bluuebunny/crossref_metadata_2025 huggingface dataset:
An Intervention Framework for Addressing Stigma on College Campuses
Authors: Tomar Nikhil , Jensen Todd M. , Pace Nelson
Published: March 2022

The ongoing COVID-19 pandemic will only exacerbate the rising mental health concerns among college students. However, stigma toward such concerns continues to hinder mental health care utilization among the students, requiring urgent evidence that can help guide college campuses in implementing effective antistigma interventions. We propose and provide evidence for an intervention based on findings from a 3-year-long antistigma intervention that was implemented on a Southeastern college campus in the United States. Unique random samples of college students, totaling N = 1727 across 3 years, were recruited as participants. Each year, participants completed a preintervention and postintervention survey comprising of questions related to demographics, stigma, and mental health care knowledge. Findings indicate that the stakeholder-led intervention decreased personal stigma and increased mental health care knowledge among students who were exposed to the intervention. Further research is needed to assess feasibility and efficacy of the proposed intervention framework on other campuses.
Personal and Bystander Harassment Experiences and Outcomes for Hospital Nurses
Authors: Wadsworth Pamela , Estrada Armando X.
Published: March 2022

OBJECTIVES

To examine experiences, context, and outcomes of personal and bystander harassment among hospital nurses.

BACKGROUND

Harassment of nurses is common, affecting victims and bystanders. Yet, little is known about the nature and context of these experiences.

METHOD

A cross-sectional study of hospital nurses was completed via an anonymous online survey.

RESULTS

A majority of nurses experienced personal or bystander harassment. Nearly half experienced both of these forms of harassment. Personal harassment victims frequently told their managers and coworkers, but actions to prevent further harassment or mitigate harm were rare. Bystanders frequently intervened to help victims of personal harassment but rarely reported it. These experiences negatively impacted work relationships and performance.

CONCLUSION

Personal and bystander harassment may co-occur in cultures that tolerate harassment. The lack of response to personal harassment and lack of reporting of bystander harassment may perpetuate it.
Clinical Evaluation of High-Resolution MRI Combined With DWI in Identifying Vulnerable Carotid Plaque
Authors: Wang Xinyi , Li Jing , Wang Xin , Gao Jialu , Jing Hongyan , Xing Ying
Published: March 2022

Background:

High-resolution magnetic resonance imaging combined with diffusion weighted imaging is used to identify vulnerable plaques (VP) and their characteristic components, and apparent diffusion coefficient (ADC) correlation analysis with serum inflammatory markers to assess plaque vulnerability.

Methods:

In this study, 60 eligible patients were included, including 29 patients in VP group and 31 patients in non-VP group (N group). The average ADC value, serum inflammatory marker levels (high-sensitivity C-reactive protein, myeloperoxidase, and erythrocyte sedimentation rate) of the 2 groups were measured, and the characteristics of different plaque components and ADC levels of vascular wall in VP group were compared, to evaluate the correlation between serum inflammatory markers and the mean value of plaque ADC.

Results:

The results showed that the ADC mean value of the plaques in the VP group was significantly lower than that in the N group, and the levels of hypersensitive C-reactive protein and myeloperoxidase were correlated with the ADC mean value of the plaques.

Conclusion:

The ADC value of plaque measured by high-resolution magnetic resonance imaging combined with diffusion weighted imaging sequence can quantify the identification of VP and its characteristic components, reflect the inflammation of plaque to a certain extent, and thus prevent and treat stroke and other adverse outcomes more effectively.
Gene Editing in Plants
Authors: Lemke Shawna L.
Published: March 2022

Gene editing has the potential to become a transformative tool of plant breeding. Modern plant breeding programs are built on a rich history of crossing and selection of desirable varieties, made more efficient in recent decades with the application of genomics. The additional precision of gene editing techniques such as CRISPR is poised to enable better identification and advancement of beneficial traits such as disease resistance that appeals to farmers or enhanced flavor that appeals to consumers. It is important to recognize, however, that gene-edited crops are coming to market in the wake of debates surrounding genetically modified organisms. Although uses of gene editing under discussion do not typically center on transferring DNA into a plant from an unrelated species, the regulatory and societal lenses though which consumers and the scientific community view gene-edited plants will be a major influence on what traits reach farms and who is able to develop them. Health professionals have a frontline role in discussing food safety and nutrition with their clients and are encouraged to consult regulatory and scientific experts to stay abreast of introduction of new breeding techniques, as well as their use and safety.
What 736 Plastic Surgeons Think about Explantation and Capsulectomy: A Global Opinion Poll
Authors: Scheflan Michael , Gronovich Yoav , Maisel Lotan Adi , Winder Gilad
Published: March 2022

Background:

Breast implant illness, although not classified as a disease entity, has recently gained significant attention globally. The purpose of this study was to assess the status of explantation practices, discuss plastic surgeon’s attitude toward requests for explantation and capsulectomy, and evaluate surgical management when accepting these challenges.

Methods:

Twenty closed-ended multiple choice questions were formulated to an opinion poll. The anonymous opinion poll was distributed to members of American Society for Aesthetic Plastic Surgery and presidents of plastic surgery societies on all continents.

