bluuebunny/crossref_metadata_2025 huggingface dataset:
Sleep disturbance in schizophrenia spectrum disorders: more than just a symptom?
Authors: Ferrarelli Fabio
Published: March 2023

Sleep disturbance is commonly reported in patients with schizophrenia spectrum disorder (SSD) in the clinical setting. Sleep features can be assessed subjectively, with self-report sleep questionnaires, and objectively with actigraphy and electroencephalogram recordings. Traditionally, electroencephalogram studies have focused on sleep architecture. More recently, numerous studies have investigated alterations in sleep-specific rhythms, including electroencephalogram oscillations, such as sleep spindles and slow waves, in patients with SSD compared with control subjects. Here, I briefly discuss how sleep disturbance is highly prevalent in patients with SSD and I present findings from studies demonstrating abnormalities in sleep architecture and sleep-oscillatory rhythms, with an emphasis on sleep spindles and slow-wave deficits, in these patients. This increasing body of evidence highlights the importance of sleep disturbance in SSD and points to several future research directions with related clinical implications, thus showing that sleep disturbance is more than just a symptom in these patients.
Early intravenous Beta-Blockade with esmolol in adults with isolated severe Traumatic Brain Injury (EBB-TBI): protocol for a phase 2a intervention design study
Authors: Thomas Matt , Hayes Kati , White Paul , Ramesh Aravind , Culliford Lucy , Ackland Gareth , Pickering Anthony
Published: March 2023

Traumatic brain injury is a leading cause of death and disability worldwide. Interventions that mitigate secondary brain injury have the potential to improve outcomes for patients and reduce the impact on communities and society. Increased circulating catecholamines are associated with worse outcomes and there is supportive animal data and indications in human studies of benefit from beta-blockade after severe traumatic brain injury. Here we present the protocol for a dose-finding study using esmolol in adults commenced within 24 hours of severe traumatic brain injury. Esmolol has practical advantages and theoretical benefits as a neuroprotective agent in this setting, but these must be balanced against the known risk of secondary injury from hypotension. The aim of this study is to determine a dose schedule for esmolol, using the continual reassessment method, that combines a clinically significant reduction in heart rate as a surrogate for catecholamine drive with maintenance of cerebral perfusion pressure. The maximum tolerated dosing schedule for esmolol can then be tested for patient benefit in subsequent randomised controlled trials.
A Systematic Review and Meta Synthesis Protocol for Examining the Factors behind African Nurses’ & Midwives Migration
Authors: Osei Stephanopoulos Kofi Junior , Barfi Michael Owusu , Frimpong Sandra , Bosro Dorinda Dela , Fosu Christopher Asamoah , Owusu Daniel , Amoako-Mensah Deborah Ntriwaa , Barimah Sammy Kwantwi , Agbavor Jerry Kofi Esinu , Delanyo Bertha Awo Agbesi
Published: March 2023

Background

There has been an increased rise of African nurses and midwives migrating to high income countries despite varying policies and restrictions to promote retention. The need to comprehensively understand the factors influencing the exodus is critical for policy formulation at the global, national, and facility levels.

Aim

To provide a comprehensive and a systematic review of the factors influencing African nurses and midwives’ migration to high income countries and the factors influencing such migrations.

Methods

A systematic review and meta-synthesis design guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement guidelines would be used. Databases including CINAHL, Pubmed, MEDLINE, and EbscoHost will be searched using a PICOS selection criteria framework. Two independent reviewers would be involved in data extraction and meta-synthesis. A third reviewer would provide an arbitrary judgement when disagreements persist after discussion. A meta-synthesis and thematic analysis would be utilised to identify emerging themes and reporting themes identified in the literature.

Ethics and dissemination

The study does not require ethical approval. The findings would be published in peer-review journals and presented at conferences.

PROSPERO registration number:CRD42023395013

Strengths and limitations

The study would shed a comprehensive light on factors influencing the migration of African trained nurses outside the continent. This is relevant in informing policies that promote retention.

The review is conducted following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA). The methodology is rigorous and meets the standards of the PRISMA guidelines.

Studies published in any language other than English would be excluded.

The period restriction set could also limit the number of studies found for a comprehensive review.
The impact of Short Tandem Repeats on grey matter brain imaging derived phenotypes in UK Biobank
Authors: Sproviero William , Ghose Upamanyu , Winchester Laura M , Fernandes Marco , Newby Danielle , Sproviero Daisy , Amin Najaf , Smets Bart , He Karen Y. , Khramtsova Ekaterina A. , Patel Parth , Sarver Brice A. J. , Howe Trevor , Black Mary Helen , van Duijn Cornelia , Nevado-Holgado Alejo
Published: March 2023

We performed a genome-wide association study of 143,067 highly polymorphic short tandem repeats (STRs) with MRI brain grey matter volumes (GMVs) on 10,702 UK Biobank (UKB) participants, including 8,751 in the discovery stage and 1,701 in the replication analysis. STRs’ repeat lengths were estimated from the UKB whole-genome sequencing data using Expansion Hunter software.

