bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamics of abdominal symptoms during the start of a new therapy with Elexacaftor/Tezacaftor/Ivacaftor using the novel CFAbd-day2day questionnaire
Authors: Mainz Jochen G. , Barucha Anton , Huang Pu , Bechinger Lilith , Duckstein Franziska , Polte Louise , Sadrieh Pauline , Nährlich Lutz , Eickmeier Olaf , van Dullemen Suzanne , Eschenhagen Patience , Schwarz Carsten , Lüth Stefan , Zagoya Carlos , Graepler-Mainka Ute
Published: August 2023

Background

Elexacaftor-tezacaftor-ivacaftor (ETI) is a novel highly effective CFTR modulator combination proven to improve lung function and body weight in people with Cystic Fibrosis (pwCF) carrying a F508del mutation. Recently, we revealed significant reductions of abdominal symptoms (AS) in German, British and Irish pwCF after 24-26 weeks of ETI using the CFAbd-Score, the first PROM specifically developed and validated for pwCF following FDA guidelines. Notably, many pwCF reported marked changes in their AS during the first days of the new treatment. To capture these immediate effects, we developed the CFAbd-day2day, a CF-specific GI-diary, following FDA and COSMIN guidelines.

Aims

To prospectively capture immediate dynamics of AS using the CFAbd-day2day 14 days before and 14-28 days after ETI initiation. In addition, we aim here to provide validation steps of the novel PROM concerning sensitivity to changes.

Methods

To develop the CFAbd-day2day, focus groups (community voice=pwCF and their proxies and CF specialists from different fields) were repeatedly consulted. Before and under the new ETI therapy pwCF prospectively scored AS on a daily basis with the CFAbd-day2day.

Results

Altogether, n=45 pwCF attended in 5 CF centers prospectively completed the CFAbd-day2day before (mean±sd: −14±7 days) and after (mean±sd: 28±23 days) ETI initiation. Whereas cumulative scores significantly decreased during the 3-4-week time frame after ETI initiation, compared to the two weeks prior to therapy, many patients who revealed a relatively stable level of AS before ETI reported changes during the first days of treatment with the highly effective CFTR modulators. Items like pain and flatulence increased in up to 21% of patients during the first 14 days of therapy but they improved during days 15-27.

Conclusion

The CFAbd-day2day, specifically developed and in process of validation to prospectively capture GI symptoms in pwCF, provides new substantial insights into the dynamics of AS in pwCF receiving a new treatment with ETI. The novel tool is also helpful to prospectively monitor patients with specific GI problems. International implementation and further validation steps of the diary are ongoing.
Public awareness of and opinions on the use of mathematical transmission modelling to inform public health policy in the United Kingdom
Authors: McCabe Ruth , Donnelly Christl A.
Published: August 2023

Mathematical transmission modelling is a key component of scientific evidence used to inform public health policy and became particularly prominent during the COVID-19 pandemic. As key stakeholders, it is vital that the public perception of this set of tools is better understood. To complement a previously published article on the science-policy interface by the authors of this study, novel data were collected via responses to a survey via two methods: via an online panel (“representative” sample) and via social media (“non-probability” sample). Many identical questions were asked separately for the period “prior to” compared to “during” the COVID-19 pandemic.

All respondents were increasingly aware of the use of modelling in informing policy during the pandemic, with significantly higher levels of awareness among social media respondents than online panel respondents. Awareness generally stemmed from the news media and social media during the pandemic. Transmission modelling informing public health policy was perceived as more reliable during the pandemic compared to the pre-pandemic period in both samples, with awareness being positively associated with reliability within both samples and time points, except for social media during the pandemic. Trust in government public health advice remained high across samples and time periods overall but was lower in the period of the pandemic compared to the pre-pandemic period. The decay in trust was notably greater among social media respondents. Many respondents from both samples explicitly made the distinction that their trust was reserved for “scientists” and not “politicians”. Almost all respondents, regardless of sample, believed governments have responsibility for the communication of modelling to the public.

These results provide an important reminder of the potentially skewed conclusions that could be drawn from non-representative samples.
Electric field based dosing for TMS
Authors: Numssen Ole , Kuhnke Philipp , Weise Konstantin , Hartwigsen Gesa
Published: August 2023

Transcranial magnetic stimulation (TMS) is an invaluable non-invasive brain stimulation (NIBS) technique to modulate cortical activity and behavior, but high within- and between-participant variability limits its efficacy and reliability. Here, we explore the potential of electric field (e-field) based TMS dosing to reduce its variability and discuss current challenges as well as future pathways. In contrast to previous dosing approaches, e-field dosing better matches the stimulation strength across cortical areas, both within and across individuals. Challenges include methodological uncertainties of the e-field simulation, target definitions, and comparability of different stimulation thresholds across cortical areas and NIBS protocols. Despite these challenges, e-field dosing promises to substantially improve NIBS applications in neuroscientific research and personalized medicine.

Outstanding Questions Box

Outstanding Questions

Does the cortical threshold for effective stimulation differ between primary regions and higher-level association areas? How large is the impact of cytoarchitectonic differences between regions on a stimulation threshold?

Do cortical stimulation thresholds differ across individuals? Are thresholds stable within an individual across the lifespan? What are the physiological factors influencing these thresholds?