Results:

A total of 736 plastic surgeons responded to the opinion poll. Although geographic variation was noted, a majority of 69.8 percent stated that explantation surgery had increased in their practice compared to the previous year. Requests for explantation without capsulectomy met with high acceptance rates among surgeons, regardless of whether patients were asymptomatic or not. Patients who also requested capsulectomy received less enthusiastic replies depending on the type of practice, years in practice, implant position, and type of capsulectomy (en bloc, total, or partial). When fat grafting was indicated, 68.7 percent stated that simultaneous lipofilling is limited when capsulectomy is performed, yet 44.5 percent stated that they would remove thin normal capsules in a symptomatic patient even when simultaneous fat grafting is requested by the patient.

Conclusion:

The opinion poll supports the hypothesis that demand for explantation and capsulectomy increased globally among symptomatic and asymptomatic patients; that attitudes toward simultaneous capsulectomy are divided; and that management may differ according to geographic location, experience, and type of practice.
Pilot of Patient Engagement in Continence Care on Geriatric Rehabilitation Units
Authors: Hunter Kathleen Frances , Dahlke Sherry , Kalogirou Maya R. , Pietrosanu Matthew , Triscott Jean , Savard Winnie , Wagg Adrian
Published: March 2022

Purpose

The aim of this study was to pilot a process of engaging geriatric rehabilitation patients in the assessment and management of their continence concerns.

Design

A descriptive study was conducted.

Methods

The study has four phases: (1) staff education on continence with a pre–post knowledge quiz, (2) design of patient engagement process by a working group, (3) a 6-week pilot of a patient symptom questionnaire and process of engaging patients with audits of disciplinary admission histories and documentation, and (4) patient and staff feedback surveys.

Results

Patients in geriatric rehabilitation identify a range of bladder and bowel symptoms. However, there was little documented evidence from the interprofessional team that corresponded to patients’ reported symptoms.

Conclusion

Further research into symptoms bothersome to patients and engagement of both patients and the interprofessional team in addressing these in the rehabilitation setting is needed.

Clinical Relevance to Rehabilitation Nursing

Patients admitted to geriatric rehabilitation have a range of bladder and bowel symptoms, which need to be addressed.
The Experiences of Robot-Assisted Gait Training in Patients With Neurological Disorders: A Qualitative Study
Authors: Chang Yi-Ya , Chang Shu-Chun , Xiao Xaviera , Chen Carl P. C.
Published: March 2022

Purpose

The aim of this study was to explore the rehabilitation experiences and perceptions of patients with neurological disorders who have used the Lokomat Augmented Feedback module, a robot-assisted gait training device.

Design

A qualitative descriptive study was conducted.

Methods

Purposive sampling was employed to recruit participants with neurological disorders who have used the Lokomat. Semistructured face-to-face interviews were completed in northern Taiwan. Interviews were recorded and transcribed verbatim. Thematic analysis was used.

Results

Thirteen interviews were analyzed. Three themes were identified: learning to walk again, inspiring the fighting spirit, and the joys and worries of technological innovation.

Conclusions

Strong positive emotions and logistical concerns were associated with the use of the Lokomat.

Clinical Relevance

Encouraging patients while also being transparent about the challenges involved in the rehabilitation process and helping set realistic goals is critical. Furthermore, attention directed toward anticipating and mitigating the physical strain associated with the Lokomat is important.
Can Location of Stiffness Measurement Impact Spleen 2-Dimensional Shear Wave Elastography Measurement?
Authors: Song Jinzhen , Li Jiawu , Luo Yan , Lu Qiang
Published: March 2022

Ultrasound-based spleen elastography is a promising surrogate to predict portal hypertension noninvasively. In contrast to defined standards for liver stiffness measurement, the standardized examination procedures for 2-dimensional (2D) shear wave elastography spleen elastography have not been established yet. The aim was to investigate the impact of location of stiffness measurement on 2D shear wave elastography spleen stiffness measurement (SSM). Patients with splenomegaly were enrolled. Both B-mode ultrasound and elastography of spleen were performed. For SSM, 3 regions were chosen for spleen measurement: lower pole region, central region, and the region between lower pole and center. Mean SSM value, success rate, and reliability predicators (standard deviation, standard deviation/mean, size of region of interest) were assessed. A total of 124 patients were included. For mean SSM value, there were no significant differences among 3 regions. Spleen stiffness measurement success rate in lower pole region, central region, and the region between them was 63.7% (79), 91.1% (113), and 78.2% (97), respectively. The success rate in the central region was significantly higher than that in the other 2 regions (P < 0.05). Reliability in the central region was also highest among the 3 regions. Location of stiffness measurement has a limited effect on SSM. Changing location of measurement will not influence mean stiffness value in spleen.
Cellulosimicrobium protaetiae sp. nov., isolated from the gut of the larva of Protaetia brevitarsis seulensis
Authors: Le Han Ho , Nguyen Tra T. H. , Li Zhun , Shin Na-Ri , Kim Song-Gun
Published: March 2022

