bluuebunny/crossref_metadata_2025 huggingface dataset:
Deciphering Oxygen Distribution and Hypoxia Profiles in the Tumor Microenvironment: A Data-Driven Mechanistic Modeling Approach
Authors: Kumar P. , Lacroix M. , Dupré P. , Arslan J. , Fenou L. , Orsetti B. , Le Cam L. , Racoceanu D. , Radulescu O.
Published: March 2024

The distribution of hypoxia within tissues plays a critical role in tumor diagnosis and prognosis. Recognizing the significance of tumor oxygenation and hypoxia gradients, we introduce mathematical frameworks grounded in mechanistic modeling approaches for their quantitative assessment within a tumor microenvironment. Our approach provides a non-invasive method to measure and predict hypoxia using known blood vasculature. Formulating a reaction-diffusion model for oxygen distribution, we apply it to derive the corresponding hypoxia profile. The modeling and simulations successfully replicate the observed inter- and intra-tumor heterogeneity in experimentally obtained hypoxia profiles across various tumor tissues (breast, ovarian, and pancreatic) in our dataset. Employing a data-driven approach, we propose a method to deduce partial differential equation (PDE) models with spatially dependent parameters, enabling us to comprehend the variability of hypoxia profiles within a tissue. The versatility of our framework lies not only in capturing diverse and dynamic behaviors of tumor oxygenation but also in categorizing states of vascularization. These categories are distinguished based on the dynamics of oxygen molecules, as identified by the model parameters.
Pawpaws prevent predictability: A locally-dominant tree alters understory beta-diversity and community assembly
Authors: Wassel Anna C. , Myers Jonathan A.
Published: March 2024

While dominant species are known to be important in ecosystem functioning and community assembly, biodiversity responses to the presence of dominant species can be highly variable. Dominant species can increase the importance of deterministic community assembly by competitively excluding species in a consistent way across local communities, resulting in low site-to-site variation in community composition (beta-diversity) and non-random community structure. In contrast, dominant species could increase the importance of stochastic community assembly by reducing the total number of individuals in local communities (community size), resulting in high beta-diversity and more random community structure. We tested these hypotheses in a large, temperate oak-hickory forest plot containing a locally-dominant tree species, pawpaw (Asimina triloba; Annonaceae), an understory tree species that occurs in dense, clonal patches in forests throughout the east-central United States. We determined how the presence of pawpaw influences local species diversity, community size, and beta-diversity by measuring the abundance of all vascular plant species in 1x1-m plots both inside and outside pawpaw patches. To test whether the presence of pawpaw influences local assembly processes, we compared observed patterns of beta-diversity inside and outside patches to a null model of random assembly. We found lower local species diversity, lower community size, and higher observed beta-diversity inside pawpaw patches than outside pawpaw patches. Moreover, standardized effect sizes of beta-diversity from the null model were lower inside pawpaw patches than outside pawpaw patches, indicating more random community composition inside pawpaw patches. Together these results suggest that pawpaw increases the importance of stochastic relative to deterministic community assembly at local scales, likely by decreasing overall numbers of individuals, and increasing random local extinctions inside patches. Our findings provide insights into the ecological processes by which locally-dominant tree species shape the assembly and diversity of understory plant communities at different spatial scales.
Task interference as a neuronal basis for the cost of cognitive flexibility
Authors: Xue Cheng , Markman Sol K. , Chen Ruoyi , Kramer Lily E. , Cohen Marlene R.
Published: March 2024

Humans and animals have an impressive ability to juggle multiple tasks in a constantly changing environment. This flexibility, however, leads to decreased performance under uncertain task conditions. Here, we combined monkey electrophysiology, human psychophysics, and artificial neural network modeling to investigate the neuronal mechanisms of this performance cost. We developed a behavioural paradigm to measure and influence participants’ decision-making and perception in two distinct perceptual tasks. Our data revealed that both humans and monkeys, unlike an artificial neural network trained for the same tasks, make less accurate perceptual decisions when the task is uncertain. We generated a mechanistic hypothesis by comparing this neural network trained to produce correct choices with another network trained to replicate the participants’ choices. We hypothesized, and confirmed with further behavioural, physiological, and causal experiments, that the cost of task flexibility comes from what we term task interference. Under uncertain conditions, interference between different tasks causes errors because it results in a stronger representation of irrelevant task features and entangled neuronal representations of different features. Our results suggest a tantalizing, general hypothesis: that cognitive capacity limitations, both in health and disease, stem from interference between neural representations of different stimuli, tasks, or memories.
Novel Approach to Advance Directive Training: Palliative Fellow Led Workshop Feasible and Effective in Increasing Confidence in End of Life Conversations
Authors: Chelsea Chang , Cano Jose , Lopez-Alvarenga Juan , Rodriguez-Paez Josenny , Montes Sonya , Rao Meghana
Published: March 2024

