bluuebunny/crossref_metadata_2025 huggingface dataset:
Digitally managing depression: a fully remote randomized attention-placebo controlled trial
Authors: Kandola Aaron , Edwards Kyra , Muller Marie AE , Dührkoop Bettina , Hein Bettina , Straatman Joris , Hayes Joseph F
Published: April 2023

Background

Depression is a common and disabling condition. Digital apps may augment or facilitate care, particularly in under-served populations. We tested the efficacy of juli, a digital self-management app for depression in a fully remote randomized controlled trial.

Methods

We completed a pragmatic single-blind trial of juli for depression. We included participants aged over 18 who self-identified as having depression and scored 5 or more on the Patient Health Questionnaire-8 (PHQ-8). Participants were randomly assigned (1:1) to receive juli for 8 weeks or a limited attention-placebo control version of the app. Our primary outcome was the difference in PHQ-8 scores at 8 weeks. Secondary outcomes were remission, minimal clinically important difference, worsening of depression, and health-related quality of life. Analyses were per protocol (primary) and modified intention-to-treat (secondary). The trial was registered at the ISRCTN registry (ISRCTN12329547).

Results

Between May 2021 and January 2023, we randomised 908 participants. 662 completed the week 2 outcome assessment and were included in the modified intention-to-treat analysis, and 456 completed the week 8 outcome assessments (per protocol). The mean baseline PHQ-8 score was consistent with a diagnosis of moderately severe depression. In the per-protocol analysis, the juli group had a lower mean PHQ-8 score (10.78, standard deviation 6.26) than the control group (11.88, standard deviation 5.73) by week 8 (baseline adjusted β-coefficient -0.94, 95%CI -1.87 to -0.22, p=0.045). Remission and minimal clinically important difference were increased in the juli group at 8 weeks (adjusted odds ratio 2.22, 95%CI 1.45-3.39, p<0.001 and adjusted odds ratio 1.56, 95%CI 1.08 to 2.27, p=0.018). There were no between-group differences in health-related quality of life physical or mental component scores or worsening of depression.

Conclusion

Use of juli reduced symptoms of depression at 8 weeks compared with an attention-placebo control. The juli app is a digital self-management tool that could increase accessibility of evidence-based depression treatments.
Experiment aversion among clinicians and the public — an obstacle to evidence-based medicine and public health
Authors: Vogt Randi L. , Heck Patrick R. , Mestechkin Rebecca M. , Heydari Pedram , Chabris Christopher F. , Meyer Michelle N.
Published: April 2023

Background

Randomized controlled trials (RCTs) are essential for determining the safety and efficacy of healthcare interventions. However, both laypeople and clinicians often demonstrate experiment aversion: preferring to implement either of two interventions for everyone rather than comparing them to determine which is best. We studied whether clinician and layperson views of pragmatic RCTs for Covid-19 or other interventions became more positive early in the pandemic, which increased both the urgency and public discussion of RCTs.

Methods

We conducted several survey studies with laypeople (totaln=2,909) and two with clinicians (n=895;n=1,254) in 2020 and 2021. Participants read vignettes in which a hypothetical decision-maker who sought to improve health could choose to implement intervention A for all, implement intervention B for all, or experimentally compare A and B and implement the superior intervention. Participants rated and ranked the appropriateness of each decision.

Results

Compared to our pre-pandemic results, we found no decrease in laypeople’s aversion to non-Covid-19 experiments involving catheterization checklists and hypertension drugs. Nor were either laypeople or clinicians less averse to Covid-19 RCTs (concerning corticosteroid drugs, vaccines, intubation checklists, proning, school reopening, and mask protocols), on average. Across all vignettes and samples, levels of experiment aversion ranged from 28% to 57%, while levels of experiment appreciation (in which the RCT is rated higher than the participant’s highest-rated intervention) ranged from only 6% to 35%.

Conclusions

Advancing evidence-based medicine through pragmatic RCTs will require anticipating and addressing experiment aversion among both patients and healthcare professionals.
Redundancy, quality appraisal, and discordance in the results of systematic reviews of early mobilization of critically ill adults. A meta-research protocol
Authors: Gutierrez-Arias Ruvistay , Pieper Dawid , Nydahl Peter , González-Seguel Felipe , Jalil Yorschua , Oliveros Maria-Jose , Torres-Castro Rodrigo , Seron Pamela
Published: April 2023

Introduction

In adult patients in intensive care units (ICU), early mobilization is one of the central non-pharmacological interventions studied for recovery from critical illness. Several systematic reviews (SRs) have been conducted to determine the effect of this intervention on ICU-acquired weakness (ICU-AW) with heterogeneous methodology and results. Redundancy in conducting SRs, unclear justification when leading new SRs or updating, and discordant results of SRs on the same research question may be generating research waste that makes it difficult for clinicians to keep up to date with the best available evidence. Therefore, this meta-research aims to assess the redundancy, methodological and reporting quality, and potential reasons for discordance in the results reported by SRs conducted to determine the effectiveness of early mobilization in critically ill adult patients on different clinical outcomes.