A Gram-stain-positive, non-spore-forming, yellow-pigmented, non-motile, non-flagellated, facultative anaerobic and rod-shaped bacterial strain, designated BI34T, was isolated from the gut of the larva of Protaetia brevitarsis seulensis. Strain BI34T grew at 15–40 °C (optimum, 37 °C), at pH 6.5–9.0 (optimum, pH 7.5) and in the presence of 0–7 % (w/v) NaCl (optimum, 2 %). Based on the results of 16S rRNA gene sequence analysis, strain BI34T belonged to the phylum

Actinobacteria

and was closely related to

Cellulosimicrobium funkei

NBRC 104118T (99.3 %),

Cellulosimicrobium cellulans

NBRC 15516T (99.1 %),

Cellulosimicrobium composti

BIT-GX5T (99.0 %),

Cellulosimicrobium fucosivorans

SE3T (99.0 %),

Cellulosimicrobium marinum

NBRC 110994T (98.4 %) and

Cellulosimicrobium terreum

DS-61T (97.0 %). The genome to genome relatedness of the average nucleotide identity (ANI) and the digital DNA–DNA hybridization (dDDH) values calculated by the Genome-to-Genome Distance Calculator between strain BI34T and its related species mentioned above were lower than the threshold of 95 and 70 % for speciation, respectively. The predominant menaquinone of strain BI34T contained MK-9(H4), and the major fatty acids were anteiso-C15 : 0, C16 : 0 and anteiso-C17 : 0. Strain BI34T had diphosphatidylglycerol and phosphatidylglycerol as major polar lipids. The whole-cell sugars were galactose, glucose and ribose, and the cell-wall peptidoglycan contained lysine, alanine, aspartic acid and glutamic acid. The DNA G+C content of strain BI34T was 73.8 mol%. The difference in physiological and biochemical characteristics and the below-threshold values of genome-to-genome relatedness indicate that strain BI34T represents a novel species in the genus

Cellulosimicrobium

, for which the name Cellulosimicrobium protaetiae sp. nov. is proposed. The type strain is BI34T (=KCTC 49302T=NBRC 114073T).
Red Knot Stopover Population Size and Migration Ecology at Delaware Bay, USA, 2021
Authors: Lyons J. E.
Published: March 2022

Red Knots (Calidris canutus rufa) stop at Delaware Bay during northward migration to feed on eggs of horseshoe crabs (Limulus polyphemus). In the late 1990s and early 2000s, the number of Red Knots found at Delaware Bay dramatically declined from ~50,000 to ~13,000. Horseshoe crabs have been harvested for use as bait in eel and whelk fisheries since at least 1990, and some avian conservation biologists hypothesized that harvest levels in the 1990s prevented sufficient refueling for successful migration to the breeding grounds, nesting, and survival for the remainder of the annual cycle. Since 2013, the harvest of horseshoe crabs in the Delaware Bay region has been managed using an Adaptive Resource Management (ARM) framework. The objective of the ARM framework is to manage sustainable harvest of Delaware Bay horseshoe crabs while maintaining ecosystem integrity and supporting Red Knot recovery with adequate stopover habitat for Red Knots and other migrating shorebirds. For annual harvest recommendations, the ARM framework requires annual estimates of horseshoe crab population size and the Red Knot stopover population. We conducted a mark-recapture-resight investigation to estimate the passage population of Red Knots at Delaware Bay in 2021. We used a Bayesian analysis of a Jolly-Seber model, which accounts for turnover in the population and the probability of detection during surveys. The 2021 Red Knot mark-resight dataset included a total of 1,591 individual birds that were recorded at least one during mark-resight surveys at Delaware Bay in 2021. The passage population size in 2021 was estimated at 42,271 (95% credible interval: 35,948 – 55,210). Like 2020, the 2021 population estimate is slightly lower than the 2018 and 2019 estimates. The 2021 population size estimate will inform decision making for harvest recommendations in the next management cycle.
Edison: measuring scaffolding accuracy with edit distance
Authors: Sur Aakash , Noble William Stafford , Sullivan Shawn , Myler Peter
Published: March 2022

Motivation

The quality of reference genomes critically affects analyses of next generation sequencing experiments. During the construction of the reference genome, contigs are organized into their underlying chromosomes in the scaffolding step. Historically, the quality of scaffolding software has been difficult to evaluate in a systematic and quantitative fashion. To this end, we identified genomic edit distance as a compelling method for evaluating the quality of a scaffold.

Results

We present Edison, a Python implementation of the Double Cut and Join (DCJ) edit distance algorithm. Edison calculates the overall accuracy of a given scaffold using a reference genome and also provides scores for characterizing different aspects of the scaffolding accuracy, including grouping, ordering, and orientation. All metrics are calculated on a length-weighted basis, which rewards the correct placement of longer contigs over shorter ones. By creating 1000 random assemblies of theS. cerevisiaegenome, we show that our scaffolding accuracy provides a more reliable metric than the commonly used metric, N50. Edison can be used to benchmark new scaffolding algorithms, providing insights into the strengths and weaknesses of each approach.