Can a cortical stimulation threshold measured with single-pulse TMS be transferred to repetitive TMS protocols for the study of cognition?

How does the cortical stimulation threshold interact with the current brain state?

Graphical abstract
Machine Learning Gene Signature to Metastatic ccRCC based on ceRNA Network
Authors: Farias Epitácio , Terrematte Patrick , Stransky Beatriz
Published: August 2023

Renal carcinoma is a pathology of silent and multifactorial development characterized by a high rate of metastases in patients. After several studies have elucidated the activity of coding genes in the metastatic progression of renal carcinoma, new studies seek to evaluate the association of non-coding genes, such as competitive endogenous RNA (ceRNA). Thus, this study aims to build a gene signature for clear cell renal cell carcinoma (ccRCC) associated with metastatic development from a ceRNA network and to analyze the probable biological functions performed by the participants of the signature. Using ccRCC data from The Cancer Genome Atlas (TCGA), we constructed the ceRNA network with the differentially expressed genes, assembled nine gene signatures from eight feature selection techniques, and analyzed the evaluation metrics of the classification models in the benchmarking process. With the signature, we performed somatic and copy number alteration analysis, survival and metastatic progression risk analysis, and functional annotation analysis. In this study, we present an 11-gene signature (SNHG15, AF117829.1, hsa-miR-130a-3p, hsa-mir-381-3p, BTBD11, INSR, HECW2, RFLNB, PTTG1, HMMR, RASD1). Validation using the external dataset of the International Cancer Genome Consortium (ICGC-RECA) made it possible to assess the generalization of the signature, which showed an Area Under Curve of 81.5%. The genomic analysis identified the signature participants on chromosomes with highly mutated regions (G-index > 2). The hsa-miR-130a-3p, AF117829.1, hsa-miR-381-3p, and PTTG1 had a significant relationship between expression and patient survival, and the first two had a significant association with metastatic development. In addition, functional annotation resulted in relevant pathways for tumor development, such as PI3K/AKT, TNF, FoxO, RNA polymerase two transcription regulation, and cell control. Finally, by analyzing the connections of the signature genes within the ceRNA network in conjunction with studies in the literature, it was possible to obtain an overview of their activities within the ccRCC. Therefore, this gene signature identified new coding and non-coding genes and could act as potential biomarkers for a better understanding of renal carcinoma and in the development of future treatments in the clinical area.
Generating an organ-deficient animal model using a multi-targeted CRISPR-Cas9 system
Authors: Lim Jonathan Jun-Yong , Yuri Shunsuke , Kawai Taro , Isotani Ayako
Published: August 2023

Gene-knockout animal models with organ-deficient phenotypes used for blastocyst complementation are generally not viable. Animals need to be maintained as heterozygous mutants, and homozygous mutant embryos yield only one-fourth of all embryos. In this study, we generated organ-deficient embryos using the CRISPR-Cas9-sgRNAmssystem that induces cell death with a single-guide RNA (sgRNAms) targeting multiple sites in the genome. The Cas9-sgRNAmssystem interrupted cell proliferation and induced cell ablationin vitro. The mouse model had Cas9 driven by theFoxn1promoter with a ubiquitous expression cassette of sgRNAmsat theRosa26locus (Foxn1Cas9;Rosa26_ms). It showed an athymic phenotype similar to that of nude mice but was not hairless. Eventually, a rat cell-derived thymus in an interspecific chimera was generated by blastocyst complementation ofFoxn1Cas9;Rosa26_msmouse embryos with rat embryonic stem cells. Theoretically, half of the total embryos have the Cas9-sgRNAmssystem because Rosa26_ms could be maintained as homozygous.
Health inequalities in SARS-CoV-2 infection during the second wave in England: REACT-1 study
Authors: Wang Haowei , Ainslie Kylie E. C. , Walters Caroline E. , Eales Oliver , Haw David , Atchison Christina , Fronterre Claudio , Diggle Peter J. , Ashby Deborah , Cooke Graham , Barclay Wendy , Ward Helen , Darzi Ara , Donnelly Christl A. , Riley Steven , Elliott Paul
Published: August 2023

Background

The rapid spread of SARS-CoV-2 infection caused high levels of hospitalisation and deaths in late 2020 and early 2021 during the second wave in England. Severe disease during this period was associated with marked health inequalities across ethnic and sociodemographic subgroups.

Methods

We analysed risk factors for test-positivity for SARS-CoV-2, based on self-administered throat and nose swabs in the community during rounds 5 to 10 of the REal-time Assessment of Community Transmission-1 (REACT-1) study between 18 September 2020 and 30 March 2021.

Results

Compared to white ethnicity, people of Asian and black ethnicity had a higher risk of infection during rounds 5 to 10, with odds of 1.46 (1.27, 1.69) and 1.35 (1.11, 1.64) respectively. Among ethnic subgroups, the highest and the second-highest odds were found in Bangladeshi and Pakistan participants at 3.29 (2.23, 4.86) and 2.15 (1.73, 2.68) respectively when compared to British whites. People in larger (compared to smaller) households had higher odds of infection. Health care workers with direct patient contact and care home workers showed higher odds of infection compared to other essential/key workers. Additionally, the odds of infection among participants in public-facing activities or settings were greater than among those not working in those activities or settings.

