characterization. Highly accurate classification based on the species (98.93%), wild-type/non-wild type (99.45%), and presence or absence of thick peptidoglycan layers in cell walls (100%), as well as at the individual strain level (99.29%). These results clearly demonstrate the potential of ME-RS as a rapid and first-stage tool for species, resistance and strain-level classification which can be followed up by WGS for confirmation. Such a workflow can facilitate efficient antimicrobial stewardship to handle and prevent the spread of AMR.
Spike Protein-independent Attenuation of SARS-CoV-2 Omicron Variant in Laboratory Mice
Authors: Liu Shufeng , Selvaraj Prabhuanand , Sangare Kotou , Luan Binquan , Wang Tony T.
Published: February 2022

Despite being more transmissible, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant was found to cause milder diseases in laboratory animals, often accompanied by a lower viral load compared to previous variants of concern. This study revealed the structural basis for a robust interaction between the receptor binding domain of the Omicron spike protein and mouse ACE2. Pseudovirus bearing the Omicron spike protein efficiently utilized mouse ACE2 for entry. By comparing viral load and disease severity among laboratory mice infected by a natural Omicron variant or recombinant ancestral viruses bearing either the entire Omicron Spike or only the N501Y/Q493R mutations in its spike, we found that mutations outside the spike protein in the Omicron variant may be responsible for the observed lower viral load. Together, our results indicated that a post-entry block to the Omicron variant exists in laboratory mice.