A total of 262 STRs reached genome-wide significance in the analyses of the autosomal and sex chromosomes’ (P= 6.9 × 10−8) in association with MRI -GMVs. Replication in a second batch extraction in the UKB and linkage disequilibrium (LD) analyses confirmed 12 associations of five STRs with hippocampal, intra-calcarine cortex, and cerebellum volumes with no evidence of single nucleotide polymorphisms (SNP) in LD detected in the surrounding DNA regions. Our study highlights the importance of STR variants involved in the genetic architecture of grey matter volumes.
Dobutamine Stress Echocardiography in Low-Gradient Aortic Stenosis
Authors: Borg Mogensen Nils Sofus , Ali Mulham , Carter-Storch Rasmus , Annabi Mohamed-Salah , Grenier-Delaney Jasmine , Møller Jacob Eifer , Øvrehus Kristian Altern , Pellikka Patricia A , Pibarot Philippe , Clavel Marie-Annick , Dahl Jordi Sanchez
Published: March 2023

Background

Dobutamine stress echocardiography (DSE) is recommended by guidelines to distinguish between true-severe and pseudo-severe aortic stenosis (AS) in patients with low-gradients and left ventricular ejection fraction (LVEF) <50%. However, DSE has mostly been tested in the setting of LVEF<35% and determination of AS severity has mostly been based on outcome data and surgeon’s evaluation. The purpose of this study was to examine the diagnostic accuracy of guideline recommendations for DSE, in patents with low-gradient severe AS with a wide range of LVEF and to examine the interaction between the diagnostic accuracy of DSE and LVEF. Furthermore, we wanted to study the safety and feasibility of DSE in patients with LVEF>50%.

Methods

Patients with aortic mean gradient <40 mmHg, AVA <1.0 cm2, and stroke volume index ≤35 mL/m2undergoing DSE and Cardiac Computer Tomography (C-CT) were identified from three prospectively collected patient cohorts, and stratified according to LVEF; LVEF <35%, LVEF 35-50% & LVEF >50%. Severe AS was defined as AVC score ≥2000 AU among men, and ≥1200 AU for women on C-CT.

Results

Two hundred twenty-one patients were included in the study. Seventy-eight (35%) presented with LVEF <35%, 67 (30%) with LVEF 35-50%, and 76 (34%) with LVEF >50%. DSE was performed without adverse symptoms or significant arrhythmias in 215 (96%) patients and stroke volume increased uniformly with no significant differences between groups (p=0.28).

Mean gradient and Vmaxduring DSE showed significantly diagnostic heterogeneity between LVEF groups, being most precise when LVEF <35% (both AUC=0.90), albeit with optimal thresholds of 30 mmHg & 377 cm/s, and a limited diagnostic yield in patients with LVEF≥35% (AUC=0.67 in LVEF 35-50% and AUC 0.65 in LVEF≥35%). Using guideline thresholds led to a sensitivity and specificity of 49%/84% for all patients with LVEF <50%.

Conclusion

While DSE is safe and leads to a uniform increase in stroke volume in patients with low gradient AS regardless of baseline LVEF, the association between DSE gradients and AS severity assessed by C-CT demonstrates important heterogeneity depending on LVEF, with highest accuracy in patients with LVEF <35%.

Clinical perspective

What is new?

Dobutamine stress echocardiography (DSE) is safe in patients with low-gradient AS with LVEF >50%, and leads to similar increase in stroke volume as in patients with LVEF <50%.

The diagnostic accuracy of DSE, compared to AVC as the reference for severe AS, depends on LVEF with highest accuracy in patients with LVEF <35%.

Suggested reference thresholds for DSE may not be the most accurate for AS severity, when compared to AVC.

What are the clinical implications?

Based on our study, we suggest that DSE should primarily be used for determining AS severity in patients with LVEF <35%.
Long non-coding RNASNHG8drives stress granule formation in tauopathies
Authors: Bhagat Reshma , Minaya Miguel A. , Renganathan Arun , Mehra Muneshwar , Marsh Jacob , Martinez Rita , Nana Alissa L. , Spina Salvatore , Seeley William W. , Grinberg Lea T. , Karch Celeste M.
Published: March 2023

Tauopathies are a heterogenous group of neurodegenerative disorders characterized by tau aggregation in the brain. In a subset of tauopathies, rare mutations in theMAPTgene, which encodes the tau protein, are sufficient to cause disease; however, the events downstream ofMAPTmutations are poorly understood. Here, we investigate the role of long non-coding RNAs (lncRNAs), transcripts >200 nucleotides with low/no coding potential that regulate transcription and translation, and their role in tauopathy. Using stem cell derived neurons from patients carrying aMAPTp.P301L, IVS10+16, or p.R406W mutation, and CRISPR-corrected isogenic controls, we identified transcriptomic changes that occur as a function of theMAPTmutant allele. We identified 15 lncRNAs that were commonly differentially expressed across the threeMAPTmutations. The commonly differentially expressed lncRNAs interact with RNA-binding proteins that regulate stress granule formation. Among these lncRNAs,SNHG8was significantly reduced in a mouse model of tauopathy and in FTLD-tau, progressive supranuclear palsy, and Alzheimer’s disease brains. We show thatSNHG8interacts with tau and stress granule-associated RNA-binding protein TIA1. Overexpression of mutant tauin vitrois sufficient to reduceSNHG8expression and induce stress granule formation. RescuingSNHG8expression leads to reduced stress granule formation and reduced TIA1 levels, suggesting that dysregulation of this non-coding RNA is a causal factor driving stress granule formation via TIA1 in tauopathies.
ORF3c is expressed in SARS-CoV-2 infected cells and suppresses immune activation by inhibiting innate sensing
Authors: Müller Martin , Herrmann Alexandra , Fujita Shigeru , Uriu Keiya , Kruth Carolin , Strange Adam , Kolberg Jan E. , Schneider Markus , Ito Jumpei , Ensser Armin ,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Sato Kei , Sauter Daniel
Published: March 2023