Interpretation

Planning for future severe waves of respiratory pathogens should include policies to reduce inequality in risk of infection by ethnicity, household size, and occupational activity.
Divergent enlarged perivascular spaces volumes in early versus late age-of-onset Alzheimer’s disease
Authors: Younes Kyan , Cobbigo Yann , Tsuie Tori , Wang Earnest , Wolf Amy , Joie Renaud La , Soleimani-Meigooni David N , Asken Breton , Tosun Duygu , Kramer Joel H , Ferguson Adam R , Miller Bruce L , Mormino Elizabeth C , Schwartz Daniel , Silbert Lisa C , Rabinovici Gil , Rosen Howard J , Elahi Fanny M
Published: August 2023

STRUCTURED ABSTRACT

INTRODUCTION

Enlarged perivascular spaces (EPVS) are considered a conduit for the brain’s waste clearance system. With aging, the brain’s ability to clear molecules is thought to decline, contributing to the retention of Alzheimer’s disease (AD) neuropathology. However, the role of EPVS in late-onset AD (LOAD) is complicated by co-morbidities. Early-onset AD (EOAD) offers a unique opportunity to understand the role of EPVS in AD.

METHODS

Automatically-segmented EPVS volumes in biomarker-confirmed EOAD (n=58), LOAD (n=43), and age-matched controls (n=60) were correlated with amyloid and tau PET and cognition. Linear regression models were used.

RESULTS

In LOAD, higher EPVS volumes were associated with better memory and functional performance. However, this association was not observed in EOAD. Additionally, higher tau was linked to increased EPVS in LOAD, but not in EOAD.

DISCUSSION

EOAD and LOAD demonstrate distinct associations between EPVS, AD hallmarks, and cognition, suggesting differences in EPVS’s role in these AD subtypes, necessitating further investigation.
How do plant RNA viruses overcome the negative effect of Muller’s ratchet despite strong transmission bottlenecks?
Authors: Lafforgue Guillaume , Lefebvre Marie , Michon Thierry , Elena Santiago F.
Published: August 2023

Muller’s ratchet refers to the irreversible accumulation of deleterious mutations in small populations, resulting in a decline in overall fitness. This phenomenon has been extensively observed in experiments involving microorganisms, including bacteriophages and yeast. While the impact of Muller’s ratchet on viruses has been largely studied in bacteriophages and animal RNA viruses, its effects on plant RNA viruses remain poorly documented. Plant RNA viruses give rise to large and diverse populations that undergo significant bottlenecks during the colonization of distant tissues or through vector-mediated horizontal transmission. In this study, we aim to investigate the role of bottleneck size, the maximum population size between consecutive bottlenecks, and the generation of genetic diversity in countering the effects of Muller’s ratchet. We observed three distinct evolutionary outcomes for tobacco etch virus under three different demographic conditions: (i) a decline in fitness following periodic severe bottlenecks inChenopodium quinoa, (ii) a consistent fitness level with moderate bottlenecks inC. quinoa, and (iii) a net increase in fitness when severe bottlenecks inC. quinoawere alternated with large population expansions inNicotiana tabacum. By fitting empirical data to anin silicosimulation model, we found that initiating a lesion inC. quinoarequired only 1-5 virions, and approximately 40 new virions were produced per lesion. These findings demonstrate that Muller’s ratchet can be halted not only by increasing the number of founder viruses but also by incorporating phases of exponential growth to large populations between bottlenecks. Such population expansions generate genetic diversity, serving as a buffer against, and potentially even leveraging, the effects of genetic drift.
The Human Microglia Atlas (HuMicA) Unravels Changes in Homeostatic and Disease-Associated Microglia Subsets across Neurodegenerative Conditions
Authors: Martins-Ferreira Ricardo , Calafell-Segura Josep , Leal Bárbara , Rodríguez-Ubreva Javier , Mereu Elisabetta , Pinho e Costa Paulo , Ballestar Esteban
Published: August 2023

Dysregulated microglia activation, leading to neuroinflammation, is crucial in neurodegenerative disease development and progression. The initial M1/M2 dual activation classification for microglia is outdated. Even the ‘disease-associated microglia’ (DAM) phenotype, firstly described in mice, falls short in representing the diverse microglia phenotypes in pathology. In this study, we have constructed a transcriptomic atlas of human brain immune cells by integrating single-nucleus (sn)RNA-seq datasets from multiple neurodegenerative conditions. Sixteen datasets were included, comprising 295 samples from patients with Alzheimer’s disease, autism spectrum disorder, epilepsy, multiple sclerosis, Lewy body diseases, COVID-19, and healthy controls. The integratedHuman Microglia Atlas(HuMicA) dataset included 60,557 nuclei and revealed 11 microglial subpopulations distributed across all pathological and healthy conditions. Among these, we identified four different homeostatic clusters as well as pathological phenotypes. These included two stages of early and late activation of the DAM phenotype and the disease-inflammatory macrophage (DIM) phenotype, which was recently described in mice, and is also present in human microglia, as indicated by our analysis. The high versatility of microglia is evident through changes in subset distribution across various pathologies, suggesting their contribution in shaping pathological phenotypes. Our analysis showed overall depletion of four substates of homeostatic microglia, and expansion of niche subpopulations within the DAM and DIM spectrum across distinct neurodegenerative pathologies. TheHuMicAis invaluable in advancing the study of microglia biology in both healthy and disease settings.
The role of cognition and movement of seed-dispersing animals in shaping plant distributions
Authors: Robira Benjamin
Published: August 2023