Despite the benefits of Advance directives, approximately only 1 in 3 U.S adults have documented advance directives. In medical school and residency, learners are often not taught or given very brief information on conducting end-of-life planning conversations with patients. Due to this deficiency, some institutions have conducted advance directive workshops but not many have been both palliative fellow and resident led, though some have been led by a geriatric fellow. Therefore, we approached advance directives with a resident and palliative fellow-led workshop. We aimed to develop and conduct a workshop on advance directives to assess feasibility and effectiveness. We sent a survey to 52 residents prior to two one-hour didactic sessions. For the first session, a small group of residents discussed common terminology and the tools available to help patients complete advanced directives in the outpatient setting. A hospice and palliative care fellow led the second session and focused on patient communication and approach. Our results showed that the workshop was well-received and improved resident confidence in discussing advance directives with patients. In conclusion, a resident and palliative fellow-led advance directive workshop for internal medicine residents was feasible and effective in increasing resident confidence.
Accelerated brain age in young to early middle-aged adults after mild to moderate COVID-19 infection
Authors: Kesler Shelli R , Franco-Rocha Oscar Y. , De La Torre Schutz Alexa , Lewis Kimberly A. , Aziz Rija M , Brode W. Michael , Melamed Esther
Published: March 2024

Cognitive decline is a common adverse effect of the Coronavirus Disease of 2019 (COVID-19), particularly in the post-acute disease phase. The mechanisms of cognitive impairment after COVID-19 (COGVID) remain unclear, but neuroimaging studies provide evidence of brain changes, many that are associated with aging. Therefore, we calculated Brain Age Gap (BAG), which is the difference between brain age and chronological age, in a cohort of 25 mild to moderate COVID-19 survivors (did not experience breathlessness, pneumonia, or respiratory/organ failure) and 24 non-infected controls (mean age = 30 +/− 8) using magnetic resonance imaging (MRI). BAG was significantly higher in the COVID-19 group (F = 4.22, p = 0.046) by 2.65 years. Additionally, 80% of the COVID-19 group demonstrated an accelerated BAG compared to 13% in the control group (X2= 20.0, p < 0.001). Accelerated BAG was significantly correlated with lower cognitive function (p < 0.041). Females in the COVID-19 group demonstrated a 99% decreased risk of accelerated BAG compared to males (OR = 0.015, 95% CI: 0.001 to 0.300). There was also a small (1.4%) but significant decrease in risk for accelerated BAG associated with longer time since COVID-19 diagnosis (OR = 0.986, 95% CI: 0.977 to 0.995). Our findings provide a novel biomarker of COGVID and point to accelerated brain aging as a potential mechanism of this adverse effect. Our results also offer further insight regarding gender-related disparities in cognitive morbidity associated with COVID-19.
PRAGMATIC - PRostate cancer diAGnosis and MAnagement – Triage In the Clinical care pathway
Authors: Sharma Abishek , Campbell Teresa , Bates Anthony , John Rincy , Adams Charlotte , Brassill Aisling , Lennon Bryony , Camilleri Philip , Sabharwal Ami , Charlton Philip , Andrade Gerard , Tuthill Mark , Protheroe Andrew , Lamb Alastair D , Leslie Tom , Leiblich Aaron , Lopez Francisco , Verrill Clare , Gleeson Fergus , MacPherson Ruth , Hamdy Freddie C , Bell Richard , Bryant Richard J
Published: March 2024

Background

It is important to investigate, diagnose and commence treatment for locally advanced and metastatic prostate cancer quickly to optimise treatment outcomes. Since the introduction of national 2-week wait and 31/62-day targets in the United Kingdom for investigation of suspected prostate cancer over 2 decades ago, the clinical pathway has become increasingly complex. This may lead to some patients with the most clinically significant disease having the rapidity of their diagnosis and commencement of treatment compromised by resource use in diagnosing less significant, or clinically insignificant, disease.

Methods

We will conduct a retrospective review of timelines for diagnosis and commencement of treatment for all men referred to a tertiary unit for investigation of suspected prostate cancer on the 2-week wait pathway in a 3-month period in 2023. In parallel, we will introduce triaging of all new 2-week wait referrals in a prospective 3-month period, with a dedicated nurse navigator streamlining patients for the most rapid investigation and treatment, based on pre-specified risk criteria including PSA, pre-biopsy mpMRI findings including TNM staging, and histology results. We hypothesise that this bespoke triaging system, above and beyond the 2-week wait and 2022 Faster Diagnostic Pathway guidance issued by NHS England, will improve timings for investigation and commencement of treatment for the most clinically significant prostate cancer cases.

Conclusions

The use of in-house criteria for triaging and stratification of the most clinically urgent and significant prostate cancer cases, identified by a nurse specialist navigator, may improve clinical outcomes for patients with greatest need for rapid prostate cancer imaging, diagnosis and treatment.
Cell-type specific contributions to theta-gamma coupled rhythms in the hippocampus
Authors: Sengupta Spandan , Talidou Afroditi , Lefebvre Jeremie , Skinner Frances K
Published: March 2024

Distinct inhibitory cell types participate in cognitively relevant nested brain rhythms, and particular changes in such rhythms are known to occur in disease states. Specifically, the co-expression of theta and gamma rhythms in the hippocampus is believed to represent a general coding scheme, but cellular-based generation mechanisms for these coupled rhythms are currently unclear. We develop a population rate model of the CA1 hippocampus that encompasses circuits of three inhibitory cell types (bistratified cells, parvalbumin (PV)-expressing and cholecystokinin (CCK)-expressing basket cells) and pyramidal cells to examine this. We constrain parameters and perform numerical and theoretical analyses. The theory, in combination with the numerical explorations, predicts circuit motifs and specific cell-type mechanisms that are essential for the co-existence of theta and gamma oscillations. We find that CCK-expressing basket cells initiate the coupled rhythms and regularize theta, and PV-expressing basket cells enhance both theta and gamma rhythms. Pyramidal and bistratified cells govern the generation of theta rhythms, and PV-expressing basket and pyramidal cells play dominant roles in controlling theta frequencies. Our circuit motifs for theta-gamma coupled rhythm generation could be applicable to other brain regions.