SARS-CoV-2 proteins are translated from subgenomic RNAs (sgRNAs). While most of these sgRNAs are monocistronic, some viral mRNAs encode more than one protein. For example, theORF3asgRNA also encodes ORF3c, an enigmatic 4l-amino acid peptide. Here, we show that ORF3c is expressed in SARS-CoV-2 infected cells and suppresses RIG-I- and MDA5-mediated immune activation and IFN-β induction. Mechanistic analyses revealed that ORF3c interacts with the signaling adaptor MAVS, induces its C-terminal cleavage and inhibits the interaction of RIG-I with MAVS. The immunosuppressive activity of ORF3c is conserved among members of the subgenus sarbecovirus, including SARS-CoV and coronaviruses isolated from bats. Notably, however, the SARS-CoV-2 delta and kappa variants harbor premature stop codons in ORF3c demonstrating that this reading frame is not essential for efficient viral replicationin vivoand likely compensated by other viral proteins. In agreement with this, disruption of ORF3c did not significantly affect SARS-CoV-2 replication in CaCo-2 or CaLu-3 cells. In summary, we here identify ORF3c as an immune evasion factor of SARS-CoV-2 that suppresses innate sensing in infected cells.
Leveraging IFNγ/CD38 regulation to unmask and target leukemia stem cells in acute myelogenous leukemia
Authors: Murtadha Mariam , Park Miso , Zhu Yinghui , Caserta Enrico , Dona Ada Alice , Singer Mahmoud , Vahed Hawa , Tasndoh Theophilus , Gonzalez Asaul , Ly Kevin , Sanchez James F , Chowdhury Arnab , Pozhitkov Alex , Ghoda Lucy , Li Ling , Zhang Bin , Krishnan Amrita , Marcucci Guido , Williams John , Pichiorri Flavia
Published: March 2023

Elimination of drug-resistant leukemia stem cells (LSCs) represents a major challenge to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), the presence of CD34 and lack of CD38 expression (CD34posCD38neg) are immunophenotypic features of both LSC-enriched AML blasts and normal hematopoietic stem cells (HSCs). We report that IFN-γ induces CD38 upregulation in LSC-enriched CD34posCD38negAML blasts, but not in CD34posCD38negHSCs. To leverage the IFN-γ mediated CD38 up-regulation in LSCs for clinical application, we created a compact, single-chain CD38-CD3-T cell engager (CD38-BIONIC) able to direct T cells against CD38posblasts. Activated CD4posand CD8posT cells not only kill AML blasts but also produce IFNγ, which leads to CD38 expression on CD34posCD38negLSC-enriched blasts. These cells then become CD38-BIONIC targets. The net result is an immune-mediated killing of both CD38negand CD38posAML blasts, which culminates in LSC depletion.

Statement of significance

This work represents a potential advancement in the treatment of AML, as it involves the release of IFN-γ by T cells to induce CD38 expression and thus sensitizing leukemia stem cells, which have been resistant to current treatment regimens, to CD38-directed T cell engagers.
Microhomology-Mediated Circular DNA Formation from Oligonucleosomal Fragments During Spermatogenesis
Authors: Hu Jun , Zhang Zhe , Xiao Sai , Cao Yalei , Chen Yinghong , Weng Jiaming , Jiang Hui , Li Wei , Chen Jia-Yu , Liu Chao
Published: March 2023

The landscape of extrachromosomal circular DNA (eccDNA) during mammalian spermatogenesis, as well as the biogenesis mechanism remains to be explored. Here, we revealed widespread eccDNA formation in human sperms and mouse spermatogenesis. We noted that germline eccDNAs are derived from oligonucleosomal DNA fragmentation in cells likely undergoing cell death, providing a potential new way for quality assessment of human sperms. Interestingly, small-sized eccDNAs are associated with euchromatin, while large-sized ones are preferentially generated from heterochromatin. By comparing sperm eccDNAs with meiotic recombination hotspots and structural variations, we found that they are barely associated withde novogermline deletions. We further developed a bioinformatics pipeline to achieve nucleotide-resolution eccDNA detection even with the presence of microhomologous sequences that interfere with precise break-point identification. Empowered by our method, we provided strong evidence to show that microhomology-mediated end joining is the major eccDNA biogenesis mechanism. Together, our results shed lights on eccDNA biogenesis mechanism in mammalian germline cells.
Elucidating Molecular Mechanisms of Protoxin-2 State-specific Binding to the Human NaV1.7 Channel
Authors: Ngo Khoa , Mateos Diego Lopez , Han Yanxiao , Rouen Kyle C. , Ahn Surl-Hee , Wulff Heike , Clancy Colleen E. , Yarov-Yarovoy Vladimir , Vorobyov Igor
Published: March 2023

Human voltage-gated sodium (hNaV) channels are responsible for initiating and propagating action potentials in excitable cells and mutations have been associated with numerous cardiac and neurological disorders. hNaV1.7 channels are expressed in peripheral neurons and are promising targets for pain therapy. The tarantula venom peptide protoxin-2 (PTx2) has high selectivity for hNaV1.7 and serves as a valuable scaffold to design novel therapeutics to treat pain. Here, we used computational modeling to study the molecular mechanisms of the state-dependent binding of PTx2 to hNaV1.7 voltage-sensing domains (VSDs). Using Rosetta structural modeling methods, we constructed atomistic models of the hNaV1.7 VSD II and IV in the activated and deactivated states with docked PTx2. We then performed microsecond-long all-atom molecular dynamics (MD) simulations of the systems in hydrated lipid bilayers. Our simulations revealed that PTx2 binds most favorably to the deactivated VSD II and activated VSD IV. These state-specific interactions are mediated primarily by PTx2’s residues R22, K26, K27, K28, and W30 with VSD as well as the surrounding membrane lipids. Our work revealed important protein-protein and protein-lipid contacts that contribute to high-affinity state-dependent toxin interaction with the channel. The workflow presented will prove useful for designing novel peptides with improved selectivity and potency for more effective and safe treatment of pain.