Methods

A meta-research of early mobilization SRs in critically ill adult patients will be conducted. A sensitive search of MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCOhost), Cochrane Library, Epistemonikos, and other search resources will be conducted. Two independent reviewers will perform study selection, data extraction, and quality appraisal. Discrepancies will be resolved by consensus or a third reviewer. The redundancy of SRs will be assessed by the degree of overlap of primary studies. In addition, the justification for conducting new SRs will be evaluated with the “Evidence-Based Research” framework. The methodological quality of the SRs will be assessed with the AMSTAR 2 tool and the quality of the reports through compliance with the PRISMA statement. To assess the potential reasons for discordance in the results of the SRs, only SRs that an MA has carried out will be analyzed, considering divergence in results and their interpretation.

Expected results

The analysis of this meta-research will assess the redundancy in the conducting of SR on the mobilization of critically ill adult patients, their methodological quality, and the quality of the reporting of their findings, as well as the causes of possible discrepancies between their results. These findings could guide the development of better and more timely SRs on the effectiveness of early mobilization of adult critically ill patients. The decrease in waste research could facilitate evidence-based decision-making by stakeholders.

Registration number

osf.io/kxwq9
Time-of-day-dependent variation of the hepatic transcriptome and metabolome is disrupted in non-alcoholic fatty liver disease patients
Authors: Johanns Manuel , Haas Joel T. , Raverdy Violetta , Vandel Jimmy , Chevalier-Dubois Julie , Guille Loic , Derudas Bruno , Legendre Benjamin , Caiazzo Robert , Verkindt Helene , Gnemmi Viviane , Leteurtre Emmanuelle , Derhourhi Mehdi , Bonnefond Amélie , Froguel Philippe , Eeckhoute Jérôme , Lassailly Guillaume , Mathurin Philippe , Pattou François , Staels Bart , Lefebvre Philippe
Published: April 2023

Liver homeostasis is ensured in part by time-of-day-dependent processes, many of them being paced by the molecular circadian clock. Liver functions are compromised in non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), and clock disruption increases susceptibility to non-alcoholic fatty liver disease (NAFLD) progression in rodent models. We therefore investigated whether time-of-day-dependent transcriptome and metabolome are significantly altered in human NAFL and NASH livers. Liver biopsies, collected within an 8 hour- window from a carefully phenotyped cohort of 290 patients and histologically diagnosed to be either normal, NAFL or NASH hepatic tissues, were analyzed by RNA sequencing and unbiased metabolomic approaches. Time-of-day-dependent gene expression patterns and metabolomes were identified and compared between histologically normal, NAFL and NASH livers. We provide here a first-of-its-kind report of a daytime-resolved human liver transcriptome-metabolome and associated alterations in NAFLD. Transcriptomic analysis showed a robustness of core molecular clock components in NAFL and NASH livers. It also revealed stage-specific, time-of-day- dependent alterations of hundreds of transcripts involved in cell-to-cell communication, intra- cellular signaling and metabolism. Similarly, rhythmic amino acid and lipid metabolomes were affected in pathological livers. Both TNFa and PPARγ signaling are predicted as important contributors to altered rhythmicity. NAFLD progression to NASH perturbs time-of-day-dependent processes in human livers, while core molecular clock component differential expression is maintained.
Immunosuppression with Cyclosporine versus Tacrolimus shows distinctive nephrotoxicity profiles within renal compartments
Authors: Demirci Hasan , Popovic Suncica , Dittmayer Carsten , Yilmaz Duygu Elif , El-Shimy Ismail Amr , Mülleder Michael , Hinze Christian , Persson Pontus B. , Mutig Kerim , Bachmann Sebastian
Published: April 2023

Calcineurin inhibitors (CNI) are the backbone for immunosuppression after solid organ transplantation. Although successful in preventing kidney transplant rejection, their nephrotoxic side effects notoriously contribute to allograft injury despite attempts to optimize their application, often with additional medications. Complex renal parenchymal damage occurs for cyclosporine A (CsA) as well as for the currently favoured tacrolimus (Tac). To test for distinct CsA and Tac damaging patterns, we combined multiomics analysis with histopathology from rat kidneys exposed to continuous CNI delivery. Damage forms varied strikingly. Both drugs caused significant albeit differential damage in vasculature and nephron. The glomerular filtration barrier was more affected by Tac than by CsA, showing prominent deteriorations in pore endothelium and podocytes along with impaired VEGF/VEGFR2 signaling and podocyte-specific gene expression. By contrast, proximal tubule epithelia were more severely affected by CsA than by Tac, revealing lysosomal dysfunction and enhanced apoptosis along with impaired proteostasis and oxidative stress. We conclude that pathogenetic alterations in renal microenvironments are specific for either treatment. Should this translate to the clinical setting, CNI choice should reflect individual risk factors for renal vasculature and tubular epithelia. As a step in this direction, we share products identified from multiomics for differential pathognomonic biomarkers.

