bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperthyroidism and depression: a clinical case of atypical thyrotoxicosis manifestation
Authors: Chiera Martina , Draghetti Stefano , De Ronchi Diana , Scaramelli Anna Rosa , Fabbri Chiara , Fanelli Giuseppe , Serretti Alessandro
Published: February 2023

The relationship between psychiatric symptoms and thyroid function has been well known and studied since antiquity. The common view is that clinical hypothyroidism is associated with depressive symptoms, whereas the psychiatric manifestations of hyperthyroidism are agitation, emotional lability, hyperexcitability, occasionally accompanied by angry outbursts, and euphoria. The case here reported overturns this conventional medical knowledge. A 73-year-old Italian woman experienced a severe major depressive episode with psychotic and melancholic features during laboratory thyrotoxicosis. No classical clinical signs and symptoms of thyrotoxicosis were present. Psychiatric symptoms improved together with the resolution of the hyperthyroid state. Historically, different cases of so-called ‘apathetic hyperthyroidism’ have been described. Recent neuroimaging and animal studies provided possible neurobiological explanations, showing how the excess thyroid hormones could affect brain structures involved in the regulation of mood, leading to depression. A direct link between hyperthyroidism and depression seems to be likely. This insight may be relevant in facilitating early diagnosis of thyroid disease and the planning of therapeutic strategies.
Lurasidone in first-episode psychosis with predominant depressive symptoms: a case report
Authors: Ricci Valerio , Di Salvo Gabriele , Maina Giuseppe
Published: February 2023

Lurasidone is an atypical antipsychotic approved for the treatment of schizophrenia and bipolar depression. It seems to have an antidepressant effect due to 5-HT7 as well as 5-HT2A and 5-HT1a receptor affinity. Here we present a case of a 19-year-old male patient with first-episode psychosis (FEP) and predominant depressive symptoms. Remarkable clinical and functional improvement was observed 3 months after the beginning of lurasidone treatment. The patient’s depressive symptoms disappear with a dramatic reduction of psychotic ones, with good tolerance of the drug and without adverse effects. Lurasidone seems to be a promising treatment option for FEP with predominant depressive symptoms.
The impact of lidocaine plaster prescribing reduction strategies: a comparison of two national health services in Europe
Authors: Mattsson Molly , Boland Fiona , Kirke Ciara , Flood Michelle , Wallace Emma , Walsh Mary E , Corrigan Derek , Fahey Tom , Croker Richard , Bacon Sebastian C J , Inglesby Peter , Evans David , Goldacre Ben , MacKenna Brian , Moriarty Frank
Published: February 2023

Introduction

In 2017, two distinct interventions were implemented in Ireland and England to reduce prescribing of lidocaine medicated plasters. In Ireland, restrictions on reimbursement were introduced. In England, updated guidance on items not to routinely prescribe in primary care, including lidocaine plasters, was published. This study aims to compare how the interventions impacted prescribing of lidocaine plasters in these countries.

Methods

We conducted an interrupted time series study using general practice data. For Ireland, monthly dispensing data (2015-2019) from the means-tested General Medical Services scheme was used. For England, data covered all patients. Outcomes were the rate of dispensings, quantity and costs of lidocaine plasters, and we modelled level and trend changes from the first full month of the policy/guidance change.

Findings

Ireland had higher rates of lidocaine dispensings compared to England throughout the study period; this was 15.22/1,000 population immediately pre-intervention, and there was equivalent to a 97.2% immediate reduction following the intervention. In England, the immediate pre-intervention dispensing rate was 0.36/1,000, with an immediate reduction of 0.0251/1,000 (a 5.8% decrease), followed by a small but significant decrease in the monthly trend relative to the pre-intervention trend of 0.0057 per month.

Interpretation

Among two different interventions aiming to decrease low-value lidocaine plaster prescribing, there was a substantially larger impact in Ireland of reimbursement restriction compared to issuing guidance in England. However, this is in the context of much higher baseline rates of use in Ireland compared to England.

Funding

This study was funded by the Health Research Board (SDAP-2019-023).
Coping with drug resistant tuberculosis alongside COVID-19 and other stressors in Zimbabwe: a qualitative study
Authors: Timire Collins , Kranzer Katharina , Pedrazzoli Debora , Kavenga Fungai , Kasozi Samuel , Mbiba Fredrick , Bond Virginia
Published: February 2023

Background

Households in low-resource settings are more vulnerable to events which adversely affect their livelihoods, including shocks such as the death of a family member, inflation, droughts and more recently COVID-19. Drug Resistant Tuberculosis (DR-TB) is also another shock that inflicts physical, psychological and socioeconomic burden on individuals and households. We describe experiences and coping strategies among people affected by DR-TB and their households in Zimbabwe during the COVID-19 pandemic, 2020 to 2021.

Methods

We conducted 16 in-depth interviews with adults who had just completed or were completing treatment. Interview themes included health seeking behaviour, impact of DR-TB on livelihoods and coping strategies adopted during treatment. We analysed data using thematic analyses.