Availability and Implementation

Edison is available under an MIT license athttps://github.com/Noble-Lab/edison.
A SARS-CoV-2 Spike Ferritin Nanoparticle Vaccine is Protective and Promotes a Strong Immunological Response in the Cynomolgus Macaque Coronavirus Disease 2019 (COVID-19) Model
Authors: Johnston Sara C. , Ricks Keersten M. , Lakhal-Naouar Ines , Jay Alexandra , Subra Caroline , Raymond Jo Lynne , King Hannah A. D. , Rossi Franco , Clements Tamara L. , Fetterer David , Tostenson Samantha , Cincotta Camila Macedo , Hack Holly R. , Kuklis Caitlin , Soman Sandrine , King Jocelyn , Peachman Kristina K. , Kim Dohoon , Chen Wei-Hung , Sankhala Rajeshwer S. , Martinez Elizabeth J. , Hajduczki Agnes , Chang William C. , Choe Misook , Thomas Paul V. , Peterson Caroline E. , Anderson Alexander , Swafford Isabella , Currier Jeffrey R. , Paquin-Proulx Dominic , Jagodzinski Linda L. , Matyas Gary R. , Rao Mangala , Gromowski Gregory D. , Peel Sheila A. , White Lauren , Smith Jeffrey M. , Hooper Jay W. , Michael Nelson L. , Modjarrad Kayvon , Joyce M. Gordon , Nalca Aysegul , Bolton Diane L. , Pitt Margaret LM
Published: March 2022

The COVID-19 pandemic has had a staggering impact on social, economic, and public health systems worldwide. Vaccine development and mobilization against SARS-CoV-2 (the etiologic agent of COVID-19) has been rapid. However, novel strategies are still necessary to slow the pandemic, and this includes new approaches to vaccine development and/or delivery, which improve vaccination compliance and demonstrate efficacy against emerging variants. Here we report on the immunogenicity and efficacy of a SARS-CoV-2 vaccine comprised of stabilized, pre-fusion Spike protein trimers displayed on a ferritin nanoparticle (SpFN) adjuvanted with either conventional aluminum hydroxide or the Army Liposomal Formulation QS-21 (ALFQ) in a cynomolgus macaque COVID-19 model. Vaccination resulted in robust cell-mediated and humoral responses and a significant reduction of lung lesions following SARS-CoV-2 infection. The strength of the immune response suggests that dose sparing through reduced or single dosing in primates may be possible with this vaccine. Overall, the data support further evaluation of SpFN as a SARS-CoV-2 protein-based vaccine candidate with attention to fractional dosing and schedule optimization.
Mosaic RBD nanoparticles protect against multiple sarbecovirus challenges in animal models
Authors: Cohen Alexander A. , van Doremalen Neeltje , Greaney Allison J. , Andersen Hanne , Sharma Ankur , Starr Tyler N. , Keeffe Jennifer R. , Fan Chengcheng , Schulz Jonathan E. , Gnanapragasam Priyanthi N.P. , Kakutani Leesa M. , West Anthony P , Saturday Greg , Lee Yu E. , Gao Han , Jette Claudia A. , Lewis Mark G. , Tan Tiong K. , Townsend Alain R. , Bloom Jesse D. , Munster Vincent J. , Bjorkman Pamela J.
Published: March 2022

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.
Distinct regulation ofHoxgenes by Polycomb Group genes in a crustacean
Authors: Sun Dennis A , Takahashi Yuri , Chang Rebecca J , Patel Nipam H
Published: March 2022

Non-insect crustaceans exhibit tremendous body plan diversity. The evolution of diverse patterns ofHoxgene expression has been implicated as a primary driver of body plan evolution between crustacean groups, but the mechanisms underlyingHoxregulatory evolution remain unknown. We identify Polycomb and Trithorax Group proteins, crucial for properHoxregulation across bilaterians, in the genome of the amphipod crustaceanParhyale hawaiensis, and demonstrate their essential functions in crustaceanHoxregulation and embryonic development using CRISPR-Cas9 mutagenesis. Examination ofHoxmisexpression patterns between individualHoxgenes with respect to timing, tissue, and PcG mutant gene in mutant embryos reveals that each crustaceanHoxgene follows its own idiosyncratic regulatory mechanism. These results suggest a distinct regulation ofHoxgenes that may have enabled crustacean body plan evolution.

Primary Findings

- The genome of the amphipod crustaceanParhyale hawaiensiscontains all core Polycomb Group (PcG) and Trithorax Group (TrxG) proteins

- CRISPR-Cas9 mutagenesis of PcG proteins induces homeotic transformations and misexpression ofHoxgenes that differ from similar experiments in insects

- PcG knockout embryos show proper initiation ofHoxexpression boundaries at early developmental stages

- Each of the three posteriorHoxgenes inParhyaledisplays distinct patterns of misexpression in response to PcG knockout

-Hoxregulation appears to occur via different mechanisms in the nervous system vs. limbs

- PcG phenotypes reveal the potential for distinct layers ofHoxregulation in crustaceans
Genetically engineered MRI-trackable extracellular vesicles as SARS-CoV-2 mimetics for mapping ACE2 bindingin vivo
Authors: Galisova Andrea , Zahradnik Jiri , Allouche-Arnon Hyla , Morandi Mattia I. , Karam Paula Abou , Avinoam Ori , Regev-Rudzki Neta , Schreiber Gideon , Bar-Shir Amnon
Published: March 2022