Translational Statement

Calcineurin inhibitors (CNI) are first-choice immunosuppressive agents. Their nephrotoxic side effects may often limit their use. Tacrolimus is currently preferred to cyclosporine although its superiority remains unclear. Within the nephron, damage to the filtration barrier is greater for tacrolimus, whereas cyclosporine side effects locate more to the proximal tubular epithelium when compared in our rodent model. We identify the distinctive location and nature of damage by both drugs and unravel involved mechanisms. By detecting differential protein signatures we make available pathognomonic biomarkers for renal allograft health under CNI treatment.
Metabolic signatures of cardiorenal dysfunction in plasma from sickle cell patients, as a function of therapeutic transfusion and hydroxyurea treatment
Authors: D’Alessandro Angelo , Nouraie S. Mehdi , Zhang Yingze , Cendali Francesca , Gamboni Fabia , Reisz Julie A. , Zhang Xu , Bartsch Kyle W. , Galbraith Matthew D. , Espinosa Joaquin M. , Gordeuk Victor R. , Gladwin Mark T
Published: April 2023

Metabolomics studies in sickle cell disease (SCD) have been so far limited to tens of samples, owing to technical and experimental limitations. To overcome these limitations, we performed plasma metabolomics analyses on 596 samples from patients with sickle cell sickle cell disease (SCD) enrolled in the WALK-PHaSST study. Clinical covariates informed the biological interpretation of metabolomics data, including genotypes (hemoglobin SS, hemoglobin SC), history of recent transfusion (HbA%), response to hydroxyurea treatment (HbF%). We investigated metabolic correlates to the degree of hemolysis, cardiorenal function, as determined by tricuspid regurgitation velocity (TRV), estimated glomerular filtration rate (eGFR), and overall hazard ratio (unadjusted or adjusted by age). Recent transfusion events or hydroxyurea treatment were associated with elevation in plasma free fatty acids and decreases in acyl-carnitines, urate, kynurenine, indoles, carboxylic acids, and glycine- or taurine-conjugated bile acids. High levels of these metabolites, along with low levels of plasma S1P and L-arginine were identified as top markers of hemolysis, cardiorenal function (TRV, eGFR), and overall hazard ratio. We thus uploaded all omics and clinical data on a novel online portal that we used to identify a potential mechanism of dysregulated red cell S1P synthesis and export as a contributor to the more severe clinical manifestations in patients with the SS genotype compared to SC. In conclusion, plasma metabolic signatures – including low S1P, arginine and elevated kynurenine, acyl-carnitines and bile acids - are associated with clinical manifestation and therapeutic efficacy in SCD patients, suggesting new avenues for metabolic interventions in this patient population.
Validity of Dried Blood Spot Testing for Sexually Transmitted and Blood-Borne Infections: A Narrative Systematic Review
Authors: Cholette François , Périnet Simone , Neufeld Bronwyn , Bryson Maggie , Macri Jennifer , Sibley Kathryn M. , Kim John , Driedger S. Michelle , Becker Marissa L. , Sandstrom Paul , Meyers Adrienne F. A. , Paquette Dana
Published: April 2023

Objective

Testing for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) using dried blood spot (DBS) specimens has been an integral part of bio-behavioural surveillance in Canada for almost two decades. A systematic review was conducted to assess the current evidence regarding the validity of sexually transmitted and blood-borne infection (STBBI) testing using DBS specimens.

Methods

A literature search was conducted using a peer-reviewed search strategy. Eligibility criteria included studies reporting use of DBS specimens for STBBI testing in populations 15 years of age or older. The intervention of interest was either commercially available or “in-house” tests used to detect STBBI from DBS specimens. Studies that reported a measure of validity such as sensitivity, specificity, positive and negative predictive values were eligible for inclusion. Quality of studies and risk of bias were assessed using the QUADAS-2 tool.

Results

A total of 6,706 records were identified. Of these records, 169 full-text articles met the criteria for inclusion. The STBBI with the most articles reporting a measure of validity for testing on DBS was HIV (n=73), followed by HCV (n=63), HBV (n=33), syphilis (n=7), HAV (n=5), HSV (n=5), HTLV (n=3), and HPV (n=1). The majority of studies reported high sensitivity (≥90%) and specificity (≥90%). However, the quality of the studies varied greatly. No evidence was found on the validity of chlamydia and gonorrhoea testing using DBS specimens.

Conclusion

Our findings support the validity of DBS testing for STBBI surveillance where sufficient evidence was available, but validity is highly dependent on thorough method development and validation.
Mandatory membership of community-based mutual health insurance in Senegal: A national survey
Authors: Ridde Valéry , Gaye Ibrahima , Ventelou Bruno , Paul Elisabeth , Faye Adama
Published: April 2023

With the low adhesion to voluntary mutual health insurance, Senegal’s policymakers have sought to understand the feasibility of compulsory health insurance membership. This study aims to measure the acceptability of mandatory membership in community-based mutual health insurance (CBHI) and to understand its possible administrative modalities.

The study consists of a national survey among a representative population sample selected by marginal quotas. The survey was conducted in 2022 over the phone, with the random composition method among 914 people. The questionnaire measured the socio-economic characteristics of households, their level of acceptability concerning voluntary and compulsory membership, and their level of confidence in CBHIs and the health system.

Respondents preferred voluntary (86 %) over mandatory (70 %) membership of a CBHI. The gap between voluntary and compulsory membership scores was smaller among women (p=0.040), people under 35 (p=0.033) and people with no health coverage (p=0.011). Voluntary or compulsory membership was correlated (p=0.000) to trust in current CBHIs and health systems. No particular preference emerged as for the preferred administrative channel (e.g. death certificate, identity card, etc.) which could enable to enforce the mandatory character.