AUTHOR SUMMARY

There are many different types of inhibitory cells in our brains that are differentially affected in disease. Concomitantly, coupled rhythms change in particular ways with disease. To help understand cell-type specific changes in coupled rhythms, we develop a mathematical network model that is both respective of the cell type and also amenable to analyses. We focus on theta-gamma coupled rhythms in the hippocampus and include three different inhibitory cell types in our model circuits. By combining theoretical analysis and numerical explorations, we find distinct contributions of these inhibitory cell types to coupled rhythms, and predict motifs that are essential for the expression of theta-gamma coupled rhythms. Moving forward, we can leverage our model insights to help unravel cell-type contributions in disease states.
Reflection confocal microscopy for quantitative assessment of airway surface liquid dysregulation and pharmacological rescue in cystic fibrosis under near-physiological conditions
Authors: Agircan Ayca Seyhan , Lampe Marko , Scheuermann Heike , Albrecht Tobias , Graeber Simon Y. , Balázs Anita , Baumann Ingo , Block Stephan , Pepperkok Rainer , Mall Marcus A. , Duerr Julia
Published: March 2024

Proper regulation of airway surface liquid (ASL) is essential for effective mucociliary clearance (MCC) in healthy airways, and ASL depletion due to deficient cystic fibrosis transmembrane conductance regulator (CFTR)-mediated anion/fluid secretion plays an important role in the pathogenesis of mucociliary dysfunction and chronic muco-obstructive lung disease in patients with cystic fibrosis (CF). The current standard for quantitative measurements of ASL height is confocal fluorescence microscopy that has the disadvantage that it requires apical addition of volume for fluorescent staining, and hence perturbation of the ASL. Therefore, our aim was to develop a method that enables studies of ASL regulation under unperturbed conditions using reflected light by confocal microscopy of primary airway epithelial cultures grown at air-liquid interface (ALI). After apical volume addition to primary tracheal mouse cultures, confocal reflection microscopy yielded comparable ASL height as confocal fluorescence microscopy on cultures of wild-type mice, and was sensitive to detect ASL depletion on cultures of βENaC-Tg mice. Under unperturbed conditions, ASL determined by confocal reflection microscopy was significantly higher in wild-type and βENaC-Tg mice compared to values obtained by confocal fluorescence microscopy. Studies in normal and CF primary human airway epithelial cultures showed that confocal reflection microscopy was sensitive to detect effects of low temperature rescue and pharmacological modulation including improvement of CFTR function by VX-809 and VX-770 in cultures from CF patients with the F508del mutation. Our results support confocal reflection microscopy as a novel sensitive technique for quantitative studies of ASL regulation and response to therapeutic intervention under unperturbed near-physiological conditions in healthy and CF airways.

NEW & NOTEWORTHY

Measurement of airway surface liquid (ASL) height by confocal fluorescence microscopy is an important tool to investigate ASL dysregulation and effects of therapeutic strategies aiming at restoring ASL volume to improve mucociliary clearance and lung function in patients with cystic fibrosis. However, confocal fluorescence microscopy has the disadvantage that it requires apical addition of volume for fluorescent staining of the ASL leading to perturbation of its height and composition. Here, we developed confocal reflection microscopy as a new method that enables quantitative assessment of ASL on highly-differentiated primary airway epithelial cultures under unperturbed near-physiological conditions by detection of refracted light.
Thymic epithelial organoids mediate T cell development
Authors: Hübscher Tania , Lorenzo-Martín L. Francisco , Barthlott Thomas , Tillard Lucie , Langer Jakob J. , Rouse Paul , Blackburn C. Clare , Holländer Georg , Lutolf Matthias P.
Published: March 2024

Although the advent of organoids opened unprecedented perspectives for basic and translational research, immune system-related organoids remain largely underdeveloped. Here we established organoids from the thymus, the lymphoid organ responsible for T cell development. We identified conditions enabling thymic epithelial progenitor cell proliferation and development into organoids with in vivo-like transcriptional profiles and diverse cell populations. Contrary to two-dimensional cultures, thymic epithelial organoids maintained thymus functionality in vitro and mediated physiological T cell development upon reaggregation with T cell progenitors. The reaggregates showed in vivo-like epithelial diversity and ability to attract T cell progenitors. Thymic epithelial organoids provide new opportunities to study TEC biology and T cell development in vitro, pave the way for future thymic regeneration strategies and are the first organoids originating from the stromal compartment of a lymphoid organ.