Results

Health seeking from providers outside the public sector, extra-pulmonary TB and health system factors resulted in delayed DR-TB diagnosis and treatment and increased financial drain on households. DR-TB reduced productive capacity and narrowed job opportunities leading to income loss that continued even after completion of treatment. Household livelihood was further adversely affected by lockdowns due to COVID-19, outbreaks of bird flu and cattle disease. Stockouts of DR-TB medicines, common during COVID-19, exacerbated loss of productive time and transport costs as medication had to be accessed from other clinics that were further away. Reversible coping strategies included: reducing number of meals; relocating in search of caregivers and/or family support; spending savings; negotiating with school authorities to keep children in school. Some households had to adopt irreversible coping strategies such as selling productive assets and withdrawing children from school.

Conclusion

DR-TB combined with COVID-19 and other stressors pushed households into deeper poverty, and vulnerability. Multi-sectoral approaches that combine health systems, psychosocial and economic interventions are crucial to mitigate diagnostic delays and suffering, and meaningfully support people with DR-TB and their households to compensate the loss of livelihoods during and post DR-TB treatment.
Genomic perspectives of SARS CoV-2 in liver disease patients with its clinical correlation: A single centre retrospective study
Authors: Bhugra Arjun , Agarwal Reshu , Gautam Pramod , Suroliya Varun , Chhabra Ruchita , Pandey Amit , Garg Prince , Rao Pooja , Babu Rosmy , Kumar Guresh , Shastry SM , Bihari Chhagan , Sarin Shiv Kumar , Gupta Ekta
Published: February 2023

Background

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2), is a causative agent of current global pandemic of Coronavirus disease-19 (COVID-19). Due to propagated outbreak and global vaccination drive an immense immunological selection pressure has been exerted on SARS CoV-2 leading to evolution of new variants. This study was performed to compare the mutational and clinical profile of liver disease patients infected with different variants of SARS CoV-2.

Methodology

This was a single-centre, retrospective, cohort study in which clinicogenomic analysis of liver disease (LD) patients infected with SARS CoV-2 was performed. Complete demographic and clinical details were retrieved from Hospital Information System (HIS). QC-threshold passed FASTA files containing sequences from COVID-19 patients (n=174) were compared with a reference genome of SARS-CoV-2 isolate named Wuhan-Hu-1 (NCBI Reference Sequence: NC_045512.2) for mutational analysis.

Results

Out of 232 finally analysed patients 137 (59.1%) were LD-CoV (+) and 95 (40.9%) were LD-CoV(-). LD patients with comorbidities were affected more with COVID-19 (p=0.002). On comparing the outcome in the terms of mortality, LD-CoV (+) had 2.29 times (OR 2.29, CI 95%, 1.25-4.29) higher of odds of succumbing to COVID-19 (p=0.006). Multivariate regression analysis revealed, abdominal distention (p=0.05), severe COVID-19 pneumonia (p=0.046) and the change in serum bilirubin levels (p=0.005) as well as Alkaline phosphatase (ALP) levels (p=0.003) to have an association with adverse outcome in LD patients with COVID-19. In Delta (22%) and Omicron (48%) groups, Spike gene harboured maximum mutations. On comparing the mutations between LD-CoV(+/D) and LD-CoV(+/O) a total of nine genes had more mutations in LD-CoV(+/O) whereas three genes had more mutations in LD-CoV(+/D).

Conclusion

We concluded that LD patients are more susceptible to COVID-19 as compared to a healthy adult with associated adverse clinical outcomes in terms of mortality and morbidity. Therefore this special group should be given priority while devising and introducing new vaccination and vaccination policies. The infection with different variants did not result in different outcome in our group of patients.
Bcl-2 supports survival and metabolic fitness of quiescent tissue-resident ILC3
Authors: King James I. , Melo-Gonzalez Felipe , Malengier-Devlies Bert , Tachó-Piñot Roser , Magalhaes Marlene S , Hodge Suzanne H. , Ros Xavier Romero , Gentek Rebecca , Hepworth Matthew R.
Published: February 2023

Group 3 innate lymphoid cells (ILC3) are potent effector cells with critical roles in enforcing immunity, barrier integrity and tissue homeostasis along the gastrointestinal tract. ILC3 are considered to be primarily tissue-resident cells, seeding the gastrointestinal tract during embryonic stages. However, the mechanisms through which ILC3 are maintained within these tissues are poorly understood. Here, we report that ILC3 are minimally replenished from bone marrow precursors in healthy adult mice, persist in the tissue for extended periods of time in the gut, and display a quiescent phenotype. Strikingly, despite robustly producing cytokines, LTi-like ILC3 remain non-proliferative during enteric bacterial infection. Survival of LTi-like ILC3 was found to be dependent upon the balance of the metabolic activity required to drive effector function and anti-apoptotic programs. Notably, the pro-survival protein Bcl-2 was required for the survival of LTi-like ILC3 but was rendered partially dispensable if mitochondrial respiration was inhibited. Together we demonstrate LTi-like ILC3 are a quiescent-like population that persists independently of haematopoietic replenishment to survive within the tissue microenvironment.
Revealing the chassis-effect on a broad-host-range genetic switch and its concordance with interspecies bacterial physiologies
Authors: Chan Dennis Tin Chat , Baldwin Geoff S. , Bernstein Hans C.
Published: February 2023