The elucidation of viral-receptor interactions and an understanding of virus-spreading mechanisms are of great importance, particularly in the era of pandemic. Indeed, advances in computational chemistry, synthetic biology, and protein engineering have allowed precise prediction and characterization of such interactions. Nevertheless, the hazards of the infectiousness of viruses, their rapid mutagenesis, and the need to study viral-receptor interactions in a complexin vivosetup, call for further developments. Here, we show the development of biocompatible genetically engineered extracellular vesicles (EVs) that display the receptor binding domain (RBD) of SARS-CoV-2 on their surface as coronavirus mimetics (EVsRBD). Loading EVsRBDwith iron oxide nanoparticles makes them MRI-visible, and thus, allows mapping of the binding of RBD to ACE2 receptors non-invasively in live subjects. Importantly, the proposed mimetics can be easily modified to display the RBD of SARS-CoV-2mutants, namely Delta and Omicron, allowing rapid screening of newly raised variants of the virus. The proposed platform thus shows relevance and cruciality in the examination of quickly evolving pathogenic viruses in an adjustable, fast, and safe manner.
Changes of Mutations and Copy-number and Enhanced Cell Migration during Breast Tumorigenesis
Authors: Lee Seung Hyuk T. , Kim Joon Yup , Kim Peter , Dong Zhipeng , Su Chia-Yi , Ahn Eun Hyun
Published: March 2022

Although cancer stem cells (CSCs) play a major role in tumorigenesis and metastasis, the role of genetic alterations in invasiveness of CSCs is still unclear. Tumor microenvironment signals, such as extracellular matrix (ECM) composition, significantly influence cell behaviors. Unfortunately, these signals are often lost inin vitrocell culture. This study determines putative CSC populations, examines genetic changes during tumorigenesis of human breast epithelial stem cells, and investigates single-cell migration properties on ECM-mimetic platforms. Whole exome sequencing data indicate that tumorigenic cells have a higher somatic mutation burden than non-tumorigenic cells, and that mutations exclusive to tumorigenic cells exhibit higher predictive deleterious scores. Tumorigenic cells exhibit distinct somatic copy number variations (CNVs) including gain of duplications in chromosomes 5 and 8. ECM-mimetic topography selectively enhances migration speed of tumorigenic cells, but not of non-tumorigenic cells, and results in a wide distribution of tumorigenic single-cell migration speeds, suggesting heterogeneity in cellular sensing of contact guidance cues. This study identifies mutations and CNVs acquired during breast tumorigenesis, which can be associated with enhanced migration of breast tumorigenic cells, and demonstrates that a nanotopographically-defined platform can be applied to recapitulate an ECM structure for investigating cellular migration in the simulated tumor microenvironment.
Histone marks retained during epigenetic reprogramming and their roles essential for fish early development
Authors: Fukushima Hiroto S. , Takeda Hiroyuki , Nakamura Ryohei
Published: March 2022

Reprograming of epigenetic modifications after fertilization is required for proper embryonic development and cell differentiation. However, histone modifications that escape reprogramming in non-mammalian vertebrates and their potential functional roles are poorly understood. Here, we quantitatively analyzed histone modification dynamics during reprogramming in Japanese Killifish, medaka (Oryzias latipes) embryos, and revealed that H3K27ac, H3K27me3 and H3K9me3 are retained, while H3K4 methylation is completely erased. Furthermore, we experimentally demonstrated the functional roles of such retained modifications at early stages; H3K27ac at promoters is required for proper patterning of H3K4 and H3K27 methylation at zygotic genome activation (ZGA) and specific retention of H3K9me3 at telomeric regions maintains genomic stability during cleavage stage. These results expand the understanding of diversity and conservation of reprogramming in vertebrates and unveil previously uncharacterized functions of histone modifications retained during epigenetic reprogramming.
A multiplexed in vivo approach to identify driver genes in small cell lung cancer
Authors: Lee Myung Chang , Cai Hongchen , Murray Christopher W. , Li Chuan , Shue Yan Ting , Andrejka Laura , He Andy L. , Holzem Alessandra , Drainas Alexandros P. , Ko Julie H. , Coles Garry L. , Kong Christina , Zhu Shirley , Zhu ChunFang , Wang Jason , van de Rijn Matt , Petrov Dmitri A. , Winslow Monte M. , Sage Julien
Published: March 2022

Small cell lung cancer (SCLC) is a highly lethal form of lung cancer. The high mutation burden in SCLC cells makes it challenging to predict key drivers of SCLC from genome sequencing data, thereby hindering the identification of possible therapeutic targets. Here we develop a quantitative multiplexed approach based on lentiviral barcoding with somatic CRISPR/Cas9-mediated genome editing to functionally investigate candidate regulators of tumor initiation and growth in genetically engineered mouse models of SCLC. Lentiviral vector-mediated SCLC initiation was greatly enhanced by naphthalene pre-treatment, enabling high multiplicity of tumor clones for analysis through high-throughput sequencing methods. Based on a meta-analysis across multiple human SCLC genomic datasets, we quantified the impact of inactivating 39 genes across many candidate pathways and captured both positive and detrimental effects on SCLC initiation and progression upon gene inactivation. This analysis and subsequent validation in human SCLC cells identified TSC1 in the PI3K-AKT-mTOR pathway as a robust tumor suppressor in SCLC. This new approach should illuminate novel drivers of SCLC, facilitate the development of precision therapies for defined SCLC genotypes, and identify new therapeutic targets.
What can 1.8 billion regressions tell us about the pressures shaping high-level visual representation in brains and machines?
Authors: Conwell Colin , Prince Jacob S. , Kay Kendrick N. , Alvarez George A. , Konkle Talia
Published: March 2022