The results confirmed the well-known challenges of building universal health coverage on the basis of CBHIs, a model which is poorly appreciated and whose low performance reduces the acceptability of populations to adhere to it, be it on a voluntary or mandatory basis. Suppose Senegal persists in its health insurance approach. In that case, it will be essential to strengthen the performance and funding of CBHIs, and to gain population trust to enable a mandatory or more systemic membership.
A protocol for a systematic critical realist synthesis of school mindfulness interventions designed to promote pupils’ mental wellbeing
Authors: Abbott Pamela , Nixon Graeme , Stanley Isabel , D’Ambruoso Lucia
Published: April 2023

Introduction

The review described in this protocol will be the first critical realist review of the literature reporting on the impact of mindfulness interventions in schools on the mental wellbeing of pupils. Mindfulness interventions are increasingly being introduced into schools to promote children’s (and teachers’) wellbeing. Findings from impact evaluations, including systematic reviews and metanalysis, suggest that school-based mindfulness interventions promote pupils’ wellbeing. However, there is a need for further evidence on how they work and for whom and under what circumstances.

Methods and analysis

A critical realist review methodology will be used to provide a causal interdisciplinary understanding of how mindfulness interventions in schools promote the mental wellbeing of pupils. This will be done through a systematic literature review and extrapolating context, agency, intervention, mechanisms, and outcome configurations. This will enable us to understand how in certain contexts, pupils can use the resources offered by a mindfulness intervention to trigger mechanisms that promote their mental wellbeing and what mechanisms in the context support, restrict or prevent change. We will then use retrodiction and retroduction to develop the most plausible interdisciplinary middle-range theory to explain the findings.

Discussion

The review findings will inform a critical realist evaluation of a mindfulness intervention in schools that we will be carrying out. The findings from the review will enable us to inform policymakers and other stakeholders about what conditions need to be in place for mindfulness interventions to promote pupils’ mental wellbeing and for which pupils. We will publish the findings from the review in academic and professional publications, policy briefs, workshops, conferences, and social media.
Inflammatory cytokines and a diverse cervicovaginal microbiome are associated with cervical disease in Hispanics living in Puerto Rico
Authors: Tosado-Rodríguez Eduardo , Mendez Loyda B. , Espino Ana M. , Dorta-Estremera Stephanie , Aquino Edna E. , Romaguera Josefina , Godoy-Vitorino Filipa
Published: April 2023

Cervical cancer (CC) is women’s fourth most common cancer worldwide. A worrying increase in CC rates in Hispanics suggests that besides Human Papillomaviruses infections, there may be other biological causes promoting the disease. We hypothesized that the cervical microbiome and the epithelial microenvironment favoring inflammation is conducive to disease progression. There is a lack of studies examining the part played by microbial populations in the development of precancerous lesions into cancer in Hispanic women. We aimed to investigate the relationship between the cervicovaginal microbiome and inflammation in Hispanic women living in PR while considering cervical neoplasia and HPV infection. Cervical samples collected from 91 participants coming to clinics in San Juan, underwent 16S rRNA genes (V4 region) profiling, and cytokines were measured using Luminex MAGPIX technology. Cytokines were grouped as inflammatory (IL-1β, TNFα, IFNγ, IL-6), anti-inflammatory (IL-4, IL-10, TGFβ1), and traffic-associated (IL-8, MIP1a, MCP1, IP10). They were related to microbes via an inflammation scoring index based on the quartile and tercile distribution of the cytokine’s concentration. We found significant differences in the diversity and composition of the microbiota according to HPV risk, cervical disease, and cytokine abundance. The most dominant community state type (CST) was CST IV with ∼ 90% dominance in participants with high-grade squamous intraepithelial lesions and high-risk HPV. The increasing concentration of pro-inflammatory cytokines was associated with a decrease inL. crispatus. In contrast, dysbiosis-associated bacteria such asGardnerella,Prevotella,Atopobiumconcomitantly increased with pro-inflammatory cytokines. Our study highlights that the cervical microbiota of Hispanics living in PR is characteristically diverse, regardless of HPV status and that dysbiosis associated with a decrease inLactobacillusmarks inflammatory processes. Therefore, the joint host-microbe interaction analyses via cytokine signaling and microbiota in precancerous lesions is confirmed to have great translational potential.
Activation of programmed cell death and counter-defense functions of phage accessory genes
Authors: Silas Sukrit , Carion Héloïse , Makarova Kira S. , Laderman Eric , Godinez David Sanchez , Johnson Matthew , Fossati Andrea , Swaney Danielle , Bocek Michael , Koonin Eugene V. , Bondy-Denomy Joseph
Published: April 2023

Viruses have been evolving host-modifying factors for billions of years. Genomes of bacterial and archaeal viruses are replete with fast-evolving, uncharacterized accessory genes (AGs), most of which likely antagonize host defenses or other viruses1, 2. Systematic investigation of AGs could uncover a multitude of biological mechanisms involved in virus-host competition, but AG identification in genomic databases remains a challenge. We developed an integrated computational and high-throughput discovery platform to identify AGs in virus genomes and assay their functions in complementary phage infection-dependent and -independent contexts. Our approach showcases how phages interact with the principal layers of antiviral immunity, including cell surface modifications, restriction systems, and abortive infection (Abi) mechanisms, which operate simultaneously in the same host. We discovered multiple Enterobacteriophage AGs associated with counter-defense functions that activate rather than inhibit antiviral immunity in cells, including the surprising finding that anti-restriction AGs elicit programmed cell death (PCD) activity of some restriction-modification (R-M) systems. We propose that counter-defense AGs that trigger PCD create a conundrum for phages whereby keeping the AGs causes PCD but losing them exposes the phage to restriction by bacteria. Strategies employed by viruses to avoid this double jeopardy could be an important factor in virus evolution that remains to be explored.
Multicellular, IVT-derived, unmodified human transcriptome for nanopore-direct RNA analysis
Authors: McCormick Caroline A. , Akeson Stuart , Tavakoli Sepideh , Bloch Dylan , Klink Isabel N. , Jain Miten , Rouhanifard Sara H.
Published: April 2023