Broad-host-range synthetic biology is an emerging frontier that aims to expand our current engineerable domain of microbial hosts for biodesign applications. As more novel species are brought to “model status”, synthetic biologists are discovering that identically engineered genetic circuits can exhibit different performances depending on the organism it operates within, an observation referred to as the “chassis-effect”. It remains a major challenge to uncover which genome encoded and physiological biological determinants will underpin chassis effects that govern the performance of engineered genetic devices. In this study, we compared model and novel bacterial hosts to ask whether phylogenomic relatedness or similarity in host physiology is a better predictor of toggle switch performance. This was accomplished using comparative framework based on multivariate statistical approaches to systematically demonstrate the chassis-effect and characterize the performance dynamics of a genetic toggle switch operating within six Gammaproteobacteria. Our results solidify the notion that genetic devices are significantly impacted by host-context. Furthermore, we formally determined that hosts exhibiting more similar metrics of growth and molecular physiology also exhibit more similar toggle switch performance, indicating that specific bacterial physiology underpins measurable chassis effects. The result of this study contributes to the field of broad-host-range synthetic biology by lending increased predictive power to the implementation of genetic devices in less-established microbial hosts.
Nanoparticle targeting of mechanically modulated glycocalyx
Authors: Kohon Afia Ibnat , Man Kun , Mathis Katelyn , Webb Jade , Yang Yong , Meckes Brian
Published: February 2023

The mechanical properties and forces in the extracellular environment surrounding alveolar epithelial cells have the potential to modulate their behavior. Particularly, breathing applies 3-dimensional cyclic stretches to the cells, while the stiffness of the interstitium changes in disease states, such as fibrosis and cancer. A platform was developed that effectively imitates the active forces in the alveolus, while allowing one to control the interstitium matrix stiffnesses to mimic fibrotic lung tumor microenvironments. Alveolar epithelial cancer cells were cultured on these platforms and changes in the glycocalyx expression were evaluated. A complex combination of stiffness and dynamic forces altered heparan sulfate and chondroitin sulfate proteoglycan expressions. Consequently, we designed liposomal nanoparticles (LNPs) modified with peptides that can target heparan sulphate and chondroitin sulfates of cell surface glycocalyx. Cellular uptake of these modified nanoparticles increased in stiffer conditions depending on the stretch state. Namely, chondroitin sulfate A targeting improved uptake efficiency in cells experiencing dynamic stretches, while cells seeded on static stiff interstitium preferentially took up heparan sulfate targeting LNPs. These results demonstrate the critical role that mechanical stiffness and stretching play in the alveolus and the importance of including these properties in nanotherapeutic design for cancer treatment.
Uncovering the hidden threat: single-organoid analysis reveals clinically relevant treatment-resistant and invasive subclones in pancreatic cancer
Authors: Compte Maxim Le , Cardenas De La Hoz Edgar , Peeters Sofía , Rodrigues Fortes Felicia , Hermans Christophe , Domen Andreas , Smits Evelien , Lardon Filip , Vandamme Timon , Lin Abraham , Vanlanduit Steve , Roeyen Geert , Van Laere Steven , Prenen Hans , Peeters Marc , Deben Christophe
Published: February 2023

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, characterized by a treatment-resistant and invasive nature. In-line with these inherent aggressive characteristics, only a subset of patients show a clinical response to the standard of care therapies, thereby highlighting the need for a more personalized treatment approach. In this study, we comprehensively unraveled the intra-patient response heterogeneity and intrinsic aggressive nature of PDAC on bulk and single-organoid resolution. We leveraged a fully characterized PDAC organoid panel (N=8) and matched our artificial intelligence-driven, live-cell organoid image analysis with retrospective clinical patient response. In-line with the clinical outcomes, we identified patient-specific sensitivities to the standard of care therapies (gemcitabine-paclitaxel and FOLFIRINOX) using a growth rate-based and normalized drug response metric. Moreover, the single-organoid analysis was able to detect resistant as well as invasive PDAC organoid clones, which was orchestrates on a patient, therapy, drug, concentration and time-specific level. Furthermore, ourin vitroorganoid analysis indicated a strong correlation with the matched patient progression-free survival (PFS) compared to the current, conventional drug response readouts. This work not only provides valuable insights on the response complexity in PDAC, but it also highlights the potential applications (extendable to other tumor types) and clinical translatability of our approach in drug discovery and the emerging era of personalized medicine.
Kinematic markers of skill in first-person shooter video games
Authors: Warburton Matthew , Campagnoli Carlo , Mon-Williams Mark , Mushtaq Faisal , Morehead J. Ryan
Published: February 2023