In the scenarios concerning the emergence and selection of spatiotemporal cognitive abilities in vagile plant-eating animals, there is always an implicit assumption: the distribution of plants does not change and ultimately shapes the cognitive abilities of the animals, hence their movement. Yet, if plant distribution patterns are likely to remain unchanged over short time periods, they may change over long time periods as a result of animal exploitation. In particular, animal movement can shape the environment by dispersing plant seeds. Using an agent-based model simulating the foraging behaviour of a seed disperser endowed with spatiotemporal knowledge of resource distribution, I investigated whether resource spatiotemporal patterns could be influenced by the level of cognition involved in foraging. This level of cognition represented how well resource location and phenology were predicted by the agent. I showed that seed dispersers could shape the long-term distribution of resources by materialising the routes repeatedly used by the agent with the newly recruited plants. This stemmed from the conjunction of two forces: competition for space between plants and a seed-dispersing agent moving from plant to plant based on spatiotemporal memory. In turn, resource landscape modifications affected the benefits of spatiotemporal memory. This could create eco-evolutionary feedback loops between animal spatiotemporal cognition and the distribution patterns of plant resources. Altogether, the results emphasise that foraging cognition is a cause and a consequence of resource heterogeneity.
Transcranial electrical stimulation over premotor cortex mimics attentional modulation of visual processing
Authors: Misselhorn Jonas , Fiene Marina , Radecke Jan-Ole , Engel Andreas K. , Schneider Till R.
Published: August 2023

Attentional control over sensory processing has been linked to neural alpha oscillations and related pulsed inhibition of the human cortex. Despite the wide consensus on the functional relevance of alpha oscillations for attention, precise neural mechanisms of how alpha oscillations shape perception and how this top-down modulation is implemented in cortical networks remain unclear. Here, we tested the hypothesis that alpha oscillations in premotor cortex are causally involved in top-down regulation of visual cortex responsivity to contrast. We applied intermittent transcranial alternating current stimulation (tACS) over bilateral premotor cortex to manipulate attentional preparation in a visual discrimination task. tACS was applied at 10 Hz (alpha) and controlled with 40 Hz (gamma) and sham stimulation. Importantly, we used a novel linear mixed modeling approach for statistical control of neurosensory side-effects of the electric stimulation. We found a frequency-specific effect of alpha tACS on the slope parameter, leading to enhanced low-contrast perception and decreased perception of high-contrast stimuli. Side-effects affected both threshold and slope parameters, leading to high variability in parameter estimates. Controlling the impact of side-effects on psychometric parameters by linear mixed model analysis reduced variability and clarified the existing effect. We conclude that alpha tACS over premotor cortex mimicked a state of increased endogenous attention potentially by modulation of fronto-occipital connectivity in the alpha band. We speculate that this network modulation allowed for improved sensory readout from visual cortex which led to a decrease in psychometric slope, effectively broadening the dynamic range for contrast perception.

Significance statement

Attention is fundamental to voluntary control of perception and behavior. Yet, despite extensive scientific efforts, precise underlying neural mechanisms remain elusive. We contribute to this ongoing discussion by providing evidence for a vital role of frontal alpha oscillations in regulating the responsivity of visual cortex. By controlled neuromodulation with intermittent transcranial alternating current stimulation (tACS), we show that alpha tACS modulates psychometric properties of visual contrast perception. This study fills an important gap between work on alpha oscillations in spatial attention and studies on the psychometrics of attention. Furthermore, we pioneered an approach for the statistical control of tACS side-effects with linear mixed modeling and thereby add to the ongoing debate on outcome variability in studies using transcranial neurostimulation methods.
Distinguishing preferences of human APOBEC3A and APOBEC3B for cytosines in hairpin loops, and reflection of these preferences in APOBEC-signature cancer genome mutations
Authors: Butt Yasha , Sakhtemani Ramin , Mohamad-Ramshan Rukshana , Lawrence Michael S. , Bhagwat Ashok S.
Published: August 2023

The APOBEC3 family of enzymes convert cytosines in single-stranded DNA to uracils thereby causing mutations. These enzymes protect human cells against viruses and retrotransposons, but in many cancers they contribute to mutations that diversify the tumors and help them escape anticancer drug treatments. To understand the mechanism of mutagenesis by APOBEC3B, we expressed the complete enzyme or its catalytic carboxy-terminal domain (CTD) in repair-deficientEschericia coliand mapped the resulting uracils using uracil pull-down and sequencing technology. The uracilomes of A3B-full and A3B-CTD showed peaks in many of the same regions where APOBEC3A also created uracilation peaks. Like A3A, the two A3B enzymes also preferred to deaminate cytosines near transcription start sites and in the lagging-strand template at replication forks. In contrast to an earlier report that A3B does not favor hairpin loops over linear DNA, we found that both A3B-full and A3B-CTD showed a strong preference for cytosines in hairpin loops. The major difference between A3A and A3B was that while the former enzyme prefers 3 nt loops the best, A3B prefers loops of 4 nt over those of other lengths. Furthermore, within 5 nt loops, A3A prefers cytosine to be in the penultimate position, while A3B prefers it to be at the 3’ end of the loop. We confirmed these loop size and sequence preferences experimentally using purified A3A and A3B-CTD proteins. Reanalysis of hairpin loop mutations in human tumors using the size, sequence and position preferences of the two enzymes found that the tumors displayed mutations with intrinsic characteristics of both the enzymes with a stronger contribution from A3A.
Comparative pathogenesis of two lineages of Powassan virus reveals distinct clinical outcome, neuropathology, and inflammation
Authors: Reynolds Erin S. , Hart Charles E. , Nelson Jacob T. , Marzullo Brandon J. , Esterly Allen T. , Paine Dakota N. , Crooker Jessica , Massa Paul T. , Thangamani Saravanan
Published: August 2023