Summary statement

Establishment of organoids from the epithelial cells of the thymus which resemble their in vivo counterpart and have thymopoietic ability in reaggregate culture.
Dual-color MINFLUX: Kinesin-1 takes Chassé-Inchworm steps
Authors: Scheiderer Lukas , Wirth Jan O. , Tarnawski Miroslaw , Hell Stefan W.
Published: March 2024

Despite tremendous efforts using various techniques, many central questions regarding the walking mechanism of the ATP-driven motor protein kinesin-1 remained contradictory and puzzling. Still, it is widely believed that kinesin-1 walks hand-over-hand, meaning that the two motor domains (heads) sequentially overtake each other with a 16 nm step so that, after each step, the two heads are 8 nm apart. Here we developed dual-color fluorophore tracking by MINFLUX, which enabled us to follow the individual steps of the two heads simultaneously, up to physiological ATP concentrations. We found that, besides hand-over-hand, kinesin-1 frequently walks in a previously undescribed chassé-inchworm mode, whereby one of the heads advances by 16 nm, whereas the other one follows suit, binding in close proximity to the first. In this mode, the two heads are either 16 nm or ∼0 nm apart. The transition between the two walking mechanisms is initiated by one of the heads making a large (>20 nm) passing step. MINFLUX also revealed that load-free kinesin-1 does not show significant limping and that the stalk folds back, pointing leftwards. The finding of the chassé-inchworm mechanism reconciles many of the contradictory results gained with other techniques, highlighting the power of multicolor MINFLUX tracking to reveal protein operation.
Derivation of elephant induced pluripotent stem cells
Authors: Appleton Evan , Hong Kyunghee , Rodríguez-Caycedo Cristina , Tanaka Yoshiaki , Ashkenazy-Titelman Asaf , Bhide Ketaki , Rasmussen-Ivey Cody , Ambriz-Peña Xochitl , Korover Nataly , Bai Hao , Quieroz Ana , Nelson Jorgen , Rathod Grishma , Knox Gregory , Morgan Miles , Malviya Nandini , Zhang Kairui , McNutt Brody , Kehler James , Kowalczyk Amanda , Bow Austin , McLendon Bryan , Cantarel Brandi , James Matt , Mason Christopher E. , Gray Charles , Koehler Karl R. , Pearson Virginia , Lamm Ben , Church George , Hysolli Eriona
Published: March 2024

The crisis of biodiversity loss in the anthropogenic era requires new tools for studying non-model organisms. Elephants, for example, are both an endangered species and excellent models studying complex phenotypes like size, social behavior, and longevity, but they remain severely understudied. Here we report the first derivation of elephant (Elephas maximus) induced pluripotent stem cells (emiPSCs) achieved via a two-step process of chemical-media induction and colony selection, followed by overexpression of elephant transcription factorsOCT4, SOX2, KLF4, MYC±NANOGandLIN28A, and modulation of theTP53pathway. Since the seminal discovery of reprogramming by Shinya Yamanaka, iPSCs from many species including the functionally extinct northern white rhinocerous have been reported, but emiPSCs have remained elusive. While for multiple species the reprogramming protocol was adopted with little changes compared to model organisms like mouse and human, our emiPSC protocol requires a longer timeline and inhibition ofTP53expansion genes that are hypothesized to confer unique cancer resistance in elephants. iPSCs unlock tremendous potential to explore cell fate determination, cell and tissue development, cell therapies, drug screening, disease modeling, cancer development, gametogenesis and beyond to further our understanding of this iconic megafauna. This study opens new frontiers in advanced non-model organism cellular models for genetic rescue and conservation.
Effect of terminal phosphate groups on collisional dissociation of RNA oligonucleotide anions
Authors: Zuo Mei-Qing , Song Ge , Dong Meng-Qiu , Sun Rui-Xiang
Published: March 2024

An increasing need of mass spectrometric analysis of RNA molecules calls for a better understanding of their gas-phase fragmentation behaviors. In this study, we investigated the effect of terminal phosphate groups on the fragmentation spectra of RNA oligonucleotides (oligos) using high-resolution mass spectrometry (MS). Negative-ion mode collision-induced dissociation (CID) and higher-energy collisional dissociation (HCD) were carried out on RNA oligos containing a terminal phosphate group on either or both ends, or neither. We find that terminal phosphate groups affect the fragmentation behavior of RNA oligos in a way that depends on the precursor charge state and the oligo length. Specifically, for precursor ions of RNA oligos of the same sequence, those with 5’- or 3’-phosphate, or both, have a higher charge state distribution and lose upon CID or HCD the phosphate group(s) in the form of a neutral (H3PO4or HPO3) or an anion ([H2PO4]-or [PO3]-). Such neutral or charged loss is most conspicuous for precursor ions of an intermediate charge state, e.g. 3-for 4-nt oligos or 4-and 5-for 8-nt oligos. This decreases the intensity of sequencing ions (a-, a-B, b-, c-, d-, w-, x-, y-, z-ions), hence unfavorable for sequencing by CID or HCD. Removal of terminal phosphate groups by calf intestinal alkaline phosphatase improved MS analysis of RNA oligos. Additionally, the intensity of a fragment ion atm/z158.925, which we have identified as a dehydrated pyrophosphate anion ([HP2O6]-), is markedly increased by the presence of a terminal phosphate group. These findings expand the knowledge base necessary for software development for MS analysis of RNA.
Rare VariableM. tuberculosisAntigens induce predominant Th17 responses in human infection
Authors: Ogongo Paul , Wassie Liya , Tran Anthony , Columbus Devin , Sharling Lisa , Ouma Gregory , Ouma Samuel Gurrion , Bobosha Kidist , Lindestam Arlehamn Cecilia S. , Gandhi Neel R. , Auld Sara C. , Rengarajan Jyothi , Day Cheryl L. , Altman John D. , Blumberg Henry M. , Ernst Joel D. ,   the TBRU ASTRa Study Group
Published: March 2024