NaV1.7, a voltage-gated sodium channel, plays a crucial role in pain perception and is specifically targeted by PTx2, which serves as a template for designing pain therapeutics. In this study,Ngo et al.employed computational modeling to evaluate the state-dependent binding of PTx2 to NaV1.7.
Substrate stiffness facilitates improved induced pluripotent stem cell production through modulation of both early and late phases of cell reprogramming
Authors: Chowdhury Mohammad Mahfuz , Zimmerman Samuel , Leeson Hannah , Nefzger Christian Maximilian , Mar Jessica Cara , Laslett Andrew , Polo Jose Maria , Wolvetang Ernst , Cooper-White Justin John
Published: March 2023

Cell reprogramming involves time-intensive, costly processes that ultimately produce low numbers of reprogrammed cells of variable quality. By screening a range of polyacrylamide hydrogels (pAAm gels) of varying stiffness (1 kPA – 1.3 MPa) we found that a gel of medium stiffness significantly increases the overall number of reprogrammed cells by up to ten-fold with accelerated reprogramming kinetics, as compared to the standard Tissue Culture PolyStyrene (TCPS)-based protocol. We observe that though the gel improves both early and late phases of reprogramming, improvement in the late (reprogramming prone population maturation) phase is more pronounced and produces iPSCs having different characteristics and lower remnant transgene expression than those produced on TCPS. Comparative RNA-Seq analyses coupled with experimental validation reveals that modulation of Bone Morphogenic Protein (BMP) signalling by a novel reprogramming regulator, Phactr3, upregulated in the gel at an earliest time-point without the influence of transcription factors used for reprogramming, plays a crucial role in the improvement in the early reprogramming kinetics and overall reprogramming outcomes. This study provides new insights into the mechanism via which substrate stiffness modulates reprogramming kinetics and iPSC quality outcomes, opening new avenues for producing higher numbers of quality iPSCs or other reprogrammed cells at shorter timescales.
A survey and antibody test following the surge of SARS-CoV-2 Omicron infection in China
Authors: Yao Yichuan , Yang Yunru , Wu Qiqin , Liu Mengyao , Bao Wei , Wang Qiutong , Cheng Meijun , Chen Yunuo , Cai Yuan , Zhang Mei , Yao Jingxue , He Hongliang , Jin Changjiang , Xue Tian , Zheng Changcheng , Jin Tengchuan , Tong Dali
Published: March 2023

The surge of SARS-CoV-2 Omicron infection in most Chinese residents at the end of 2022 provided a unique opportunity to understand how the immune system responds to the Omicron infection in a population with limited contact to prior SARS-CoV-2 variants. Moreover, whether the prototype SARS-CoV-2 booster vaccination could help induce the antibody against Omicron variants? Here, we tested the level of IgG, IgA, and IgM specific to the prototype SARS-CoV-2 spike RBD (Receptor Binding Domain) from the collected blood samples from 636 individuals. Sequential inoculation of different vaccines showed higher IgG levels after infection. As the antibody level against Omicron BA.5, BF.7, and XBB 1.5 of the individuals has highly positive correlation with the antibody level against prototype SARS-CoV2, the IgG level specific to the prototype SARS-CoV-2 spike RBD could also represent the IgG level against Omicron variants. Furthermore, the 4thbooster vaccination could induce a comparable antibody level against prototype, Omicron BA.5, BF.7, and XBB 1.5 variants in the patients with 2 or 3-dose vaccination and protect people from being infected. In conclusion, these data suggest that the prototype SARS-CoV-2 booster vaccination helps induce a high level of antibody against prototype, BA.5, BF.7, and XBB 1.5 variants after Omicron infection.
A biologically plausible decision-making model based on interacting neural populations
Authors: Baspinar Emre , Cecchini Gloria , DePass Michael , Andujar Marta , Pani Pierpaolo , Ferraina Stefano , Moreno-Bote Rubén , Cos Ignasi , Destexhe Alain
Published: March 2023

We present a novel decision-making model with two populations. Each population is composed of Regularly Spiking (excitatory) and Fast Spiking (inhibitory) cells in cortical layer 2/3. Each population votes for one of the two visual alternatives shown on a monitor in human and macaque experiments. The model is biophysically plausible since it is based on long-range cortico-cortical connections between the layer 2/3 populations. These connections are excitatory. They contact both Regularly Spiking and Fast Spiking cells. This long-range excitation is conflicted by an inhibition based on local connections within the populations. This configuration introduces a competition between the layer 2/3 populations, sufficient for making a decision to choose between two alternatives shown on the monitor. We integrate the model with a reward-driven learning mechanism. This allows the model to learn the optimal strategy maximizing the cumulative reward in the long term. We test the model on two decision-making tasks applied on human and macaque. This model elaborates certain biophysical details which were not considered by simpler phenomenological models proposed for similar decision-making tasks. Finally, the model can be embedded in a brain simulator such as The Virtual Brain to study decision-making in terms of large-scale brain dynamics.
Single-cell RNA sequencing identifies KSHV-infected Mesenchymal stem cell subpopulations precursors of Kaposi’s Sarcoma
Authors: Lacunza Ezequiel , Ahuja Anuj , Coso Omar A. , Abba Martin , Mesri Enrique , Naipauer Julian
Published: March 2023