Tick-borne flaviviruses (TBFV) can cause severe neuroinvasive disease which may result in death or long-term neurological deficit in over 50% of survivors. Multiple mechanisms for invasion of the central nervous system (CNS) by flaviviruses have been proposed including axonal transport, transcytosis, endothelial infection, and Trojan horse routes. Flaviviruses may utilize different or multiple mechanisms of neuroinvasion depending on the specific virus, infection site, and host variability. In this work we have shown that infection of BALB/cJ mice with either Powassan virus lineage I (Powassan virus) or lineage II (deer tick virus) results in distinct spatial tropism of infection in the CNS which correlated with unique clinical presentation for each lineage. Comparative transcriptomics of infected brains demonstrates activation of different immune pathways and downstream host responses. Ultimately the comparative pathology and transcriptomics are congruent with different clinical signs in a murine model. These results suggest that different disease presentations would be occur in clinical cases due to the innate differences in the two lineages of Powassan virus.

Author Summary

Powassan virus causes a nationally notifiable disease which can cause severe neurological disease in humans and has no approved vaccines or therapeutics. Although two distinct lineages circulate in North America, clinical differentiation is not typically performed, and pathology has been assumed to be similar between lineages. In this work, a direct comparison of lineage I (Powassan virus) and lineage II (deer tick virus) demonstrated distinct differences in the clinical presentation, pathology of the central nervous system, and immune response in immunocompetent mice. These differences suggest that deer tick virus and Powassan virus do not utilize the same mechanisms for neuroinvasion and dissemination within the CNS. This is clinically relevant as the development of treatment plans and therapeutics need to be evaluated for these virus lineages.
Grid-like entorhinal representation of an abstract value space during prospective decision making
Authors: Nitsch Alexander , Garvert Mona M. , Bellmund Jacob L. S. , Schuck Nicolas W. , Doeller Christian F.
Published: August 2023

Everyday decisions require us to predict how valuable different choice options will be in the future. Prior studies have identified a cognitive map in the hippocampal-entorhinal system that encodes relationships between states and enables prediction of future states, but does not inherently convey value during prospective decision making. Here, we investigated whether the entorhinal cortex integrates relational information about changing values by representing an abstract value space. To this end, we combined fMRI with a prospective decision making task that required participants to track and predict changing values of two choice options in a sequence. Such a sequence formed a trajectory through an underlying two-dimensional value space. Our results show that participants successfully integrated and extrapolated changes along the two value dimensions. Participants’ choice behavior was explained by a prospective reinforcement learning model and the degree to which they updated values over time correlated with self-reported navigational abilities and preferences. Crucially, while participants traversed the abstract value space, the entorhinal cortex exhibited a grid-like representation, with the phase of the hexadirectional fMRI signal (i.e., the orientation of the estimated grid) being aligned to the most informative axis through the value space. A network of brain regions, including the ventromedial prefrontal cortex (vmPFC), tracked the prospective value difference between options and the occipital-temporal cortex represented the more valuable option. These findings suggest that the entorhinal grid system might support the prediction of future values by representing a cognitive map, which might be used to generate lower-dimensional signals of the value difference between options and their identities for choices. Thus, these findings provide novel insight for our understanding of cognitive maps as a mechanism to guide prospective decision making in humans.
A transient modified mRNA encoding Myc and Cyclin T1 induces cardiac regeneration and improves cardiac function after myocardial injury
Authors: Boikova Aleksandra , Quaife-Ryan Gregory A. , Batho Christopher A.P. , Lawrence Elsa , Robinson Harley , Ascanelli Camilla , Jennbacken Karin , Wang Qing-Dong , Hansson Kenny M. , Seaton Adam , Noci Victoria Rodriguez , Bywater Megan , Straube Jasmin , Sokolowski Kamil A. , Tse Brian W.C. , Krieg Thomas , Vujic Ana , Porrello Enzo R. , Sinha Sanjay , Hudson James E. , Wilson Catherine H.
Published: August 2023