Video games present a unique opportunity to study motor skill. First-person shooter (FPS) games have particular utility because they require visually-guided hand movements that are similar to widely studied planar reaching tasks. However, there is a need to ensure the tasks are equivalent if FPS games are to yield their potential as a powerful scientific tool for investigating sensorimotor control. Specifically, research is needed to ensure that differences in visual feedback of a movement do not affect motor learning between the two contexts. In traditional tasks, a movement will translate a cursor across a static background, whereas FPS games use movements to pan and tilt the view of the environment. To this end, we designed an online experiment where participants used their mouse or trackpad to shoot targets in both contexts. Kinematic analysis showed player movements were nearly identical between conditions, with highly correlated spatial and temporal metrics. This similarity suggests a shared internal model based on comparing predicted and observed displacement vectors, rather than primary sensory feedback. A second experiment, modelled on FPS-style aim-trainer games, found movements exhibited classic invariant features described within the sensorimotor literature. We found that two measures of mouse control, the mean and variability in distance of the primary sub-movement, were key predictors of overall task success. More broadly, these results show that FPS games offer a novel, engaging, and compelling environment to study sensorimotor skill, providing the same precise kinematic metrics as traditional planar reaching tasks.

Significance statement

Sensorimotor control underpins human behaviour and is a predictor of education, health, and socioemotional wellbeing. First-person shooter (FPS) games hold promise for studying sensorimotor control at scale, but the visual feedback provided differs from traditional laboratory tasks. There is a need to ensure they provide measures that relate to traditional tasks. We designed an experiment where the visual contingency of movements could be varied whilst participants shot targets. Participant’s movements were similar between contexts, suggesting the use of a common internal model despite the sensory differences. A second experiment observed canonical learning patterns with practice and found two measures of mouse control strongly predicted overall performance. Our results highlight the opportunity offered by FPS games to study situated skilled behaviour.
A novel implementation of spinal fMRI demonstrates segmental organisation of functionally connected networks in the cervical spinal cord: A test-retest reliability study
Authors: Kowalczyk Olivia S. , Medina Sonia , Tsivaka Dimitra , McMahon Stephen B. , Williams Steven C. R. , Brooks Jonathan C. W. , Lythgoe David J. , Howard Matthew A.
Published: February 2023

Resting fMRI studies have identified intrinsic spinal cord activity, which forms organised motor (ventral) and sensory (dorsal) resting-state networks. However, to facilitate the use of spinal fMRI in, for example, clinical studies, it is crucial to first assess the reliability of the method, particularly given the unique anatomical, physiological, and methodological challenges associated with acquiring the data. Here we demonstrate a novel implementation for acquiring BOLD-sensitive resting-state spinal fMRI, which was used to characterise functional connectivity relationships in the cervical cord and assess their test-retest reliability in 23 young healthy volunteers. Resting-state networks were estimated in two ways: (1) by extracting the mean timeseries from anatomically constrained seed masks and estimating voxelwise connectivity maps and (2) by calculating seed-to-seed correlations between extracted mean timeseries. Seed regions corresponded to the four grey matter horns (ventral/dorsal and left/right) of C5-C8 segmental levels. Test-retest reliability was assessed using the intraclass correlation coefficient (ICC) in the following ways: for each voxel in the cervical spine; each voxel within an activated cluster; the mean signal as a summary estimate within an activated cluster; and correlation strength in the seed-to-seed analysis. Spatial overlap of clusters derived from voxelwise analysis between sessions was examined using Dice coefficients. Following voxelwise analysis, we observed distinct unilateral dorsal and ventral organisation of cervical spinal resting-state networks that was largely confined in the rostro-caudal extent to each spinal segmental level, with more sparse connections observed between segments (Bonferroni correctedp< 0.003, threshold-free cluster enhancement with 5000 permutations). Additionally, strongest correlations were observed between within-segment ipsilateral dorso-ventral connections, followed by within-segment dorso-dorsal and ventro-ventral connections. Test-retest reliability of these networks was mixed. Reliability was poor when assessed on a voxelwise level, with more promising indications of reliability when examining the average signal within clusters. Reliability of correlation strength between seeds was highly variable, with highest reliability achieved in ipsilateral dorso-ventral and dorso-dorsal/ventro-ventral connectivity. However, the spatial overlap of networks between sessions was excellent. We demonstrate that while test-retest reliability of cervical spinal resting-state networks is mixed, their spatial extent is similar across sessions, suggesting that these networks are characterised by a consistent spatial representation over time.
Smaug regulates germ plasm synthesis and primordial germ cell number in Drosophila embryos by repressing theoskarandbruno 1mRNAs
Authors: Siddiqui Najeeb U. , Karaiskakis Angelo , Goldman Aaron L. , Eagle Whitby V.I. , Smibert Craig A. , Gavis Elizabeth R. , Lipshitz Howard D.
Published: February 2023

During Drosophila oogenesis, the Oskar (OSK) RNA-binding protein (RBP) determines the amount of germ plasm that assembles at the posterior pole of the oocyte. Here we identify the mechanisms that regulate theoskmRNA in the early embryo. We show that the Smaug (SMG) RBP is transported into the germ plasm of the early embryo where it accumulates in the germ granules. SMG binds to and represses translation of theoskmRNA itself as well as thebruno 1(bru1) mRNA, which encodes an RBP that we show promotes germ plasm production. Loss of SMG or mutation of SMG’s binding sites in theoskorbru1mRNAs results in ectopic translation of these transcripts in the germ plasm and excess PGCs. SMG therefore triggers a post-transcriptional regulatory pathway that attenuates germ plasm synthesis in embryos, thus modulating the number of PGCs.
The Big (Genetic) Sort? Reassessing Migration Patterns and Their Genetic Imprint in the UK
Authors: Furuya Shiro , Liu Jihua , Sun Zhongxuan , Lu Qiongshi , Fletcher Jason M.
Published: February 2023