Nanopore direct RNA sequencing (DRS) enables measurements of RNA modifications. Modification-free transcripts are a practical and targeted control for DRS, providing a baseline measurement for canonical nucleotides within a matched and biologically derived sequence context. However, these controls can be challenging to generate and carry nanopore-specific nuances that can impact analysis. We produced DRS datasets using modification-free transcripts fromin vitrotranscription (IVT) of cDNA from six immortalized human cell lines. We characterized variation across cell lines and demonstrated how these may be interpreted. These data will serve as a versatile control and resource to the community for RNA modification analysis of human transcripts.
Where Initial rates are directly proportional to Substrate concentrations with Application in Molar-mass Determination, Zero-order Specificity constant is Inappropriate
Authors: Udema Ikechukwu Iloh
Published: April 2023

Background

“High-ranking scientists” employ the initial rate (vi), expression without consideration for the conditions under which theviexpression can be used. The consequence is the suggestion that theviis equal to the product of maximum velocity,Vmax, andsubstrate concentration [S0] divided by the Michaelis-Menten constant,KM.

Objectives

The main objectives are: 1) to show thatviis not equal toVmax[S0]/KM; 2) to show that the equilibrium dissociation constant,Kd, is strictly proportional to the concentration ([E0]) of the enzyme; and 3) to show that the two standard quasi-steady-state assumptions (sQSSA) and reverse QSSA (rQSSA) have a limited domain of validity.

Methods

The study was experimental and theoretical, supported by the Bernfeld method of enzyme assay.

Result

Kdis directly proportional to [E0], andviis not equal toVmax[S0]/KM.. AKM-like value that is greater than the putativeKdvalue, 2.482 g/L, is equal to 2.569 g/L. TheKM-like values in other situations are 2.396 and 2.407 g/L; the corresponding equilibrium dissociation constant (Kd) values are, respectively, 2.288 and 2.299 g/L; the molar mass of insoluble potato starch ranges between 62.296 and 65.616 exp. (+6) g/mol.

Conclusion

The equations that invalidate the assumption thatviis equal toVmax[S0]/KMwhenever [S0] is much less thanKMwere derived; the proposition thatKdis strictly proportional to [E0] was confirmed; the molar mass of starch could be calculated from the derived equation; and it was shown graphically and mathematically that both the sQSSA and rQSSA domains have a limit of validity; the equation with which to calculate the second order rate constant based on the conditions that validate the rQSSA is not applicable to the sQSSA. AKM-like value that is greater than the putativeKdvalue is possible.

GRAPHICAL ABSTRACT

The graphical abstract illustrates three zones: the zone in which the sQSSA is valid, the zone in which the rQSSA is valid, and the zone in which neither assumption is exclusively valid. The curved arrow (oxblood) pointing to the red line depicts a tendency towards conditions that validate the rQSSA if the assay is conducted with an appropriate [S0]/[E0] ratio (< 1 to ≪1) while the red curved arrow pointing to the blue line depicts a tendency towards conditions that validate the sQSSA if the assay is conducted with an appropriate [S0]/[E0] ratio (>1 to ≫1). The enzyme-substrate complex (ES) is in a quasi-steady state with respect to S as depicted by ∂ [ES]/ ∂t≈0, the sQSSA case, while in the rQSSA, it is the S that is in a quasi-steady state with respect to ES as depicted by ∂[S0]/∂t≈0. The double-headed arrow merely shows, artistically, the limit of the data points.
Lumbar V3 Interneurons Provide Direct Excitatory Synaptic Input Onto Thoracic Sympathetic Preganglionic Neurons, Linking Locomotor And Autonomic Spinal Systems
Authors: Chacon Camila , Nwachukwu Chioma V , Shahsavani Narjes , Cowley Kristine C , Chopek Jeremy W
Published: April 2023

Spinal cord injury (SCI) is a life-altering event causing sensation loss, motor paralysis and impaired autonomic function. Electrical spinal cord stimulation has shown promise for restoring lost motor, and impaired autonomic function, despite targeting lumbar locomotor networks. Sympathetic preganglionic neurons (SPNs), primarily located in the intermediate laminae of thoracic and upper lumbar segments (T1-L2), provide neural input to excite sympathetic tissues and organs that provide homeostatic and metabolic support during movement and exercise. We hypothesized that ascending propriospinal neurons located in the lumbar spinal cord provide synaptic input to thoracic SPNs, providing a spinal neural mechanism explaining improved motor and autonomic function in response to spinal cord stimulation. Here, we demonstrate that synaptic contacts from locomotor-related V3 interneurons (INs) are present in all thoracic laminae. Injection of an anterograde tracer into lumbar segments demonstrated that 8-20% of glutamatergic input onto SPNs originated from lumbar V3 INs and displayed a somatotopographical organization of synaptic input to thoracic SPNs, with rostral lumbar V3 INs projecting to rostral thoracic, and caudal lumbar V3 INs projecting to caudal thoracic SPNs. Whole cell patch clamp recording in SPNs demonstrated prolonged depolarizations or action potentials in response to optical activation of either lumbar V3 INs in spinal cord preparations or in response to optical activation of V3 terminals in thoracic slice preparations. This work demonstrates a direct intraspinal connection between lumbar locomotor and thoracic sympathetic networks and suggests communication between motor and autonomic systems may be a general function of the spinal cord.