Cardiac injury, such as myocardial infarction (MI), results in permanent loss of cardiomyocytes and in many cases heart failure. Transgenic expression of the pro-proliferative transcription factor Myc and Cyclin T1 can drive substantial adult cardiomyocyte proliferation to replace lost cardiomyocytes. Herein, we show that Myc and Cyclin T1 induced cardiomyocyte proliferation leads to myocardial repair and functional (long-term) recovery post-MI in mice. To provide a more translational approach, we developed modified mRNA (modRNA) encoding Myc-Ccnt1 as a transient and non-integrating strategy for regeneration. One dose of Myc-Ccnt1 modRNA is sufficient to transiently drives cardiomyocyte proliferation in human pluripotent stem cell-derived cardiomyocytes and a mouse MI model, where it leads to better heart function. Using single nuclei sequencing and proteomics, we show this was functionally mediated by transcriptional activation of cell-cycle regulating genes, which ultimately results in mitosis and cytokinesis of cardiomyocytes. Collectively, these findings indicate that Myc-Ccnt1 modRNA has the potential to be an effective regenerative therapeutic.
Proteome and phospholipidome interrelationship of synovial fluid-derived extracellular vesicles in equine osteoarthritis: An exploratory ‘multi-omics’ study to identify composite biomarkers
Authors: Clarke Emily J , Varela Laura , Jenkins Rosalind E , Lozano−Andrés Estefanía , Cywińska Anna , Przewozny Maciej , van Weeren P. René , van de Lest Chris H.A. , Peffers Mandy , Wauben Marca H.M.
Published: August 2023

Osteoarthritis causes progressive joint deterioration, severe morbidity, and reduced mobility in both humans and horses. Currently, osteoarthritis is diagnosed at late stages through clinical examination and radiographic imaging, hence it is challenging to address and provide timely therapeutic interventions to slow disease progression or ameliorate symptoms. Extracellular vesicles are cell–derived vesicles that play a key role in cell–to–cell communication and are potential sources for specific composite biomarker panel discovery. We here used a multi–omics strategy combining proteomics and phospholipidomics in an integral approach to identify composite biomarkers associated to purified extracellular vesicles from synovial fluid of healthy, mildly and severely osteoarthritic equine joints. Although the number of extracellular vesicles was unaffected by osteoarthritis, proteome profiling of extracellular vesicles by mass spectrometry identified 40 differentially expressed proteins (non–adjusted p<0.05) in osteoarthritic joints associated with 7 significant canonical pathways in osteoarthritis. Moreover, pathway analysis unveiled changes in disease and molecular functions during osteoarthritis development. Phospholipidome profiling by mass spectrometry showed a relative increase in sphingomyelin and a decrease in phosphatidylcholine, phosphatidylinositol, and phosphatidylserine in extracellular vesicles derived from osteoarthritic joints compared to healthy joints. Unsupervised data integration revealed positive correlations between the proteome and the phospholipidome. Comprehensive analysis showed that some phospholipids and their related proteins increased as the severity of osteoarthritis progressed, while others decreased or remained stable. Altogether our data show interrelationships between synovial fluid extracellular vesicle–associated phospholipids and proteins responding to osteoarthritis pathology and which could be explored as potential composite diagnostic biomarkers of disease.
Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase
Authors: Blomgren Linnea K. M. , Huber Melanie , Mackinnon Sabrina R. , Bürer Céline , Baslé Arnaud , Yue Wyatt W. , Froese D. Sean , McCorvie Thomas J.
Published: August 2023

5,10-methylenetetrahydrofolate reductase (MTHFR) commits folate-derived one-carbon units to generate the methyl-donor S-adenosyl-L-methionine (SAM). Eukaryotic MTHFR appends to the well-conserved catalytic domain (CD) a unique regulatory domain (RD) that confers feedback inhibition by SAM. We determined cryo-electron microscopy structures of human MTHFR bound to SAM and its demethylated product S-adenosyl-L-homocysteine (SAH). In the active state, with the RD bound to a single SAH, the CD is flexible and exposes its active site for catalysis. However, in the inhibited state the RD pocket is remodelled, exposing a second SAM-binding site that was previously occluded. Dual-SAM bound MTHFR demonstrates a substantially rearranged inter-domain linker that reorients the CD, inserts a loop into the active site, positions Tyr404 to bind the cofactor FAD, and blocks substrate access. Our data therefore explain the long-distance regulatory mechanism of MTHFR inhibition, underpinned by the transition between dual-SAM and single-SAH binding in response to cellular methylation status.
Mosquito midgut stem cell cellular defense response limitsPlasmodiumparasite infection
Authors: Barletta Ana-Beatriz F. , Smith Jamie C. , Burkart Emily , Bondarenko Simon , Sharakhov Igor , Criscione Frank , O’Brochta David , Barillas-Mury Carolina
Published: August 2023

A novel cellular response of midgut progenitors (stem cells and enteroblasts) toPlasmodium bergheiinfection was investigated inAnopheles stephensi. The presence of developing oocysts triggers proliferation of midgut progenitors that is modulated by the Jak/STAT pathway, and proportional to the number of oocysts on individual midguts. The percentage of parasites in direct contact with enteroblasts increases over time, as progenitors proliferate. Enhancing proliferation of progenitors significantly decreases oocyst numbers, while limiting proliferation increases oocyst survival. Live imaging revealed that enteroblasts interact directly with oocysts and eliminate them. Midgut progenitors sense the presence ofPlasmodiumoocysts and mount a cellular defense response that involves extensive proliferation and tissue remodeling, followed by oocysts lysis and phagocytosis of parasite remnants by enteroblasts.