Kaposi’s sarcoma (KS) may derive from Kaposi’s Sarcoma Herpesvirus (KSHV)-infected human Mesenchymal Stem Cells (hMSCs) migrating into an inflammatory and angiogenic site, enhancing KS initiation. KSHV infection of primary hMSCs uncovers specific cell subpopulations, mechanisms, and conditions involved in the first steps of the KSHV-induced transformation and reprogramming process toward KS progenitor cells. The pro-angiogenic environmental conditions allowed KSHV to reprogram hMSCs closer to KS gene expression profiles and points to KSHV infection as an important factor inducing the Mesenchymal-to-Endothelial (MEndT) transition of hMSC. Single-cell RNA-sequencing analysis revealed a subpopulation of infected cells growing in a pro-angiogenic environment with both viral and host oncogenes upregulation. This highlights the importance of this condition in boosting the KSHV-induced transformation and reprogramming of hMSC towards MEndT and closer to KS gene expression profiles, reinforcing the notion of these cell subpopulations as KS precursors.
Photoreceptor genes in a trechine beetle,Trechiama kuznetsovi, living in the upper hypogean zone
Authors: Niida Takuma , Terashima Yuto , Aonuma Hitoshi , Koshikawa Shigeyuki
Published: March 2023

To address how organisms adapt to a new environment, subterranean organisms whose ancestors colonized subterranean habitats from surface habitats have been studied. Photoreception abilities have been shown to have degenerated in organisms living in caves and calcrete aquifers. Meanwhile, the organisms living in a shallow subterranean environment, which are inferred to reflect an intermediate stage in an evolutionary pathway to colonization of a deeper subterranean environment, have not been studied well. In the present study, we examined the photoreception ability in a trechine beetle,Trechiama kuznetsovi, which inhabits the upper hypogean zone and has a vestigial compound eye. Byde novoassembly of genome and transcript sequences, we were able to identify photoreceptor genes and phototransduction genes. Specifically, we focused onopsingenes, where onelong wavelength opsingene and oneultraviolet opsingene were identified. The encoded amino acid sequences had neither a premature stop codon nor a frameshift mutation, and appeared to be subject to purifying selection. Subsequently, we examined the internal structure of the compound eye and nerve tissue in the adult head, and found potential photoreceptor cells in the compound eye and nerve bundle connected to the brain. The present findings suggest thatT. kuznetsovihas retained the ability of photoreception. This species represents a transitional stage of vision, in which the compound eye regresses, but it may retains the ability of photoreception using the vestigial eye.
Mechanism of barotaxis in marine zooplankton
Authors: Calderón Luis Alberto Bezares , Shahidi Réza , Jékely Gáspár
Published: March 2023

Hydrostatic pressure is a dominant environmental cue for vertically migrating marine organisms but the physiological mechanisms of responding to pressure changes remain unclear. Here we uncovered the cellular and circuit bases of a barokinetic response in the planktonic larva of the marine annelidPlatynereis dumerilii. Increased pressure induced a rapid, graded and adapting upward swimming response due to the faster beating of cilia in the head multiciliary band. By calcium imaging, we found that brain ciliary photoreceptors showed a graded response to pressure changes. The photoreceptors in animals mutant forciliary opsin-1had a smaller sensory compartment and mutant larvae showed diminished pressure responses. The ciliary photoreceptors synaptically connect to the head multiciliary band via serotonergic motoneurons. Genetic inhibition of the serotonergic cells blocked pressure-dependent increases in ciliary beating. We conclude that ciliary photoreceptors function as pressure sensors and activate ciliary beating through serotonergic signalling during barokinesis.
Tracking the progression of Alzheimer’s disease with peripheral blood monocytes
Authors: Bavykina Viktoriia , Avino Mariano , Husain Mohammed Amir , Zimmer Adrien , Parent-Roberge Hugo , Khalil Abdelouahed , Brunet Marie A. , Fülöp Tamas , Laurent Benoit
Published: March 2023

Background

Alzheimer’s disease (AD) is the most common form of dementia with the symptoms gradually worsening over the years. However, the driving pathological processes occur well before the appearance of symptoms. AD patients display signs of systemic inflammation, suggesting that it could precede the well-established AD hallmarks. We recently showed that the innate immune response in the form of monocyte activation is detectable at the pre-clinical stage.

Objectives

Our goal here is to characterize changes of gene expression in peripheral blood monocytes from patients at different stages of AD progression and validate potential biomarkers for a better prognosis and diagnosis of AD clinical spectrum.

Results

We performed a whole transcriptome analysis on monocytes purified from healthy subjects, Mild Cognitive Impairment (MCI) and AD patients, and established the list of genes differentially expressed in monocytes during the disease evolution. We observed that, in the top 500 genes differentially expressed, a majority of these genes were upregulated (65%) during AD progression. These genes are mainly involved in chemokine/cytokine-mediated signaling pathways. We further confirmed several biomarkers by quantitative PCR and immunoblotting and showed that they are often deregulated at pre-clinical stages of the disease (MCI stage), supporting the hyperactivation of monocytes in MCI patients.