This study reassesses Abdel Abdellaoui et al.’s findings that genetically selective migration may lead to persistent and accumulating socioeconomic and health inequalities between “types” (rich or poor) of places in the UK. Their work categorized migrants who moved to the same “type” of place (rich-to-rich or poor-to-poor) as non-migrants. We re-investigate the question of genetically selective migration by examining migration patterns between places rather than “place-types” and find genetic selectively inwhetherpeople migrate rather thanwhere. For example, we find evidence of positive selection of people with genetic variants correlated better education moving from rich to poor places with our measure of migration that was obscured in the earlier work that used a non-standard measure of migration.
Gene conversion drives allelic dimorphism in two paralogous surface antigens of the malaria parasiteP. falciparum
Authors: Letcher Brice , Maciuca Sorina , Iqbal Zamin
Published: February 2023

While the malaria parasiteP. falciparumhas low average genome-wide diversity levels, likely due to its recent introduction from a gorilla-infecting ancestor (∼10,000-50,000 years ago), some genes display extremely high diversity levels. In particular, certain proteins expressed on the surface of human red-blood-cell-infecting merozoites (merozoite surface proteins, MSPs) possess exactly two deeply-diverged allelic forms that have not recombined. This phenomenon, called allelic dimorphism, is of considerable interest, but its origin and maintenance remains unknown.

In this study, we analysed the dimorphism in two highly-variable and paralogous MSPs, DBLMSP and DBLMSP2. Despite thousands of available Illumina WGS datasets from malaria-endemic countries, diversity in these genes has been hard to fully characterise as reads containing highly-diverged alleles fail to align to the reference genome. To solve this, we developed a pipeline leveraging genome graphs, enabling us to genotype them at high accuracy and completeness in comparison to a state-of-the-art GATK-based pipeline.

Using our newly-resolved sequences we found both genes are dimorphic in a specific protein domain (DBL), and that one of the two forms is shared across the genes. We identified clear evidence of non-allelic gene conversion between the two genes as the likely mechanism behind sharing, leading us to propose a new model for allelic dimorphism through gene conversion between diverged paralogs. This model is consistent with high diversity levels in these two genes despite the strong historicalP. falciparumtransmission bottleneck.
An interchangeable prion-like domain is required for Ty1 retrotransposition
Authors: Beckwith Sean L. , Nomberg Emily J. , Newman Abigail C. , Taylor Jeannette V. , Guerrero Ricardo C. , Garfinkel David J.
Published: February 2023

Retrotransposons and retroviruses shape genome evolution and can negatively impact genome function.Saccharomyces cerevisiaeand its close relatives harbor several families of LTR-retrotransposons, the most abundant being Ty1 in several laboratory strains. The cytosolic foci that nucleate Ty1 virus-like particle (VLP) assembly are not well-understood. These foci, termed retrosomes or T-bodies, contain Ty1 Gag and likely Gag-Pol and the Ty1 mRNA destined for reverse transcription. Here, we report a novel intrinsically disordered N-terminalprion-likedomain (PrLD) within Gag that is required for transposition. This domain contains amino-acid composition similar to known yeast prions and is sufficient to nucleate prionogenesis in an established cell-based prion reporter system. Deleting the Ty1 PrLD results in dramatic VLP assembly and retrotransposition defects but does not affect Gag protein level. Ty1 Gag chimeras in which the PrLD is replaced with other sequences, including yeast and mammalian prionogenic domains, display a range of retrotransposition phenotypes from wildtype to null. We examine these chimeras throughout the Ty1 replication cycle and find that some support retrosome formation, VLP assembly, and retrotransposition, including the yeast Sup35 prion and the mouse PrP prion. Our interchangeable Ty1 system provides a useful, genetically tractablein vivoplatform for studying PrLDs, complete with a suite of robust and sensitive assays, and host modulators developed to study Ty1 retromobility. Our work invites study into the prevalence of PrLDs in additional mobile elements.

Significance

Retrovirus-like retrotransposons help shape the genome evolution of their hosts and replicate within cytoplasmic particles. How their building blocks associate and assemble within the cell is poorly understood. Here, we report a novelprion-likedomain (PrLD) in the budding yeast retrotransposon Ty1 Gag protein that builds virus-like particles. The PrLD has similar sequence properties to prions and disordered protein domains that can drive the formation of assemblies that range from liquid to solid. We demonstrate that the Ty1 PrLD can function as a prion and that certain prion sequences can replace the PrLD and support Ty1 transposition. This interchangeable system is an effective platform to study additional disordered sequences in living cells.
Permutation-based group sequential analyses for cognitive neuroscience
Authors: Veillette John P. , Ho Letitia , Nusbaum Howard C.
Published: February 2023