Key points

We provide direct anatomical and electrophysiological evidence of an ascending intraspinal synaptic connection between lumbar motor and thoracic sympathetic autonomic neural systems.

These connections are formed between lumbar locomotor related V3 interneurons and thoracic sympathetic preganglionic neurons (SPNs)

V3 synaptic input accounts for ∼ 20% of glutamatergic input to SPNs.

Optical activation of lumbar V3 interneurons elicit action potentials in thoracic SPNs.

This intraspinal pathway may explain why electrical stimulation of the lumbar region in persons with long-standing motor complete spinal cord injury improves both motor and sympathetic function.

These findings suggest communication between motor and autonomic systems may be a general feature of spinal cord function and await further research to explore this concept.
Boreal moss-microbe interactions are revealed through metagenome assembly of novel bacterial species
Authors: Ishak Sarah , Rondeau-Leclaire Jonathan , Faticov Maria , Roy Sebastien , Laforest-Lapointe Isabelle
Published: April 2023

Moss-microbe interactions contribute to ecosystem processes in boreal forests. Yet, how host-specific characteristics and the environment drive the composition and metabolic potential of moss microbiomes is still poorly understood. In this study, we use shotgun metagenomics to identify the taxonomy and metabolic potential of the bacteria of four moss species of the boreal forests of Northern Quebec, Canada. To characterize moss bacterial community composition and diversity, we assembled the genomes of 110 potentially novel bacterial species. Our results highlight that moss genus, species, gametophyte section, and to a lesser extent soil pH and soil temperature, drive moss-associated bacterial community composition and diversity. In the brown gametophyte section, two Stigonema spp. showed partial pathway completeness for photosynthesis and nitrogen fixation, while all brown-associated Hyphomicrobiales had complete assimilatory nitrate reduction pathways and many nearly complete carbon fixation pathways. Several brown-associated species showed partial to complete pathways for coenzyme M and F420 biosynthesis, important for methane metabolism. In addition, green-associated Hyphomicrobiales (Methylobacteria spp.) displayed potential for the anoxygenic photosystem II pathway. Overall, our findings demonstrate how host-specific characteristics and environmental factors shape the composition and metabolic potential of moss bacteria, highlighting their roles in carbon fixation, nitrogen cycling, and methane metabolism in boreal forests.
RNAi-mediated regulation ofalg-3andalg-4coordinates the spermatogenesis developmental program inC. elegans
Authors: McCormick Cara , Rogers Alicia K.
Published: April 2023

Coordination of gene regulatory networks is necessary for proper execution of cellular programs throughout development. InC. elegans,spermatogenesis and oogenesis occur during different life stages (L4 and adult, respectively) within the hermaphroditic germline tissue. Yet, it remains unclear how these developmental programs are robustly executed, particularly during stressful conditions. Here we show evolutionarily conserved RNA interference (RNAi) pathways act to restrict expression of spermatogenesis genes to the L4 stage. Our findings indicate a novel RNAi-mediated regulatory cascade is essential for properly coordinating the spermatogenesis developmental program, particularly during heat stress. This is achieved through RNAi-mediated genetic switches that regulate the expression of the Argonautes, ALG-3 and ALG-4, to control ALG-3/4 pathway function. Moreover, this work provides key insights into the different molecular mechanisms RNAi pathways employ to maintain both maternal and paternal germ cells’ reproductive potential, and further highlights the complexities and importance of RNAi-mediated gene regulation in development.
A sweet new set of inducible and constitutive promoters for haloarchaea
Authors: Rados Theopi , Andre Katherine , Cerletti Micaela , Bisson Alex
Published: April 2023

Inducible promoters are one of cellular and molecular biology’s most important technical tools. The ability to deplete, replete, and overexpress genes on demand is the foundation of most functional studies. Here, we developed and characterized a new xylose-responsive promoter (Pxyl), the second inducible promoter system for the model haloarcheonHaloferax volcanii. Generating RNA-seq datasets from cultures in the presence of four historically used inducers (arabinose, xylose, maltose, and IPTG), we mapped upregulated genomic regions primarily repressed in the absence of the above inducers. We found a highly upregulated promoter that controls the expression of thexacEA(HVO_B0027-28) operon in the pHV3 chromosome. To characterize this promoter region, we cloned msfGFP (monomeric superfold green fluorescent protein) under the control of two different 5’ UTR fragments into a modified pTA962 vector: the first 250 bp (P250) and the whole 750 bp intergenic region (P750). The P250 region expressed msfGFP constitutively, and its expression did not respond to the presence or absence of xylose. However, the P750 promoter showed not only to be repressed in the absence of xylose but also expressed higher levels of msfGFP than the previously described inducible promoter PtnaA in the presence of the inducer. Finally, we validated the inducible Pxyl promoter by reproducing morphological phenotypes already described in the literature. By overexpressing the tubulin-like FtsZ1 and FtsZ2, we observed similar but slightly more pronounced morphological defects than the tryptophan-inducible promoter PtnaA. FtsZ1 overexpression created larger, deformed cells, whereas cells overexpressing FtsZ2 were smaller but mostly retained their shape. In summary, this work contributes a new xylose-inducible promoter, Pxyl, that can be used simultaneously with the well-established PtnaA in functional studies inH. volcanii.
Monosynaptic inputs to ventral tegmental area glutamate and GABA co-transmitting neurons
Authors: Prévost Emily D. , Phillips Alysabeth , Lauridsen Kristoffer , Enserro Gunnar , Rubinstein Bodhi , Alas Daniel , McGovern Dillon J. , Ly Annie , Banks Makaila , McNulty Connor , Kim Yoon Seok , Fenno Lief E. , Ramakrishnan Charu , Deisseroth Karl , Root David H.
Published: April 2023