Perspectives

Our findings provide evidence that the pre-clinical stage of AD can be detected in monocytes using a specific set of biomarkers, highlighting the importance to study the early innate immune response in AD. Our results open the possibility to use these biomarkers with different diagnostic methodologies to better predict and efficiently treat AD.
Discovery of decreased ferroptosis in male colorectal cancer patients with KRAS mutations
Authors: Yan Hong , Talty Ronan , Jain Abhishek , Cai Yuping , Zheng Jie , Shen Xinyi , Muca Engjel , Paty Philip B. , Bosenberg Marcus W. , Khan Sajid A. , Johnson Caroline H.
Published: March 2023

Aberrant tumor metabolism is a hallmark of cancer in which metabolic rewiring can support tumor growth under nutrient deficient conditions. KRAS mutations occur in 35-45% of all colorectal cancer (CRC) cases and are difficult to treat. The relationship between mutant KRAS and aberrant metabolism in CRCs has not been fully explored and could be a target for intervention. We previously acquired non-targeted metabolomics data from 161 tumor tissues and 39 normal colon tissues from stage I-III chemotherapy naïve CRC patients. In this study, we revealed that tumors from male patients with KRAS mutations only, had several altered pathways that suppress ferroptosis, including glutathione biosynthesis, transsulfuration activity, and methionine metabolism. To validate this phenotype, MC38 CRC cells (KRASG13R) were treated with a ferroptosis inducer; RAS-selected lethal (RSL3). RSL3 altered metabolic pathways in the opposite direction to that seen in KRAS mutant tumors from male patients confirming a suppressed ferroptosis metabolic phenotype in these patients. We further validated gene expression data from an additional CRC patient cohort (Gene Expression Omnibus (GEO), and similarly observed differences in ferroptosis-related genes by sex and KRAS status. Further examination of the relationship between these genes and overall survival (OS) in the GEO cohort showed that KRAS mutant tumors are associated with poorer 5-year OS compared to KRAS wild type tumors, and only in male patients. Additionally, high compared to low expression ofGPX4, FTH1, FTL, which suppressed ferroptosis, were associated with poorer 5-year OS only in KRAS mutant tumors from male CRC patients. Low compared to high expression ofACSL4was associated with poorer OS for this group. Our results show that KRAS mutant tumors from male CRC patients have suppressed ferroptosis, and gene expression changes that suppress ferroptosis associate with adverse outcomes for these patients, revealing a novel potential avenue for therapeutic approaches.
Development and validation of an experimental life support system to study the impact of ultraviolet B radiation and temperature on coral reef microbial communities
Authors: Stuij T.M. , Cleary D.F.R. , Rocha R.J.M. , Polonia A.R.M. , Silva D.A.M. , Frommlet J.C. , Louvado A. , Huang Y. M. , Van der Windt N. , De Voogd N.J. , Gomes N.C.M.
Published: March 2023

In the present study, we developed and validated an experimental life support system (ELSS) designed to investigate the response of coral reef associated bacterial communities to increases in temperature and UVB intensity. The ELSS consisted of 32 independent microcosms, which enables researchers to study the individual and interactive effects of up to three factors using a full factorial experimental design. Temperature can be controlled using water-baths. UV exposure was introduced to the system using UV fluorescent lights. Individual UVB-opaque polyester films were added to the microcosms using a random design. In the validation experiment (stable temperature and no UVB), a coral reef environment was simulated using a layer of coral reef sediment, synthetic seawater, and specimens from five benthic reef species. The species used were two hard coralsMontipora digitataandMontipora capricornis, a soft coralSarcophyton glaucum, a zoanthidZoanthussp., and a spongeChondrillasp.. To validate the system, we assessed physical and chemical parameters and characterised host and free-living bacterial communities of the ELSS over 34 days and compared these data to those observed in natural reef ecosystems. Water temperature, dissolved oxygen, pH, salinity and dissolved nutrients in the ELSS were similar to those at shallow coral reef sites. Sediment bacterial diversity and composition were more similar to natural-type communities at day 29 and 34 than at day 8 after transfer to the microcosms, indicating a return to natural-type conditions following an initial, apparent perturbation phase. Transplantation significantly altered the bacterial community composition ofM. digitataandChondrillasp. and increased coral photosynthetic efficiency compared to before transplantation. These results highlight the importance ofM. digitataandChondrillasp. microbiomes to host adaptation following potential stress events.. Altogether, our results validated the suitability of the ELLS developed in this study as a model system to investigate the responses of coral reef associated bacterial communities to shifts of temperature and UVB radiation and potentially other environmental conditions (e.g., environmental pollution).
Rapid molecular phenotypic antimicrobial susceptibility test forNeisseria gonorrhoeaebased on propidium monoazide viability PCR
Authors: Tjandra Kristel C. , Ram-Mohan Nikhil , Abe Ryuichiro , Wang Tza-Huei , Yang Samuel
Published: March 2023

Neisseria gonorrhoeae(NG) is an urgent threat to antimicrobial resistance (AMR) worldwide. NG has acquired rapid resistance to all previously recommended treatments leaving ceftriaxone monotherapy as the first and last line of therapy for uncomplicated NG. The ability to rapidly determine susceptibility, which is currently nonexistent for NG, has been proposed as a strategy to preserve ceftriaxone by using alternative treatments. Herein, we used a DNA-intercalating dye in combination with NG-specific primers/probes to generate qPCR cycle threshold (Ct) values at different concentrations of 2 NG-relevant antimicrobials. Our proof of concept dual-antimicrobial logistic regression model based on the differential Ct measurements achieved an AUC of 0.93 with a categorical agreement for susceptibility of 84.6%. When surveying the performance against each antimicrobial separately, the model predicted 90% and 75% susceptible and resistant strains respectively to ceftriaxone and 66.7% and 83.3% susceptible and resistant strains respectively to ciprofloxacin. We further validated the model against the individual replicates and determined the accuracy of the model in classifying susceptibility agnostic of the inoculum size. We demonstrated a novel PCR-based approach to determine phenotypic ciprofloxacin and ceftriaxone susceptibility information for NG with reasonable accuracy in under 30 min, a significant improvement compared to the conventional method which takes 3 days.