CD4 T cells are essential for immunity toM. tuberculosis(Mtb), and emerging evidence indicates that IL-17-producing Th17 cells contribute to immunity toMtb. While identifying protective T cell effector functions is important for TB vaccine design, T cell antigen specificity is also likely to be important. To identify antigens that induce protective immunity, we reasoned that as in other pathogens, effective immune recognition drives sequence diversity in individualMtbantigens. We previously identifiedMtbgenes under evolutionary diversifying selection pressure whose products we term Rare Variable Mtb Antigens (RVMA). Here, in two distinct human cohorts with recent exposure to TB, we found that RVMA preferentially induce CD4 T cells that express RoRγt and produce IL-17, in contrast to ‘classical’Mtbantigens that induce T cells that produce IFNγ. Our results suggest that RVMA can be valuable antigens in vaccines for those already infected withMtbto amplify existing antigen-specific Th17 responses to prevent TB disease.
The relationship between ethnicity and socioeconomic deprivation as determinants of health: a systematic review
Authors: Coates Melanie , Shah Aroon Bhardwaj , Igwe Richard , Wan Yize I
Published: March 2024

Background

Ethnicity and socioeconomic status (SES) are well known social determinants of health. However, the impact of the intersection between ethnicity and SES on health remains poorly understood, with many studies examining these factors separately.

Methods

We conducted a systematic review using MEDLINE (PubMed), EMBASE, and The Cochrane Library databases. Studies were eligible if they compared outcomes defined by mortality, attendance, readmission, or hospital length of stay, for any acute or chronic illness, according to one or more measures of both ethnicity and SES in adult patients (≥18 years of age) attending primary care or admitted to hospital.

Results

Nine studies met eligibility criteria. There was significant heterogeneity in cohort demographics, key variables, and outcome measures. Therefore, qualitative analysis was used. Definitions and categories of ethnicity were inconsistent, using race, country of origin, and sociocultural characteristics. Definitions of SES varied, with studies using between one and seven metrics. Different sub-categories were often used, even when the same metric was utilised. Primary outcomes were mortality (n=7) or admissions-related (n=2). Approaches varied between studies, regarding cause, time periods, and end points. Of those looking at mortality, four reported seeing an interaction between ethnicity and SES groups on outcomes.

Conclusions

Heterogeneity in the categorisation of ethnicity and SES is a barrier to research and understanding of health inequalities. This could be tackled by standardising data collection in healthcare routine data nationally and internationally, to enable translation of information between settings. For SES, using multifaceted methods could better capture the complexity of this factor.
Influenza mortality as an indicator of the effectiveness of public health interventions and their impact on United States COVID mortality
Authors: Morris Robert
Published: March 2024

The synergistic nature of non-pharmaceutical interventions (NPIs) for control of COVID makes it difficult to assess the efficacy of any individual strategy. This study uses influenza mortality reduction (IMR) during the pandemic as an indicator of the aggregate efficacy of NPIs to assess their impact on COVID mortality.

Age-adjusted COVID mortality for US states were modeled as a function of four variables: mortality prior to the introduction of NPIs, vaccination rates, IMR relative to historical averages, and population density.

A simple linear model with only these variables explained 69% of the state-to-state variability in age adjusted COVID mortality. The resulting model suggests that NPIs alone prevented 840,000 COVID related deaths in the United States over the course of the pandemic. These results demonstration the utility of IMRs as an indicator of the aggregate impact of NPIs for controlling transmission of respiratory infections, including COVID.
WITHDRAWN: Onchocerciasis Elimination Mapping in Tanzania Mainland: A case of Kilindi DC, Handeni DC and Kilolo DC, Iringa DC
Authors: Chihoma Evangelina , Mbwambo Stephen G. , Moirana Ezekiel , Masayi Casmil , Masanika Julius , Lalji Shabbir , Crowley Kathlyn , Post Rory , Evans Darin , Katabarwa Moses , Mwingira Upendo , Kabona George
Published: March 2024

Withdrawal Statement

“This manuscript has been withdrawn by the authors as they did not obtain the necessary ethical clearance for the study. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.”
The importance of mothers: The social transmission of COVID-19 vaccination attitudes and uptake
Authors: Thompson Oscar , Cristea Mioara , Tamariz Monica
Published: March 2024

The global fight against the COVID-19 pandemic has underscored the critical importance of widespread vaccination to mitigate the impact of the virus on public health. The current study aimed to investigate which social influences might be most important for predicting attitudes towards COVID-19 vaccination and vaccine uptake among young students in the UK. We focused on the cultural evolution and social transmission aspects, i.e., parent-to-child versus peer-to-peer, of attitudes and vaccine uptake during the COVID-19 pandemic. A sample of 192 UK students (aged 18 to 35 years old) filled in an online survey including measures for attitudes towards COVID-19 vaccination and vaccine uptake and/or intention, age, and gender. Participants were also asked about their mother’s, father’s, and best friend’s attitudes towards COVID-19 vaccination and vaccine uptake. Finally, they provided a subjective measure of the quality relationship with their parents. Overall, our results suggest that both parents and very close friends are important agents in understanding the students’ attitudes towards COVID-19 vaccination and vaccine uptake. More specifically, our findings suggest the mother’s vaccine uptake as the most salient predictor of students’ attitudes towards COVID-19 vaccination and vaccine uptake, particularly when the students disclose having a positive relationship with their parents. In cases where students’ experience negative relationship with their parents, the best friend’s vaccine uptake may supersede the mother’s influence. Despite these nuances, a general trend emerges from our data suggesting that vaccine uptake could be primarily guided by vertical transmission (i.e., parent to child). Our results have the potential to influence public health strategies, communication campaigns, and targeted interventions to enhance vaccination uptake. Identifying key social predictors can enable policymakers and health authorities to tailor vaccination promotion efforts towards mothers’ and peers’ vaccine uptake to increase overall positive attitudes and vaccine uptake among young people.
Neurodevelopmental defects in Dravet syndromeScn1a+/-mice: targeting GABA-switch rescues behavioral dysfunctions but not seizures and mortality
Authors: Pizzamiglio Lara , Capitano Fabrizio , Rusina Evgeniia , Fossati Giuliana , Menna Elisabetta , Léna Isabelle , Antonucci Flavia , Mantegazza Massimo
Published: March 2024

Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) caused by mutations of theSCN1Agene (NaV1.1 sodium channel) and characterized by seizures, motor disabilities and cognitive/behavioral deficits, including autistic traits. The relative role of seizures and neurodevelopmental defects in disease progression, as well as the role of the mutation in inducing early neurodevelopmental defects before symptoms’ onset, are not clear yet. A delayed switch of GABAergic transmission from excitatory to inhibitory (GABA-switch) was reported in models of DS, but its effects on the phenotype have not been investigated.

Using a multi-scale approach, here we show that targeting GABA-switch with the drugs KU55933 (KU) or bumetanide (which upregulate KCC2 or inhibits NKCC1 chloride transporters, respectively) rescues social interaction deficits and reduces hyperactivity observed in P21Scn1a+/-DS mouse model. Bumetanide also improves spatial working memory defects. Importantly, neither KU nor bumetanide have effect on seizures or mortality rate. Also, we disclose early behavioral defects and delayed neurodevelopmental milestones well before seizure onset, at the beginning of NaV1.1 expression.

We thus reveal that neurodevelopmental components in DS, in particular GABA switch, selectively underlie some cognitive/behavioral defects, but not seizures. Our work provides further evidence that seizures and neuropsychiatric dysfunctions in DEEs can be uncoupled and can have differential pathological mechanisms. They could be treated separately with targeted pharmacological strategies.
Vitrification by high pressure freezing of a wide variety of sample using the HPM Live µ
Authors: Kodera Chie , Bret Yann , Eyraud Frederic , Heiligenstein Jérôme , Belle Martin , Heiligenstein Xavier
Published: March 2024

This study explores the efficacy and reliability of high-pressure freezing (HPF) as a sample preparation technique for electron microscopy (EM) analysis across a diverse range of biological samples. Utilizing the HPM Live µ technology, based on the historical hydraulic HPM010 from BalTec, we demonstrate the reliability of our industrial equipment to achieve the critical parameters necessary for vitrification. By directly measuring physical values within the HPF chamber, we ensure the proper functioning of the equipment, contributing to the technique’s reliability. A meticulous approach was adopted for each sample type, acknowledging the uniqueness of each specimen, and associating final sample analysis with its HPF curve, aiding in protocol optimization. Samples including human cell pellets, cell monolayer, mouse brain and liver biopsies,C. elegans, zebrafish, andA. thalianaroot and seedlings were processed for EM analysis following HPF. The ultrastructure of each sample type was rigorously examined, revealing homogeneous preservation and minimal ice nucleation artifacts. Challenges such as plant leaf vitrification were addressed, highlighting the importance of methodological adaptation. Overall, our findings underscore the robustness and versatility of our HPM Live µ in preserving biological ultrastructure, offering valuable insights for researchers employing EM techniques in diverse biological studies.
The role of olivary phase-locking oscillations in cerebellar sensorimotor adaptation
Authors: Luque Niceto R. , Carrillo Richard R. , Naveros Francisco , Ros Eduardo , Arleo Angelo
Published: March 2024

Abstract

The function of the olivary nucleus is key to cerebellar adaptation as it modulates long term synaptic plasticity between parallel fibres and Purkinje cells. Here, we posit that the neural dynamics of the inferior olive (IO) network, and in particular the phase of subthreshold oscillations with respect to afferent excitatory inputs, plays a role in cerebellar sensorimotor adaptation. To test this hypothesis, we first modelled a network of 200 multi-compartment Hodgkin-Huxley IO cells, electrically coupled via anisotropic gap junctions. The model IO neural dynamics captured the properties of real olivary activity in terms of subthreshold oscillations and spike burst responses to dendritic input currents. Then, we integrated the IO network into a large-scale olivo-cerebellar model to study vestibular ocular reflex (VOR) adaptation. VOR produces eye movements contralateral to head motion to stabilise the image on the retina. Hence, studying cerebellar-dependent VOR adaptation provided insights into the functional interplay between olivary subthreshold oscillations and responses to retinal slips (i.e., image movements triggering optokinetic adaptation). Our results showed that the phase-locking of IO subthreshold oscillations to retina slip signals is a necessary condition for cerebellar VOR learning. We also found that phase-locking makes the transmission of IO spike bursts to Purkinje cells more informative with respect to the variable amplitude of retina slip errors. Finally, our results showed that the joint action of IO phase-locking and cerebellar nuclei GABAergic modulation of IO cells’ electrical coupling is crucial to increase the state variability of the IO network, which significantly improves cerebellar adaptation.