One-Sentence Summary

Mosquito midgut stem cells detectPlasmodiumparasites, proliferate and enteroblasts actively eliminate oocysts.
Requirement of GrgA forChlamydiainfectious progeny production, optimal growth, and efficient plasmid maintenance
Authors: Lu Bin , Wang Yuxuan , Wurihan Wurihan , Cheng Andrew , Yeung Sydney , Fondell Joseph D. , Lai Zhao , Wan Danny , Wu Xiang , Li Wei Vivian , Fan Huizhou
Published: August 2023

Chlamydia, an obligate intracellular bacterial pathogen, has a unique developmental cycle involving the differentiation of invading elementary bodies (EBs) to noninfectious reticulate bodies (RBs), replication of RBs, and redifferentiation of RBs into progeny EBs. Progression of this cycle is regulated by three sigma factors, which direct the RNA polymerase to their respective target gene promoters. We hypothesized that theChlamydia-specific transcriptional regulator GrgA, previously shown to activate σ66 and σ28, plays an essential role in chlamydial development and growth. To test this hypothesis, we applied a novel genetic tool known as dependence on plasmid-mediated expression (DOPE) to createChlamydia trachomatiswith conditional GrgA-deficiency. We show that GrgA-deficientC. trachomatisRBs have a growth rate that is approximately half of the normal rate and fail to transition into progeny EBs. In addition, GrgA-deficientC. trachomatisfail to maintain its virulence plasmid. Results of RNA-seq analysis indicate that GrgA promotes RB growth by optimizing tRNA synthesis and expression of nutrient-acquisition genes, while it enables RB-to-EB conversion by facilitating the expression of a histone and outer membrane proteins required for EB morphogenesis. GrgA also regulates numerous other late genes required for host cell exit and subsequent EB invasion into host cells. Importantly, GrgA stimulates the expression of σ54, the third and last sigma factor, and its activator AtoC, and thereby indirectly upregulating the expression of σ54-dependent genes. In conclusion, our work demonstrates that GrgA is a master transcriptional regulator inChlamydiaand plays multiple essential roles in chlamydial pathogenicity.

IMPORTANCE

Hallmarks of the developmental cycle of the obligate intracellular pathogenic bacteriumChlamydiaare the primary differentiation of the infectious elementary body (EB) into the proliferative reticulate body (RB) and the secondary differentiation of RBs back into EBs. The mechanisms regulating these transitions remain unclear. In this report, we developed an effective novel strategy termed DOPE that allows for the knockdown of essential genes inChlamydia. We demonstrate that GrgA, aChlamydia-specific transcription factor, is essential for the secondary differentiation and optimal growth of RBs. We also show that GrgA, a chromosome-encoded regulatory protein, controls the maintenance of the chlamydial virulence plasmid. Transcriptomic analysis further indicates that GrgA functions as a critical regulator of all three sigma factors that recognize different promoter sets at developmental stages. The DOPE strategy outlined here should provide a valuable tool for future studies examining chlamydial growth, development, and pathogenicity.
Local adaptation to an altitudinal gradient: the interplay between mean phenotypic trait variation and phenotypic plasticity inMimulus laciniatus
Authors: Syrotchen Jill M. , Ferris Kathleen G.
Published: August 2023

Organisms can adapt to environmental heterogeneity through two mechanisms: (1) expression of population genetic variation or (2) phenotypic plasticity. In this study we investigated whether patterns of variation in both trait means and phenotypic plasticity along elevational and latitudinal clines in a North American endemic plant,Mimulus laciniatus, were consistent with local adaptation. We grew inbred lines ofM. laciniatusfrom across the species’ range in two common gardens varying in day length to measure mean and plastic trait expression in several traits previously shown to be involved in adaptation toM. laciniatus’srocky outcrop microhabitat: flowering time, size-related traits, and leaf shape. We examined correlations between the mean phenotype and phenotypic plasticity, and tested for a relationship between trait variation and population elevation and latitude. We did not find a strong correlation between mean and plastic trait expression at the individual genotype level suggesting that they operate under independent genetic controls. We identified multiple traits that show patterns consistent with local adaptation to elevation: critical photoperiod, flowering time, flower size, mean leaf lobing, and leaf lobing plasticity. These trends occur along multiple geographically independent altitudinal clines indicating that selection is a more likely cause of this pattern than gene flow among nearby populations with similar trait values. We also found that population variation in mean leaf lobing is associated with latitude. Our results indicate that both having more highly lobed leaves and greater leaf shape plasticity may be adaptive at high elevation withinM. laciniatus.Our data strongly suggest that traits known to be under divergent selection betweenM. laciniatusand close relativeMimulus guttatusare also under locally varying selection withinM. laciniatus.
WITHDRAWN: Alpha oscillations support the efficiency of guided visual search by inhibiting both target and distractor features in early visual cortex
Authors: Duecker Katharina , Shapiro Kimron L. , Hanslmayr Simon , Wolfe Jeremy , Pan Yali , Jensen Ole
Published: August 2023