A unique population of ventral tegmental area (VTA) neurons co-transmits glutamate and GABA as well as functionally signals rewarding and aversive outcomes. However, the circuit inputs to VTA VGluT2+VGaT+ neurons are unknown, limiting our understanding of the functional capabilities of these neurons. To identify the inputs to VTA VGluT2+VGaT+ neurons, we coupled monosynaptic rabies tracing with intersectional genetic targeting of VTA VGluT2+VGaT+ neurons in mice. We found that VTA VGluT2+VGaT+ neurons received diverse brain-wide inputs. The largest numbers of monosynaptic inputs to VTA VGluT2+VGaT+ neurons were from superior colliculus, lateral hypothalamus, midbrain reticular nucleus, and periaqueductal gray, whereas the densest inputs relative to brain region volume were from dorsal raphe nucleus, lateral habenula, and ventral tegmental area. Based on these and prior data, we hypothesized that lateral hypothalamus and superior colliculus inputs were glutamatergic neurons. Optical activation of glutamatergic lateral hypothalamus neurons robustly activated VTA VGluT2+VGaT+ neurons regardless of stimulation frequency and resulted in flee-like ambulatory behavior. In contrast, optical activation of glutamatergic superior colliculus neurons activated VTA VGluT2+VGaT+ neurons for a brief period of time at high stimulation frequency and resulted in head rotation and arrested ambulatory behavior (freezing). For both pathways, behaviors induced by stimulation were uncorrelated with VTA VGluT2+VGaT+ neuron activity. However, stimulation of glutamatergic lateral hypothalamus neurons, but not glutamatergic superior colliculus neurons, was associated with VTA VGluT2+VGaT+ footshock-induced activity. We interpret these results such that inputs to VTA VGluT2+VGaT+ neurons may integrate diverse signals related to the detection and processing of motivationally-salient outcomes. Further, VTA VGluT2+VGaT+ neurons may signal threat-related outcomes, possibly via input from lateral hypothalamus glutamate neurons, but not threat-induced behavioral kinematics.
Methotrexate-modulated talin-dynamics drives cellular mechanical phenotypes via YAP signaling
Authors: Chowdhury Debojyoti , Dhabal Sukhamoy , Bhatt Madhu , Maity Debashruti , Chakraborty Soham , Ahuja Keshav Kant , Priyadarshi Shreyansh , Haldar Shubhasis
Published: April 2023

Methotrexate is a well-known antineoplastic drug used to prevent cancer aggravation. Despite being a targeted therapeutic approach, its administration comes with the risk of cancer recurrence, plausibly through its proven off-target effect on focal adhesions. Since FA dynamics is dependent on force transmission through its constituent proteins, including talin, methotrexate might affect the mechanical activity of these proteins. Here we have combined single-molecule studies, computational dynamics, cell-based assays, and genomic analysis to unveil the focal adhesion-regulating role of methotrexate central to its effect on talin dynamics and downstream pathways. Interestingly, our single-molecule force spectroscopic study shows that methotrexate modulates the bimodal force distribution of talin in a concentration-dependent manner. Steered molecular dynamics reveal that methotrexate-talin interactions alter talin mechanical stability exposing their vinculin binding sites. Finally, we found that methotrexate-regulated talin-dynamics remodel cancer cell mechanical phenotypes like cell polarity, adhesion, and migration by regulating talin-vinculin association-mediated YAP signaling. These results further correlate with genomic analysis of methotrexate-treated patients, demonstrating its clinical importance. Taken together, these findings disseminate the effects of methotrexate-modulated mechanosensitivity of adhesion proteins on cellular events.
Understanding the personality of Europe’s only world surfing reserve
Authors: Martins Ana Filipa , Penela Daniela , Cardoso Margarida G.M.S.
Published: April 2023

Purpose

This study aims to uncover the destination personality of the World Surfing Reserve (WSR) in Europe, Ericeira, from local stakeholders’ perspectives; understand if WSR recognition influences the perception of destination personality; and understand if there is an alignment between the vision of the destination management Organization (DMO) and stakeholders in terms of destination personality.

Design/methodology/approach

An extensive literature search was conducted to identify personality traits, which were then filtered and included in a survey of Ericeira's stakeholders and in a DMO interview. A principal components analysis enabled the identification of the most relevant personality traits.