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Repurposing host-guest chemistry to sequester virulence and eradicate biofilms in multidrug resistantPseudomonas aeruginosaandAcinetobacter baumannii
Authors: Jonkergouw Christopher , Beyeh Ngong Kodiah , Osmekhina Ekaterina , Leskinen Katarzyna , Taimoory S. Maryamdokht , Federov Dmitrii , Anaya-Plaza Eduardo , Kostiainen Mauri A. , Trant John F. , Ras Robin H. A. , Saavalainen Päivi , Linder Markus B.
Published: March 2023

The limited diversity in targets of available antibiotic therapies has put tremendous pressure on the treatment of bacterial pathogens, where numerous resistance mechanisms that counteract their function are becoming increasingly prevalent. Here, we utilize an unconventional anti-virulence screen of host-guest interacting macrocycles, and identify a water-soluble synthetic macrocycle, Pillar[5]arene, that is non-bactericidal/bacteriostatic and has a mechanism of action that involves binding to both homoserine lactones and lipopolysaccharides, key virulence factors in Gram-negative pathogens. Pillar[5]arene is active against Top Priority carbapenem- and third/fourth-generation cephalosporin-resistantPseudomonas aeruginosaandAcinetobacter baumannii, suppressing toxins and biofilms and increasing the penetration and efficacy of standard-of-care antibiotics in combined administrations. The binding of homoserine lactones and lipopolysaccharides also sequesters their direct effects as toxins on eukatryotic membranes, neutralizing key tools that promote bacterial colonization and impede immune defenses, bothin vitroandin vivo. Pillar[5]arene evades both existing antibiotic resistance mechanisms, as well as the build-up of rapid tolerance/resistance. The versatility of macrocyclic host-guest chemistry provides ample strategies for tailored targeting of virulence in a wide range of Gram-negative infectious diseases.
The epigenetic Oct4 gene regulatory network: stochastic analysis of different cellular reprogramming approaches
Authors: Bruno Simone , Del Vecchio Domitilla
Published: March 2023

In the last decade, several experimental studies have shown how chromatin modifications (histone modifications and DNA methylation) and their effect on DNA compaction have a critical effect on cellular reprogramming, i.e., the conversion of differentiated cells to a pluripotent state. In this paper, we compare three reprogramming approaches that have been considered in the literature: (a) prefixed overexpression of transcription factors (TFs) alone (Oct4), (b) prefixed overexpression of Oct4 and DNA methylation “eraser” TET, and (c) prefixed overexpression of Oct4 and H3K9me3 eraser JMJD2. To this end, we develop a model of the pluritpotency gene regulatory network, that includes, for each gene, a circuit recently published encapsulating the main interactions among chromatin modifications and their effect on gene expression. We then conduct a computational study to evaluate, for each reprogramming approach, latency and variability. Our results show a faster and less stochastic reprogramming process when also eraser enzymes are overexpressed, consistent with previous experimental data. However, TET overexpression leads to a faster and more efficient reprogramming compared to JMJD2 overexpression when the recruitment of DNA methylation by H3K9me3 is weak and the MBD protein level is sufficiently low such that it does not hamper TET binding to methylated DNA. The model developed here provides a mechanistic understanding of the outcomes of former experimental studies and is also a tool for the development of optimized reprogramming approaches that combine TF overexpression with modifiers of chromatin state.
Ambient temperature structure of phosphoketolase from Bifidobacterium longum determined by serial femtosecond X-ray crystallography
Authors: Nakata Kunio , Kashiwagi Tatsuki , Kunishima Naoki , Naitow Hisashi , Matsuura Yoshinori , Miyano Hiroshi , Mizukoshi Toshimi , Tono Kensuke , Yabashi Makina , Nango Eriko , Iwata So
Published: March 2023

Phosphoketolase and transketolase are thiamine diphosphate-dependent enzymes and play a central role in the primary metabolism of bifidobacteria: the bifid shunt. The enzymes both catalyze phosphorolytic cleavage of xylulose 5-phosphate or fructose 6-phosphate in the first reaction step, but possess different substrate specificity in the second reaction step, where phosphoketolase and transketolase utilize inorganic phosphate (Pi) and D-ribose 5-phosphate, respectively, as the acceptor substrate. Structures of Bifidobacterium longum phosphoketolase holoenzyme and its complex with a putative inhibitor, phosphoenolpyruvate, were determined at 2.5 Å resolution by serial femtosecond crystallography using an X-ray free-electron laser. In the complex structure, phosphoenolpyruvate was present at the entrance to the active-site pocket and plugged the channel to thiamine diphosphate. The phosphate-group position of phosphoenolpyruvate coincided well with those of xylulose 5-phosphate and fructose 6-phosphate in the structures of their complexes with transketolase. The most striking structural change was observed in a loop consisting of Gln546-Asp547-His548-Asn549 (the QN-loop) at the entrance to the active-site pocket. Contrary to the conformation of the QN-loop that partially covers the entrance to the active-site pocket (`closed form') in the known crystal structures, including the phosphoketolase holoenzyme and its complexes with reaction intermediates, the QN-loop in the current ambient structures showed a more compact conformation with a widened entrance to the active-site pocket (`open form'). In the phosphoketolase reaction, the `open form' QN-loop may play a role in providing the binding site for xylulose 5-phosphate or fructose 6-phosphate in the first step, and the `closed form' QN-loop may help confer specificity for Pi in the second step.
Satisfaction dimensions influencing consumers’ behavioral intentions through structural topic modeling analysis of restaurant reviews
Authors: Burkov Ivan , Gorgadze Aleksei , Trabskaia Iuliia
Published: March 2023