The rapid development and open-source release of highly performant computer vision models offers new potential for examining how different inductive biases impact representation learning and emergent alignment with the high-level human ventral visual system. Here, we assess a diverse set of 224 models, curated to enable controlled comparison of different model properties, testing their brain predictivity using large-scale functional magnetic resonance imaging data. We find that models with qualitatively different architectures (e.g. CNNs versus Transformers) and markedly different task objectives (e.g. purely visual contrastive learning versus vision-language alignment) achieve near equivalent degrees of brain predictivity, when other factors are held constant. Instead, variation across model visual training diets yields the largest, most consistent effect on emergent brain predictivity. Overarching model properties commonly suspected to increase brain predictivity (e.g. greater effective dimensionality; learnable parameter count) were not robust indicators across this more extensive survey. We highlight that standard model-to-brain linear re-weighting methods may be too flexible, as most performant models have very similar brain-predictivity scores, despite significant variation in their underlying representations. Broadly, our findings point to the importance of visual diet, challenge common assumptions about the methods used to link models to brains, and more concretely outline future directions for leveraging the full diversity of existing open-source models as tools to probe the common computational principles underlying biological and artificial visual systems.
STEPS 4.0: Fast and memory-efficient molecular simulations of neurons at the nanoscale
Authors: Chen Weiliang , Carel Tristan , Awile Omar , Cantarutti Nicola , Castiglioni Giacomo , Cattabiani Alessandro , Marmol Baudouin Del , Hepburn Iain , King James G , Kotsalos Christos , Kumbhar Pramod , Lallouette Jules , Melchior Samuel , Schürmann Felix , De Schutter Erik
Published: March 2022

Abstract

Recent advances in computational neuroscience have demonstrated the usefulness and importance of stochastic, spatial reaction-diffusion simulations. However, ever increasing model complexity renders traditional serial solvers, as well as naive parallel implementations, inadequate. This paper introduces a new generation of the STochastic Engine for Pathway Simulation (STEPS) project, denominated STEPS 4.0, and its core components which have been designed for improved scalability, performance, and memory efficiency. STEPS 4.0 aims to enable novel scientific studies of macroscopic systems such as whole cells while capturing their nanoscale details. This class of models is out of reach for serial solvers due to the vast quantity of computation in such detailed models, and also out of reach for naive parallel solvers due to the large memory footprint. Based on a distributed mesh solution, we introduce a new parallel stochastic reaction-diffusion solver and a deterministic membrane potential solver in STEPS 4.0. The distributed mesh, together with improved data layout and algorithm designs, significantly reduces the memory footprint of parallel simulations in STEPS 4.0. This enables massively parallel simulations on modern HPC clusters and overcomes the limitations of the previous parallel STEPS implementation. Current and future improvements to the solver are not sustainable without proper software engineering practices. For this reason, we also give an overview of how the STEPS codebase and the development environment have been updated to follow modern software development practices. We benchmark performance improvement and memory footprint on three published models with different complexities, from a simple spatial stochastic reaction-diffusion model, to a more complex one that is coupled to a deterministic membrane potential solver to simulate the calcium burst activity of a Purkinje neuron. Simulation results of these models suggest that the new solution dramatically reduces the per-core memory consumption by more than a factor of 30, while maintaining similar or better performance and scalability.
Finding the strongest gene drive: Simulations reveal unexpected performance differences betweenAnopheleshoming suppression drive candidates
Authors: Champer Samuel E. , Kim Isabel K. , Clark Andrew G. , Messer Philipp W. , Champer Jackson
Published: March 2022

Recent experiments have produced severalAnopheles gambiaehoming gene drives that disrupt female fertility genes, thereby eventually inducing population collapse. Such drives may be highly effective tools to combat malaria. One such homing drive, based on thezpgpromoter driving CRISPR/Cas9, was able to eliminate a cage population of mosquitoes. A second version, purportedly improved upon the first by incorporating an X-shredder element (which biases inheritance towards male offspring), was similarly successful. Here, we re-analyze the data of each of these gene drives and suggest an alternative interpretation of their performance. We assess each suppression drive within an individual-based simulation framework that models mosquito population dynamics in continuous space. We find that the combined homing/X-shredder drive is actually less effective at population suppression within the context of our mosquito population model. In particular, the combined drive often fails to completely suppress the population, instead resulting in an unstable equilibrium between drive and wild-type alleles. By contrast, otherwise similar drives based on thenospromoter may prove to be more promising candidates for future development due to potentially superior performance.
Cortical integration of higher-order thalamic inputs is lineage-dependent
Authors: Buchan Matthew J. , Mahfooz Kashif , van Rheede Joram J. , Gothard Gemma , Avery Sophie V. , Ellender Tommas J. , Newey Sarah E. , Akerman Colin J.
Published: March 2022