Author summary

This study aims to elucidate the dual functionality of the inferior olive (IO) in cerebellar motor control, reconciling hypotheses regarding its role as either a timing or instructive signal. Specifically, we explore the role of subthreshold oscillations (STOs) within the IO, investigating their potential influence on the climbing fibres-to-Purkinje cell spike pattern responses and subsequent cerebellar adaptation, notably during the vestibulo ocular reflex. Aiming these objectives, we constructed a detailed olivary network model within a cerebellar neural network, enabling a mechanistic analysis of the functional relevance of STOs in spike burst generation, propagation, and modulation within target Purkinje cells. Our findings reveal the intricate nature of complex spike bursts triggered by climbing fibres—IO axons—into Purkinje cell dendrites, demonstrating a hybrid nature involving binary clock-like signals and graded spikelet components acting as an instructive signal.
Human immunodeficiency virus-1 induces host genomic R-loop and preferentially integrates its genome near the R-loop regions
Authors: Park Kiwon , Lee Dohoon , Jeong Jiseok , Lee Sungwon , Kim Sun , Ahn Kwangseog
Published: March 2024

Although HIV-1 integration sites favor active transcription units in the human genome, high-resolution analysis of individual HIV-1 integration sites has shown that the virus can integrate into a variety of host genomic locations, including non-genic regions. The invisible infection by HIV-1 integrating into non-genic regions, challenging the traditional understanding of HIV-1 integration site selection, is more problematic because they are selected for preservation in the host genome during prolonged antiretroviral therapies. Here, we showed that HIV-1 integrates its viral genome into the vicinity of R-loops, a genomic structure composed of DNA– RNA hybrids. VSV-G-pseudotyped HIV-1 infection initiates the formation of R-loops in both genic and non-genic regions of the host genome and preferentially integrates into R-loop-rich regions. Using a HeLa cell model that can independently control transcriptional activity and R-loop formation, we demonstrated that the exogenous formation of R-loops directs HIV-1 integration-targeting sites. We also found that HIV-1 integrase proteins physically bind to the host genomic R-loops. These findings provide novel insights into the mechanisms underlying retroviral integration and the new strategies for antiretroviral therapy against HIV-1 latent infection.
Ectopic DNA integration and marker-free CRISPR/Cas9 strategies for the halotolerant black yeastHortaea werneckii
Authors: Hernandez-Rodriguez Yainitza , Bullard A. Makenzie , Busch Rebecca J. , Marshall Aidan , Vargas-Muñiz José M.
Published: March 2024

Hortaea werneckiiis a halotolerant black yeast commonly found in hypersaline environments. This yeast is also the causative agent of tinea nigra, a superficial mycosis of the palm of the hand and soles of the feet of humans. In addition to their remarkable halotolerance, this black yeast exhibits an unconventional cell division cycle, alternating between fission and budding cell division. Cell density and the salt concentration in their environment regulate which cell division cycleH. werneckiiuses. AlthoughH. werneckiihave been extensively studied due to their unique physiology and cell biology, deciphering the underlying mechanisms behind these remarkable phenotypes has been limited due to the lack of genetic tools available. Here, we report a new ectopic integration protocol forH. werneckiiusing PEG-CaCl2mediated protoplast transformation. This approach relies on a drug (hygromycin B) resistance gene to select for successful integration of the genetic construct. The same construct was used to express cytosolic green fluorescent protein. Finally, we developed a marker-free CRISPR/Cas9 protocol for targeted gene deletion using the melanin synthesis pathway as a visual reporter of successful transformation. These transformation strategies will allow testing hypotheses related toH. werneckiicell biology and physiology.

Importance

Hortaea werneckiiis a remarkable yeast capable of growing in high salt concentration, and its cell division cycle alternates between fission-like and budding. For these unique attributes,H. werneckiihas gathered interest in a research program studying extremophile fungi and cell division. Most of our understanding ofH. werneckiibiology comes from genomic analyses, usage of drugs to target a particular pathway or heterologous expression of its gene inS. cerevisiae. Nonetheless,H. werneckiihas remained genetically intractable. Here, we report on two strategies to transformH. werneckii: ectopic integration of a plasmid and gene deletion using CRISPR/Cas9. These approaches will be fundamental to expanding the experimental techniques available to studyH. werneckii, including live cell imaging of cellular processes and reverse genetic approaches.
Centriole structural integrity defects are a crucial feature of Hydrolethalus Syndrome
Authors: Curinha Ana , Huang Zhaoyu , Anglen Taylor , Strong Margaret A. , Gliech Colin R. , Jewett Cayla E. , Friskes Anoek , Holland Andrew J.
Published: March 2024

Hydrolethalus Syndrome (HLS) is a lethal, autosomal recessive ciliopathy caused by the mutation of the conserved centriole protein HYLS1. However, how HYLS1 facilitates the centriole-based templating of cilia is poorly understood. Here, we show that mice harboring the HYLS1 disease mutation die shortly after birth and exhibit developmental defects that recapitulate several manifestations of the human disease. These phenotypes arise from tissue-specific defects in cilia assembly and function caused by a loss of centriole integrity. We show that HYLS1 is recruited to the centriole by CEP120 and functions to recruit centriole inner scaffold proteins that stabilize the centriolar microtubule wall. The HLS mutation disrupts the interaction of HYLS1 with CEP120 leading to HYLS1 displacement and degeneration of the centriole distal end. We propose that tissue-specific defects in centriole integrity caused by the HYLS1 mutation prevent ciliogenesis and drive HLS phenotypes.
CD47 is Required for Mesenchymal Progenitor Proliferation and Fracture Repair
Authors: Zondervan Robert L. , Capobianco Christina A. , Jenkins Daniel C. , Reicha John D. , Fredrick Livia M. , Lam Charles , Isenberg Jeffery S. , Ahn Jaimo , Marcucio Ralph S. , Hankenson Kurt D.
Published: March 2024