Purpose

This study aims to identify the impact of affective components on behavioral intentions applying electronic word of mouth (eWOM) and is based on the “cognitive–affective–conative” model. EWOM allows researchers to get new insights about consumers’ behavior and explores new patterns of consumers’ decision-making processes.

Design/methodology/approach

This study is based on the theory of planned behavior (Ajzen, 1991), doubled with “cognitive–affective–conative” model (Oliver, 2014). This study applies structural topic modeling to examine the impact of satisfaction dimensions from all the Tripadvisor reviews on consumer behavioral intentions. The research sample covers all restaurants located in St. Petersburg (n = 10,424) and all consumers’ reviews (n = 286,642).

Findings

In this study, the dimensions of the affective component were identified. The results demonstrate that dimensions of the affective component (food quality, service quality, atmosphere and cost fairness) affect behavioral intention (willingness to share positive emotions). In total, 20 topics, forming these dimensions, have been indicated. Consumers tend to pay more attention toward food quality and restaurant staffs’ work when they are willing to share positive emotions and tend to point out auxiliary service when they have less willingness to share positive emotions. Random restaurant visits tend to increase the willingness to share positive emotions.

Originality/value

Research originality lies in a new methodological approach which is based on text mining techniques. To the best of the authors’ knowledge, this study is the first attempt to examine consumer behavior through the lens of the “cognitive–affective–conative” model based on eWOM and covers all businesses in the specific economic sphere. This has allowed the researchers to reveal new dimensions of consumer behavior and brought more insights into the consumers’ decision-making process.
Can social interaction-oriented content trigger viewers' purchasing and gift-giving behaviors? Evidence from live-streaming commerce
Authors: Yang Qiang , Huo Jiale , Li Hongxiu , Xi Yue , Liu Yong
Published: March 2023

Purpose

This study investigates how social interaction-oriented content in broadcasters' live speech affects broadcast viewers' purchasing and gift-giving behaviors and how broadcaster popularity moderates social interaction-oriented content's effect on the two different behaviors in live-streaming commerce.

Design/methodology/approach

A research model was proposed and empirically tested using a panel data set collected from 537 live streams via Douyin (the Chinese version of TikTok), one of the most popular live broadcast platforms in China. A fixed-effects negative binomial regression model was used to examine the proposed research model.

Findings

This study's results show that social interaction-oriented content in broadcasters' live speech has an inverted U-shaped relationship with broadcast viewers' purchasing behavior and shares a positive linear relationship with viewers' gift-giving behavior. Furthermore, broadcaster popularity significantly moderates the effect of social interaction-oriented content on viewers' purchasing and gift-giving behaviors.

Originality/value

This research enriches the literature on live-streaming commerce by investigating how social interaction-oriented content in broadcasters' live speech affects broadcast viewers' product-purchasing and gift-giving behaviors from the perspective of broadcast viewers' attention. Moreover, this study provides some practical guidelines for developing live speech content in the live-streaming commerce context.
Critical managerial measures on financial risks of sustainable public–private partnership projects: a PRISMA review
Authors: Akomea-Frimpong Isaac , Jin Xiaohua , Osei-Kyei Robert , Pariafsai Fatemeh
Published: March 2023

Purpose

Public–private partnership (PPP), a project financing arrangement between private investors and the public sector, has revolutionized the approach to the funding and development of public infrastructure worldwide. However, the increasing cases of financial risks and poor financial risk management related to the model threaten the sustainability and financial success of PPP projects leading to huge financial investment losses. This study aims to review existing literature to establish the key measures to control the financial risks of sustainable PPP projects.

Design/methodology/approach

A PRISMA-compliant systematic literature review method was used in this study. Data were sourced from academic databases consisting of 56 impactful peer-reviewed journal articles.

Findings

The review outcomes demonstrate 41 critical factors (measures) in mitigating the financial risks of sustainable PPP projects. They include minimum revenue guarantee, strategic alliance with private investors, financial transparency and accountability and sound macroeconomic policies. The principal results of the study were categorized and conceptualized into a financial risk management maturity model for sustainable PPP projects. Lastly, the study reveals that further studies and project policies must focus more on addressing financial challenges relating to climate risks, and health and safety concerns such as COVID-19 outbreak that have negative impacts on PPP projects.

Research limitations/implications

The results provide essential research gaps and directions for future studies on measures to mitigate the financial risks of sustainable PPP projects. However, this study used small but significant existing publications.

Practical implications

A checklist and a conceptual maturity model are provided in this study to help practitioners to learn and improve upon their practices to mitigate the financial risks of sustainable PPP projects.

Originality/value

This study contributes to managerial measures to reduce huge losses in financial investments of PPP projects and the attainment of sustainability in public infrastructure projects with a financial risk maturity model.