Primary sensory cortex receives and integrates inputs from first-order and higher-order thalamic nuclei. First-order inputs convey sensory information from the periphery and exhibit simple response properties, whereas higher-order inputs exhibit more complex response properties, provide contextual feedback, and can modulate first-order inputs. Here we show that the way in which cortical neurons integrate these thalamic inputs, reflects the progenitor cell from which the cortical neurons derive. Within layer 4 of mouse primary somatosensory cortex, excitatory neurons that derive from apical intermediate progenitors exhibit multi-whisker response properties and receive higher-order thalamic input, in a manner consistent with their dendritic morphology. These properties depend upon the expression levels of the transcription factor Lhx2, which when increased, abolishes the higher-order properties of apical intermediate progenitor-derived neurons, and disrupts the induction of sensory-evoked plasticity. These data reveal a lineage-dependent mechanism that establishes the integration and functional contribution of higher-order thalamic inputs within cortex.
Wild common crossbills produce redder body feathers when their wings are clipped
Authors: Fernández-Eslava Blanca , Cantarero Alejandro , Alonso Daniel , Alonso-Alvarez Carlos
Published: March 2022

The animal signaling theory posits that conspicuous colorations exhibited by many animals have evolved as reliable signals of individual quality. Red carotenoid-based ornaments may depend on enzymatic transformations (oxidation) of dietary yellow carotenoids, which could occur in the inner mitochondrial membrane (IMM). Thus, carotenoid ketolation and cell respiration could share the same biochemical pathways. Accordingly, the level of trait expression (redness) would directly reveal the efficiency of individuals’ metabolism and hence, the bearer quality in an unfalsifiable way. Different avian studies have described that the flying effort may induce oxidative stress. A redox metabolism modified during the flight could thus influence the carotenoid conversion rate and, ultimately, animal coloration. Here, we aimed to infer the link between red carotenoid-based ornament expression and flight metabolism by increasing flying effort in wild male common crossbillsLoxia curvirostra(Linnaeus). In this order, 295 adult males were captured during winter in an Iberian population. Half of the birds were experimentally handicapped through wing feather clipping to increase their flying effort, the other half being used as a control group. The rump feathers were also plucked in all the birds to stimulate plumage regrown of a small surface during a short time-lapse. Thirty-four birds with fully grown rump feathers could be recaptured in the subsequent weeks. Among them, male crossbills with experimentally impaired flying capacity showed redder rump feathers than controls. This result would support the hypothesis that the flying metabolism influences the redox enzymatic reactions required for converting yellow dietary carotenoids to red ketocarotenoids.

Summary statement

Carotenoid-based colorations may depend on pigment enzymatic transformations linked to mitochondrial function. The flight metabolism could influence this. Here, common crossbills with clipped wings produced redder feathers than controls.
miR-34a negatively regulates cell cycle factor Cdt2/DTL in HPV infected Cervical Cancer Cells
Authors: Singh Garima , Sharma Sonika Kumari , Singh Samarendra Kumar
Published: March 2022

MicroRNAs have emerged as an important factor in regulating cell cycle and various other cellular processes. Aberration in microRNAs has been linked with development of several cancers and other diseases but still very little is known about the mechanism behind their function in regulating cellular processes. 99% of cervical cancer is caused by the infection of high-risk HPVs (HR HPVs) which suppresses multiple tumor suppressors and checkpoint factors of the host cell. It also stabilizes oncogenic proteins, one of them is Cdt2/DTL which promotes cell transformation and proliferation. In this study, we have reported that in cervical cancer cell lines miR-34a by targeting HPV E6 protein, regulates Cdt2/DTL protein level and leads to its destabilization. Destabilization of Cdt2 stabilizes onco-suppressor proteins like p21 and Set8 in these cell lines. We have also shown that the overexpression of miR-34a suppresses cell proliferation, invasion and migration capabilities of HPV positive cervical cancer cells which was reverted by overexpression of either HPV E6 or Cdt2 genes. This is the first-ever report to show that miR-34a regulates cell cycle factor Cdt2 by suppressing viral E6 protein level, which opens up the scope of exploring miR-34a as a specific therapy for cervical cancer treatment.

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Effects of haemosporidian co-infection and parasitemia on reproductive strategies in a polymorphic species
Authors: Delefortrie Zoé , Gante Hugo F. , Gordo Oscar , Schwab Kristopher R. , Gonser Rusty A.
Published: March 2022