CD47 is a ubiquitous and pleiotropic cell-surface receptor. Disrupting CD47 enhances injury repair in various tissues but the role of CD47 has not been studied in bone injuries. In a murine closed-fracture model, CD47-null mice showed decreased callus bone volume, bone mineral content, and tissue mineral content as assessed by microcomputed tomography 10 days post-fracture, and increased fibrous volume as determined by histology. To understand the cellular basis for this phenotype, mesenchymal progenitors (MSC) were harvested from bone marrow. CD47-null MSC showed decreased large fibroblast colony formation (CFU-F), significantly less proliferation, and fewer cells in S-phase, although osteoblast differentiation was unaffected. However, consistent with prior research, CD47-null endothelial cells showed increased proliferation relative to WT cells. Similarly, in a murine ischemic fracture model, CD47-null mice showed reduced fracture callus bone volume and bone mineral content relative to WT. Consistent with ourin vitroresults,in vivoEdU labeling showed decreased cell proliferation in the callus of CD47-null mice, while staining for CD31 and endomucin demonstrated increased endothelial cell mass. Finally, WT mice administered a CD47 morpholino, which blocks CD47 protein production, showed a callus phenotype similar to that of non-ischemic and ischemic fractures in CD47-null mice, suggesting the phenotype was not due to developmental changes in the knockout mice. Thus, inhibition of CD47 during bone healing reduces both non-ischemic and ischemic fracture healing, in part, by decreasing MSC proliferation. Furthermore, the increase in endothelial cell proliferation and early blood vessel density caused by CD47 disruption is not sufficient to overcome MSC dysfunction.
Cryo-EM structure of the tetra-phosphorylated R-domain in Ycf1 reveals key interactions for transport regulation
Authors: de Carvalho Rodolpho S. A. , Rasel Md Shamiul I. , Khandelwal Nitesh K. , Tomasiak Thomas M.
Published: March 2024

Many ATP-binding cassette (ABC) transporters are regulated by phosphorylation on long and disordered loops which present a challenge to visualize with structural methods. We have trapped an activated state of the regulatory domain (R-domain) of Yeast Cadmium Factor 1 (Ycf1) by enzymatically enriching the phosphorylated state. A 3.2 Å cryo-EM structure reveals an R-domain structure with four phosphorylated residues and a position for the entire R-domain. The structure reveals key R-domain interactions including a bridging interaction between NBD1 and NBD2 as well as an interaction with the R-insertion, another regulatory region. We systematically probe these interactions with a linker substitution strategy along the R-domain and find a close match with these interactions and survival under Ycf1-dependent growth conditions. We propose a model where four overlapping phosphorylation sites bridge several regions of Ycf1 to engage in a transport-competent state.
Quantum algorithm for the radiative-transfer equation
Authors: Igarashi Asuka , Kadowaki Tadashi , Kawabata Shiro
Published: March 2024

The radiation transfer equation is widely used for simulations, for example, heat transfer in engineering, diffuse optical tomography in healthcare, and radiation hydrodynamics in astrophysics. By combining the lattice Boltzmann method, we propose a quantum algorithm for radiative transfer. This algorithm encompasses all the essential physical processes of radiative transfer: absorption, scattering, and emission. Although a sufficient number of measurements are required to precisely estimate the quantum state, and the initial encoding of the quantum state remains a challenging problem, our quantum algorithm exponentially accelerates radiative-transfer calculations compared to classical algorithms. In order to verify the quantum algorithm, we perform quantum circuit simulation using IBM Qiskit Aer and find good agreement between our numerical result and the exact solution. The algorithm paves the way for applications, such as fault-tolerant quantum computers for plasma engineering, telecommunications, nuclear-fusion technology, healthcare, and astrophysics.

Published by the American Physical Society
2024
Fermion mass, axion dark matter, and leptogenesis in SO(10) GUT
Authors: Kaladharan Ajay , Saad Shaikh
Published: March 2024

SO(10) grand unified theory with minimum parameters in the Yukawa sector employs the Peccei-Quinn symmetry that solves the strong CP problem. Such an economical Yukawa sector is highly appealing and has been extensively studied in the literature. However, when the running of the renormalization group equations of the Yukawa couplings are considered, this scenario shows some tension with the observed fermion masses and mixing. In this work, we propose an extension of the minimal framework that utilizes lower dimensional representations and alleviates this tension by introducing only a few new parameters. The proposed model consists of a fermion in the fundamental and a scalar in the spinorial representations. While the latter is needed to implement the Peccei-Quinn symmetry successfully, the presence of both is essential in obtaining an excellent fit to the fermion mass spectrum. In our model, axions serve the role of dark matter, and the out-of-equilibrium decays of the right-handed neutrinos successfully generate the matter-antimatter symmetry of the Universe.

Published by the American Physical Society
2024