Cognitive neuroscientists have been grappling with two related experimental design problems. First, the complexity of neuroimaging data (e.g. often hundreds of thousands of correlated measurements) and analysis pipelines demands bespoke, non-parametric statistical tests for valid inference, and these tests often lack an agreed-upon method for performing a priori power analyses. Thus, sample size determination for neuroimaging studies is often arbitrary or inferred from other putatively but questionably similar studies, which can result in underpowered designs – undermining the efficacy of neuroimaging research. Second, when meta-analyses estimate the sample sizes required to obtain reasonable statistical power, estimated sample sizes can be prohibitively large given the resource constraints of many labs. We propose the use of sequential analyses to partially address both of these problems. Sequential study designs – in which the data is analyzed at interim points during data collection and data collection can be stopped if the planned test statistic satisfies a stopping rule specified a priori – are common in the clinical trial literature, due to the efficiency gains they afford over fixed-sample designs. However, the corrections used to control false positive rates in existing approaches to sequential testing rely on parametric assumptions that are often violated in neuroimaging settings. We introduce a general permutation scheme that allows sequential designs to be used with arbitrary test statistics. By simulation, we show that this scheme controls the false positive rate across multiple interim analyses. Then, performing power analyses for seven evoked response effects seen in the EEG literature, we show that this sequential analysis approach can substantially outperform fixed-sample approaches (i.e. require fewer subjects, on average, to detect a true effect) when study designs are sufficiently well-powered. To facilitate the adoption of this methodology, we provide a Python package “niseq” with sequential implementations of common tests used for neuroimaging: cluster-based permutation tests, threshold-free cluster enhancement,t-max,F-max, and the network-based statistic with tutorial examples using EEG and fMRI data.
Stress Recovery Triggers Rapid Transcriptional Reprogramming and Activation of Immunity in Plants
Authors: Illouz-Eliaz Natanella , Yu Jingting , Swift Joseph , Lande Kathryn , Jow Bruce , Tuang Za Khai , Lee Travis , Yaaran Adi , Castanon Rosa Gomez , Nery Joseph R. , Nobori Tatsuya , Zait Yotam , Burdman Saul , Ecker Joseph R.
Published: February 2023

All organisms experience stress as an inevitable part of life, from single-celled microorganisms to complex multicellular beings. The ability to recover from stress is a fundamental trait that determines the overall resilience of an organism, yet stress recovery is understudied. To begin unraveling the stress recovery process we studies recovery from drought stress inArabidopsis thaliana. We performed a fine-scale time series of bulk RNA sequencing starting 15 minutes after rehydration following moderate drought. We reveal that drought recovery is a rapid process involving the activation of thousands of recovery-specific genes. To capture these rapid recovery responses in different leaf cell types, we performed single-nucleus transcriptome analysis at the onset of post-drought recovery, identifying a cell type-specific transcriptional state developing within 15 minutes of rehydration independently across cell types. Furthermore, we reveal a recovery-induced activation of the immune system that occurs independent of infection, which enhances pathogen resistancein vivoinA. thaliana, wild tomato (Solanum pennellii)and domesticated tomato (Solanum lycopersicumcv. M82). Since rehydration promotes microbial proliferation and thereby increases the risk of infection1–2, drought recovery-induced immunity may be crucial for plant survival in natural environments. These findings indicate that drought recovery coincides with a preventive defense response, unraveling the complex regulatory mechanisms that facilitate stress recovery in different plant cell types.
Games and the treatment convexity of cancer
Authors: Bayer Péter , West Jeffrey
Published: February 2023

Evolutionary game theory has been highly valuable in studying frequency-dependent selection and growth between competing cancer phenotypes. We study the connection between the type of competition as defined by properties of the game, and the convexity of the treatment response function. Convexity is predictive of differences in the tumor’s response to treatments with identical cumulative doses delivered with different variances. We rely on a classification of 2 × 2 games based on the signs of ‘dilemma strengths’, containing information about the kind of selection through the game’s equilibrium structure. With the disease starting in one game class, we map the type of effects treatment may have on the game depending on dosage and the implications of treatment convexity. Treatment response is a linear function of dose if the game is a prisoner’s dilemma, coordination, or harmony game and does not change game class, but may be convex or concave for anti-coordination games. If the game changes class, there is a rich variety in response types including convex-concave and concave-convex responses for transitions involving anti-coordination games, response discontinuity in case of a transition out of coordination games, and hysteresis in case of a transition through coordination games.
An Ensemble Metabolome-Epigenome Interaction Network Identifies Metabolite Modulators of Epigenetic Drugs
Authors: Campit Scott E. , Bhowmick Rupa , Lu Taoan , Saoji Aaditi Vivek , Jin Ran , Shay Madeline R. , Robida Aaron M. , Chandrasekaran Sriram
Published: February 2023