Withdrawal Statement

The authors have withdrawn this manuscript owing to having received feedback that prompted a reconsideration of the findings in light of potential confounds associated with time-on-task effects, as highlighted by Benwell et al. (2019, NeuroImage). Subsequent in-depth analysis has led the authors to reassess the central assertions made in our original manuscript, and the main claims can no longer be supported. 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.
Presence of the ER-Golgi intermediate compartment that matures into the Golgi in yeast
Authors: Tojima Takuro , Suda Yasuyuki , Jin Natsuko , Kurokawa Kazuo , Nakano Akihiko
Published: August 2023

Cargo traffic through the Golgi apparatus is mediated by cisternal maturation, but it remains largely unclear how thecis-cisternae, the earliest Golgi sub-compartment, is generated. Here, we use high-speed, high-resolution confocal microscopy to analyze the spatiotemporal dynamics of a diverse set of proteins that reside in and around the Golgi in budding yeast. We find many mobile punctate structures that harbor yeast counterparts of mammalian endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) proteins, which we term “yeast ERGIC”. It occasionally attaches onto the ER exit sites and gradually matures into thecis-Golgi. Upon treatment with the Golgi-disrupting agent brefeldin A, the ERGIC proteins form larger aggregates corresponding to the Golgi entry core compartment in plants, whilecis- and medial-Golgi proteins are absorbed into the ER. We further analyze the dynamics of several late Golgi proteins. Together with our previous studies, we demonstrate a detailed spatiotemporal profile of the cisternal maturation process from ERGIC to Golgi and further to thetrans-Golgi network.

Tojima et al. perform spatiotemporal mapping of a variety of proteins residing in and around the Golgi apparatus in budding yeast using super-resolution live imaging microscopy. They identified the ER-Golgi intermediate compartment that matures into the Golgi.
How future innovations benefit from current innovations
Authors: Shi Yan , Zou Bo , Xin Hao
Published: August 2023

Purpose

In high-tech markets, innovation is always generative and continuous both within the iteration in a product's development process and throughout the upgrade of multi-generational products. Inspired by this practical phenomenon, this study aims to explore the mechanism of innovation generativity and continuity to explain how future innovations benefit from current innovations.

Design/methodology/approach

The study conducted qualitative research to explore innovation generativity and continuity by investigating five electronic information enterprises. The authors employed the ambidexterity perspective to explore the research question.

Findings

The authors found innovation generativity has three dimensions: inheritance, metabolism and inspection. These three dimensions and their interactions are what forms the mechanism of innovation generativity and continuity. The authors also found many paradoxes that prompt enterprises to pursue innovation generativity and continuity, and through this innovation process, enterprises are able to attain continuous innovation.

Originality/value

This study theoretically uncovers “how” to carry out innovation generativity and continuity, as well as the antecedents and the outcome. The findings contribute to research on product innovation, continuous innovation and ambidexterity, and have implications for managers who seek to improve innovation generativity and continuity.
Transitioning from industry to teaching in VET: profiles of VET teachers in Chile
Authors: Sevilla María Paola , Luengo-Aravena Daniela , Madero Cristóbal
Published: August 2023

Purpose

Situated in the Chilean context, this study investigates how Vocational Education and Training (VET) teacher profiles, based on their perceptions of prior work experience in industry, relate to their current motivation and perception of teaching in VET. By doing so, the authors seek to provide valuable evidence to inform the development of policies to attract and maintain well-qualified teachers from industry in Chile and other countries facing similar changes.

Design/methodology/approach

The authors used a descriptive cross-sectional design to collect data from 660 VET teachers using a two-scale instrument: Perception of Prior Occupation (PPO) and adapted FIT-Choice scales. By adopting a typological approach, the authors constructed profiles of VET teachers based on their perception of past industry experience. The authors then analyzed how these profiles vary regarding individual teacher characteristics, motivation and perception of teaching in VET.

Findings

The authors found a significant degree of heterogeneity among VET teachers' prior industry experiences, leading them to identify three distinct VET teacher profiles: “High Perception of Prior Occupation,” “Learning and Teaching-Oriented” and “Low Perception of Prior Occupation.” Notably, the most distinguishing characteristics across these profiles were age, VET teaching area, holding a job outside of teaching and years of prior industry experience. Furthermore, the authors found that motivation and perceptions of teaching varied significantly across these VET teacher profiles.

Originality/value

There needs to be more research on the factors that attract and retain industry workers as VET teachers in high schools. This study is among the first to address this topic in a non-European context.
Factors influencing career decision of undergraduate and postgraduate students: an Indian context
Authors: Thomas Princy , John Daniel , Thomas Lijo
Published: August 2023

Purpose

The objective of the study was to explore the factors influencing the career decisions of students doing the students' undergraduate (UG) and postgraduate (PG) programmes from urban private universities/colleges in the Indian context.

Design/methodology/approach

Career decision-making is determined by different factors and is contextual. The present study explores and identifies the prominent factors influencing career decision-making. A pool of 33 questions was developed, and these questions were initially administered to a sample of 233 students. Principal component analysis with Varimax Rotation identified salient factors. In the second study, confirmatory analysis was performed based on the opinion of 304 students.

Findings

The study shows that the student's career deciding factors include (1) career clarity, (2) career exploration, (3) career reward and recognition and (4) career initiative for professional and personal growth.

Originality/value

The study focussed on career-deciding factors for UG and PG students from urban universities/colleges in the Indian context and the findings can be used for planning career counselling interventions.