Findings

Cool, appealing and self-assured emerged as destination-specific personality traits of Ericeira, indicating that other similar destinations can consider them in future branding actions. The findings indicate that WSR recognition can be a determinant for local tourism but has no impact on destination personality as viewed by local stakeholders. Therefore, one can suggest that personality is embedded in a tourist destination and is somewhat resistant to external WSR recognition. In general, alignment was found between the views of the local stakeholders and the DMO.

Originality/value

This study reinforces the literature on the importance of stakeholder involvement in place brand development. It also suggests that external recognition may have an impact on local tourism but has a limited impact on destination personality. Finally, this research constitutes a baseline for further studies on the destination personality traits of current and prospective WSR.
Problems in information classification: insights from practice
Authors: Andersson Simon
Published: April 2023

Purpose

This study aims to identify problems connected to information classification in theory and to put those problems into the context of experiences from practice.

Design/methodology/approach

Five themes describing problems are discussed in an empirical study, having informants represented from both a public and a private sector organization.

Findings

The reasons for problems to occur in information classification are exemplified by the informants’ experiences. The study concludes with directions for future research.

Originality/value

Information classification sustains the basics of security measures. The human–organizational challenges are evident in the activities but have received little attention in research.
Industrial impact analysis of foreign direct investment on economic development in Cambodia
Authors: Kenh Sovath , Wei Qidi
Published: April 2023

Purpose

Cambodia's sustained and robust growth performance since the post-reform era in 1993 has been attributed to the boom in inward foreign direct investment (FDI) attracted to the country's labor-intensive industries, where it has comparative advantages. The purpose of this study is twofold. First, it aims to assess the consistency between Cambodia's revealed comparative advantage in exports and its sectoral inward FDI. Second, it examines the relationship between industry-level FDI and growth performance by accounting for heterogeneity across industries.

Design/methodology/approach

The paper uses descriptive methods and an industry-level dataset provided by the Council for the Development of Cambodia to elucidate the issue. Additionally, it applies instrumental variable two-stage least squares (IV-2SLS) regression to investigate the impact of industry-specific FDI on economic growth from 1994 to 2017, which also aims to address the endogeneity issue.

Findings

On the one hand, our research finds that Cambodia's FDI has been attracted to sectors in which it has a comparative advantage during the aforementioned period. On the other hand, both FDI and the comparative advantage index significantly impact economic growth in Cambodia. The greater the flow of foreign investment into sectors with comparative advantage, the stronger the impetus for growth.

Originality/value

This study fills a gap in the literature and contributes to a better understanding of the relationship between FDI and economic growth in Cambodia. It is the first paper to investigate the heterogeneity of industry-specific FDI and provides practical recommendations for policymakers to effectively harness foreign investments and avoid malign FDI inflows.
Shadow economy and FDI: the role of corruption and land resource
Authors: Yusuf Rukaiyat Adebusola , Nguyen Loan Thi Quynh
Published: April 2023

Purpose

This research examines how shadow economy affects foreign direct investment (FDI).

Design/methodology/approach

The study utilizes a panel dataset including 124 nations between 1997 and 2015. Information on shadow economy, FDI and macro-economic characteristics is obtained from the United Nations Conference on Trade and Development (UNCTAD) and World Bank database. Various econometric methods are employed, such as the panel ordinary least squares (OLS) with fixed-effect estimator and the two-step system generalized method of moments estimation.

Findings

The findings of the study illustrate that shadow economy negatively influences total FDI inflows, and this adverse impact is mainly driven by greenfield investments – a component of FDI. Moreover, the authors provide evidence that the shadow economy has more devastating influences on FDI inflows in countries with higher corruption levels and fewer land resources.

Practical implications

Overall, this research suggests an important policy implication that the shadow economy should be controlled more strictly since it harms the FDI inflows, especially greenfield investment.

Originality/value

This research is among the first attempt of evaluating the effect of shadow economy on different FDI types. Furthermore, it examines how the shadow economy–FDI inflows nexus is changed when considering factors including corruption and land resource.
Matrix approach to digitalization of management objects
Authors: Tyapukhin Alexey Petrovich
Published: April 2023

Purpose

The purpose of this study is to substantiate the matrix approach to digitalization of management objects based on identification of relevant qualitative characteristics of these objects and its dichotomies, which allowing determine the quantity and quality of their main variants, as well as the relationships between them.

Design/methodology/approach

Methods of classification and typology are selected as study methods, and binary matrices are used as the tool to determine the main variants of management objects, assign binary codes to it and form codes of more complex management objects on its basis, depending on the content of study tasks.

Findings

The main results of study include the classification of organization components; variants for choosing qualitative characteristics of chains components; adjusted content of methodology of qualitative research of management objects; sequences of “up” and “down” digitization of these objects; actual qualitative characteristics of e components of management objects and dichotomies; and variants of forming of ciphers of these objects.

Practical implications

The use of study results allows to reduce the complexity of substantiating and making managerial decisions in organization and supply chains, to structure these decisions by man-agement levels and positions and to reduce costs, time and lost profits for fulfilling orders of end consumers of products and/or services.

Originality/value

The originality of this study is confirmed by the substantiation of choice and use of actual qualitative characteristics of management objects and its dichotomies, which allow obtaining two variants of these objects and assigning them binary codes processed using computer software for management activities.