Metabolites such as acetyl-CoA and citrate play an important moonlighting role by influencing the levels of histone post-translational modifications (PTMs) and regulating gene expression. This cross talk between metabolism and epigenome impacts numerous biological processes including development and tumorigenesis. However, the extent of moonlighting activities of cellular metabolites in modulating the epigenome is unknown. We developed a data-driven screen to discover moonlighting metabolites by constructing a histone PTM-metabolite interaction network using global chromatin profiles, metabolomics, and epigenetic drug sensitivity data from over 600 cell lines. Our ensemble statistical learning approach uncovered metabolites that are predictive of histone PTM levels and epigenetic drug sensitivity. We experimentally validated synergistic and antagonistic interactions between histone deacetylase and demethylase inhibitors with epigenetic metabolites kynurenic acid, pantothenate, and 1-methylnicotinamide. We apply our approach to track metaboloepigenetic interactions during the epithelial-mesenchymal transition. Overall, our data-driven approach unveils a broader range of metaboloepigenetic interactions than anticipated from previous studies, with implications for reversing aberrant epigenetic alterations and enhancing epigenetic therapies through diet.
A data-fusion approach to identifying developmental dyslexia from multi-omics datasets
Authors: Carrion Jackson , Nandakumar Rohit , Shi Xiaojian , Gu Haiwei , Kim Yookyung , Raskind Wendy H. , Peter Beate , Dinu Valentin
Published: February 2023

This exploratory study tested and validated the use of data fusion and machine learning techniques to probe high-throughput omics and clinical data with a goal of exploring the etiology of developmental dyslexia. Developmental dyslexia is the leading learning disability in school aged children affecting roughly 5-10% of the US population. The complex biological and neurological phenotype of this life altering disability complicates its diagnosis. Phenome, exome, and metabolome data was collected allowing us to fully explore this system from a behavioral, cellular, and molecular point of view. This study provides a proof of concept showing that data fusion and ensemble learning techniques can outperform traditional machine learning techniques when provided small and complex multi-omics and clinical datasets. Heterogenous stacking classifiers consisting of single-omic experts/models achieved an accuracy of 86%, F1 score of 0.89, and AUC value of 0.83. Ensemble methods also provided a ranked list of important features that suggests exome single nucleotide polymorphisms found in the thalamus and cerebellum could be potential biomarkers for developmental dyslexia and heavily influenced the classification of DD within our machine learning models.
A comparative study ofin vitroair-liquid interface culture models of the human airway epithelium evaluating cellular heterogeneity and gene expression at single cell resolution
Authors: Prescott Rachel A. , Pankow Alec P. , de Vries Maren , Crosse Keaton , Patel Roosheel S. , Alu Mark , Loomis Cynthia , Torres Victor , Koralov Sergei , Ivanova Ellie , Dittmann Meike , Rosenberg Brad R.
Published: February 2023

The airway epithelium is composed of diverse cell types with specialized functions that mediate homeostasis and protect against respiratory pathogens. Human airway epithelial cultures at air-liquid interface (HAE) are a physiologically relevantin vitromodel of this heterogeneous tissue, enabling numerous studies of airway disease1–7. HAE cultures are classically derived from primary epithelial cells, the relatively limited passage capacity of which can limit experimental methods and study designs. BCi-NS1.1, a previously described and widely used basal cell line engineered to express hTERT, exhibits extended passage lifespan while retaining capacity for differentiation to HAE5. However, gene expression and innate immune function in HAE derived from BCi-NS1.1 versus primary cells have not been fully characterized. Here, combining single cell RNA-Seq (scRNA-Seq), immunohistochemistry, and functional experimentation, we confirm at high resolution that BCi-NS1.1 and primary HAE cultures are largely similar in morphology, cell type composition, and overall transcriptional patterns. While we observed cell-type specific expression differences of several interferon stimulated genes in BCi-NS1.1 HAE cultures, we did not observe significant differences in susceptibility to infection with influenza A virus andStaphylococcus aureus. Taken together, our results further support BCi-NS1.1-derived HAE cultures as a valuable tool for the study of airway infectious disease.
Repetitive Spreading Depolarization induces gene expression changes related to synaptic plasticity and neuroprotective pathways
Authors: Dell’Orco Michela , Weisend Jordan E. , Perrone-Bizzozero Nora I. , Carlson Andrew P. , Morton Russell A. , Linsenbardt David N , Shuttleworth C. William
Published: February 2023