Host-parasite interactions play a significant role in evolution. Parasite infections impose fitness costs that can trigger trade-off responses in host reproductive strategies. Individuals can invest limited resources in parasite defense, such as stimulating the immune system, or perform terminal reproductive investment. Here, we investigated how haemosporidian co-infection and parasitemia influence different reproductive strategies in a polymorphic bird species (the white-throated sparrow, Zonotrichia albicollis). We provided an account of the impacts of co-infection and parasitemia on host reproductive success and reproductive strategies in response to parasite infection. We tested the effect of co-infection and parasitemia on reproductive success (fledgling number, extra-pair paternity, ratio social/genetic offspring) and the effect of parental infection on nestling quality (mean nestling growth rate and body condition). We found that co-infection increases reproductive extra-pair paternity and nestling mean body condition. Parental high parasitemia positively impacts the ratio of genetic offspring belonging to the social father and has mixed results on nestling quality. We observed that co-infection in females and parasitemia in males might trigger a switch in reproductive strategy towards a terminal investment for co-infected individuals. In contrast, high parasitemia in females negatively impacted their offspring fitness, possibly due to the reallocation of resources for fighting the infection.
Sperm mosaicism predicts transmission of de novo mutations to human blastocysts
Authors: Breuss Martin W. , Yang Xiaoxu , Stanley Valentina , McEvoy-Venneri Jennifer , Xu Xin , Morales Arlene J. , Gleeson Joseph G.
Published: March 2022

De novo mutations underlie individually rare but collectively common pediatric congenital disorders. Some of these mutations can also be detected in tissues and from cells in a parent, where their abundance and tissue distribution can be measured. We previously reported that a subset of these mutations is detectable in sperm from the father, predicted to impact the health of offspring. Here, in three independent couples undergoing in vitro fertilization, we first assessed male gonadal mosaicism, then assessed the transmission of the mutations to their preimplantation blastocysts. We found an overall predictable transmission but slight under-transmission of mutations to blastocysts based upon measured mutational abundance in sperm, and we replicated this conclusion in an independent family-based cohort. Therefore, unbiased preimplantation genetic testing for gonadal mosaicism may represent a feasible approach to reduce the transmission of potentially harmful de novo mutations, which could help to reduce their impact on miscarriage and pediatric disease.
Dynamic adaptation of sequential action benefits from cortico-basal ganglia-related temporal variability
Authors: Ferguson Lachlan A. , Matamales Miriam , Balleine Bernard W. , Bertran-Gonzalez Jesus
Published: March 2022

Performing several actions in swift succession is often necessary to exploit known contingencies in the environment. However, in order to remain successful when contingency rules change, streamlined action sequences must be adaptable. Here, by combining analyses of behavioural microstructure with circuit-specific manipulation in mice, we report on a relationship between action timing variability and successful adaptation that relies on post-synaptic targets of primary motor cortical (M1) projections to dorsolateral striatum (DLS). Using a two-lever instrumental task, we found that mice build successful action sequences by first establishing action scaffolds, from which they dynamically elongate as task requirements extend. Specific interruption of the M1→DLS circuit altered these dynamics, prompting actions that were less variable in their timing, overall reducing opportunities for success. Our results reveal a role for M1→DLS circuitry in setting the exploration/exploitation balance that is required for adaptively guiding the timing and success of instrumental action. Based on evidence from transsynaptic tracing experiments, we propose that such function may involve additional downstream subcortical processing relating to collateralisation of descending motor pathways to multiple basal ganglia centres.
Uracil/H+ symport by the FurE transporter challenges the rocking-bundle mechanism of transport in APC transporters
Authors: Zantza Iliana , Papadaki Georgia F. , Raniolo Stefano , Pyrris Yiannis , Lambrinidis George , Limongelli Vittorio , Diallinas George , Mikros Emmanuel
Published: March 2022

Transporters mediate the uptake of solutes, metabolites and drugs across the cell membrane. The eukaryotic FurE nucleobase/H+ symporter of Aspergillus nidulans has been used as a model protein to address structure-function relationships in the APC transporter superfamily, members of which are characterized by the LeuT-fold and seem to operate by the so-called ‘rocking-bundle’ mechanism. In this study, we reveal the binding mode, translocation and release pathway of uracil/H+ by FurE, using path collective variable, funnel metadynamics and rationally designed mutational analysis. Our study reveals a step-wise, induced-fit, mechanism of ordered sequential transport of proton and uracil, which in turn suggests that the FurE symporter, and probably structurally similar transporters, functions as a multi-step gated pore, rather than employing ‘rocking’ of compact domains, as generally proposed for APC transporters. In addition, our work further supports the emerging concept that specific elements of cytosolic terminal regions of transporters might be functionally important.
Stability and learning in excitatory synapses by nonlinear inhibitory plasticity
Authors: Miehl Christoph , Gjorgjieva Julijana
Published: March 2022

Synaptic changes underlie learning and memory formation in the brain. But synaptic plasticity of excitatory synapses on its own is unstable, leading to unlimited growth of synaptic strengths without additional homeostatic mechanisms. To control excitatory synaptic strengths we propose a novel form of synaptic plasticity at inhibitory synapses. We identify two key features of inhibitory plasticity, dominance of inhibition over excitation and a nonlinear dependence on the firing rate of postsynaptic excitatory neurons whereby inhibitory synaptic strengths change in the same direction as excitatory synaptic strengths. We demonstrate that the stable synaptic strengths realized by this novel inhibitory plasticity achieve a fixed excitatory/inhibitory set-point in agreement with experimental results. Applying a disinhibitory signal can gate plasticity and lead to the generation of receptive fields and strong bidirectional connectivity in a recurrent network. Hence, a novel form of nonlinear inhibitory plasticity can simultaneously stabilize excitatory synaptic strengths and enable learning upon disinhibition.