Spreading depolarization (SD) is a slowly propagating wave of profound depolarization that sweeps through cortical tissue. While much emphasis has been placed on the damaging consequences of SD, there is uncertainty surrounding the potential activation of beneficial pathways such as cell survival and plasticity. The present study used unbiased assessments of gene expression to evaluate that compensatory and repair mechanisms could be recruited following SD, regardless of the induction method, which prior to this work had not been assessed. We also tested assumptions of appropriate controls and the spatial extent of expression changes that are important forin vivoSD models. SD clusters were induced with either KCl focal application or optogenetic stimulation in healthy mice. Cortical RNA was extracted and sequenced to identify differentially expressed genes (DEGs). SDs using both induction methods significantly upregulated 16 genes (versus sham animals) that included the cell proliferation-related genes FOS, JUN, and DUSP6, the plasticity-related genes ARC and HOMER1, and the inflammation-related genes PTGS2, EGR2, and NR4A1. The contralateral hemisphere is commonly used as control tissue for DEG studies, but its activity could be modified by near-global disruption of activity in the adjacent brain. We found 21 upregulated genes when comparing SD-involved cortex versus tissue from the contralateral hemisphere of the same animals. Interestingly, there was almost complete overlap (21/16) with the DEGs identified using sham controls. Neuronal activity also differs in SD initiation zones, where sustained global depolarization is required to initiate propagating events. We found that gene expression varied as a function of the distance from the SD initiation site, with greater expression differences observed in regions further away. Functional and pathway enrichment analyses identified axonogenesis, branching, neuritogenesis, and dendritic growth as significantly enriched in overlapping DEGs. Increased expression of SD-induced genes was also associated with predicted inhibition of pathways associated with cell death, and apoptosis. These results identify novel biological pathways that could be involved in plasticity and/or circuit modification in brain tissue impacted by SD. These results also identify novel functional targets that could be tested to determine potential roles in recovery and survival of peri-infarct tissues.
Robust backstepping control for maneuver aircraft based on event-triggered mechanism and nonlinear disturbance observer
Authors: Shen Yaohua , Chen Mou
Published: February 2023

Purpose

This study aims to achieve the post-stall pitching maneuver (PSPM) and decrease the deflection frequency of aircraft actuators controlled by the robust backstepping method based on event-triggered mechanism (ETM), nonlinear disturbance observer (NDO) and dynamic surface control (DSC) techniques.

Design/methodology/approach

To estimate unsteady aerodynamic disturbances (UADs) to suppress their adverse effects, the NDO is designed. To avoid taking the derivative of the virtual control law directly and eliminate the coupling term of the system states and dynamic surface errors in the stability analysis, an improved DSC is developed. Combined with the NDO and DSC techniques, a robust backstepping method is proposed to achieve the PSPM. Furthermore, to decrease the deflection frequency of the aircraft actuators, a state-dependent ETM is introduced.

Findings

An ETM-and-NDO-based backstepping method with an improved DSC technique is developed to achieve the PSPM and decrease the deflection frequency of aircraft actuators. And simulation results are presented to verify the effectiveness of the proposed paper.

Originality/value

Few studies have been conducted on the control of the PSPM in which the lateral and longitudinal attitude dynamics are coupled with each other considering the UADs. Moreover, the mechanism that can decrease the deflection frequency of aircraft actuators is rarely developed in existing research. This study proposes an ETM-and-NDO-based backstepping scheme to address these problems with satisfactory performance of the PSPM.
Promotion or inhibition of different incubation services? Evidence from government funding of China
Authors: Qi Xinzhou , Ning Zhong
Published: February 2023

Purpose

The purpose of this paper is to investigate the relationship between the characteristics of the incubation industry, government funding, and the intensity of funding for different services. Because the incubation industry has particular characteristics, government funding varies for different services, and its intensity varies with service.

Design/methodology/approach

Government funding is classified as incubation subsidy and incubation incentive. Besides, incubation services include property management, business mentoring as well as investment and financing. Based on this, this study examines the influence mechanism of different subsidy and incentive on incubation services by using the generalized propensity score matching method.

Findings

The empirical results show that subsidy and incentive have an inverse-U shape effect on property management service, but a linear effect on business guidance service. Furthermore, subsidy does not affect investment and financing service, but incentive that can have a significant impact.

Originality/value

The theme of government funding and incubator services plays an important role in helping entrepreneurs expand their businesses. Incubation subsidy and incentive can provide important support to help enterprises obtain more preferential loans, technical services and technical support in the incubator. Applying it to incubator services can provide better technology and entrepreneurship guidance. These services can help new entrepreneurs understand products and markets, and how to develop more successfully in the early stage. In short, incubators supported by government funds can provide important support to entrepreneurs to help them successfully realize their business plans.
Social media on the route to circular economy transition from a dialogic perspective: evidence from the agri-food industry
Authors: Esposito Benedetta , Sica Daniela , Malandrino Ornella , Supino Stefania
Published: February 2023

Purpose

This paper investigates circular economy communications and stakeholder dialogic engagement with circular economy posts published by European agri-food companies on Twitter from the spread of the COVID-19 pandemic. It explores the use of social media as a dialogic tool to activate circular economy engagement in order to involve all supply-chain actors on the route to a circular transition.

Design/methodology/approach

A coding framework based on the reclassification of the Glossary of Circular Economy, according to a 4-R paradigm (reduce, reuse, recycle and recover), was developed for the analysis. All tweets published by a sample of European agri-food companies, starting from the start of the COVID-19 pandemic until data extraction, were collected, purified and analysed.

Findings

Agri-food companies showed a higher level of engagement through social media, even if mainly focused on “recycling” and “general circular economy” issues. In general, awareness among social network users of the need to be part of the circular economy transition emerged. Moreover, the highest percentage of posts published by the companies' Twitter accounts was informative rather than interactive. In addition, starting with the COVID-19 pandemic crisis, the circular economy has arisen as a central topic of debate and a driver for the rethinking process of the agri-food business community.

Originality/value

To the best of the authors' knowledge, this research represents the first study focused on circular economy engagement through social media from the company perspective in the agri-food industry.