bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal influenza-like illness and neonatal health during the 1918 influenza pandemic in a Swiss city
Authors: Le Vu Mathilde , Matthes Katarina L , Schneider Eric , Moerlen Aline , Hösli Irene , Baud David , Staub Kaspar
Published: December 2024

Background

Exposure to the 1918 influenza pandemic may have been associated with preterm birth (<37 weeks). Other outcomes, such as infant size or weight, have rarely been explored.

Objective

To estimate whetherin uteroexposure to maternal influenza-like illness (ILI) during the 1918 pandemic was associated with pregnancy outcomes, and whether associations varied depending on ILI timing or on fetal sex.

Design

Cross-sectional study using historical birth records.

Setting

Lausanne maternity hospital.

Participants

2,177 singletons born during the pandemic.

Measurements

The impact of ILI on gestational age, stillbirth, and anthropometric measurements, adjusted on covariates in generalized linear models. Analyses were stratified by fetal sex.

Results

282 women developed ILI during pregnancy. ILI exposure was associated with lower anthropometric measurements: the odds ratio (OR) of low birth weight (<2,500g) was 2.06 [95%CI 1.33; 3.20]. In multivariable models, there was strong evidence that third trimester exposure was associated with adverse pregnancy outcomes, including with a higher preterm birth rate (OR 2.87 [95%CI 1.53; 5.39]). There was moderate evidence that first-trimester ILI exposure was associated with lower anthropometric measurements, in univariable models only. The magnitude of the declines in anthropometric parameters was higher among male fetuses, and they had a higher stillbirth risk. Only 41% of infants exposed to first-trimester ILI were males.

Limitation

our findings may not generalize to the entire population of Lausanne, as 34% of births were homebirths at the time.

Conclusion

maternal ILI may have triggered premature birth. The low sex ratio at birth for first-trimester exposure may indicate selection against males through miscarriage, but males were still more vulnerable than females to third trimester exposure.

Primary funding source

Swiss National Science Foundation.
Safety, tolerability and clinical effects of BC007 (Rovunaptabin) on fatigue and quality of life in patients with post-COVID syndrome (reCOVer): a prospective, exploratory, randomised, placebo-controlled, double-blind, crossover phase IIa clinical trial
Authors: Hohberger Bettina , Ganslmayer Marion , Harrer Thomas , Kruse Friedrich , Maas Stefanie , Borst Tobias , Heimke-Brinck Ralph , Stog Andreas , Knauer Thomas , Rühl Eva , Zeisberg Victoria , Skornia Adam , Bartsch Alexander , Ströbel Armin , Wytopil Monika , Merkel Carolin , Hofmann Sophia , Schmidt Katja G. , Lakatos Petra , Schottenhamml Julia , Herrmann Martin , Mardin Christian , Rech Jürgen
Published: December 2024

Background

As recent data suggest an involvement of GPCR-fAAb in PCS pathogenesis, neutralisation of such GPCR-fAAbs by BC007 could improve PCS symptoms. The aim of the reCOVer trial was to investigate safety, tolerability and clinical effects of BC007 on fatigue, its severity and quality of life in PCS patients.

Methods

reCOVer is a prospective, exploratory, randomised, placebo-controlled, double-blind, crossover phase IIa clinical trial with 1350 mg BC007 at the University of Erlangen-Nürnberg, Germany. Eligible participants were 18-80 years with GPCR-fAAb, whose PCS symptoms persisted ≥3 months after PCR-confirmed COVID-19, with fatigue as the major symptom (Bell score ≤60) and at least three of eight defined PCS symptoms. Participants were randomly assigned (1:1) according to a crossover design to either receive BC007 (sequence A) or placebo (sequence B) at day 0 and day 48 with a follow-up of 28 days, respectively. A crossover design was chosen to increase patient adherence. Occurrence of treatment-emergent adverse events (TEAEs) in comparison between sequence A and B from d0 to d28 and d0 to d70 were the primary and co-primary endpoint, respectively.

Findings

Between 31.10.2023 and 12.06.2024, 30 PCS patients were randomised and analysed. The trial has been concluded. Summarising all AE rates, no statistically significant differences between sequence A und sequence B were observed within day 28 and day 70. One report of a serious adverse event, not related to treatment, was recorded. As a secondary endpoint, BC007 showed a significant improvement on self-reported fatigue and its severity, as well as quality of life.

Interpretation

As BC007 was well tolerated and showed a significant improvement of fatigue and quality of life, it might offer a therapeutic option for an autoimmune subgroup of PCS patients.

Trial registration

EudraCT, number 2022-001781-35.

Funding

German Federal Ministry of Education and Research, German Research Foundation.
Pragmatic modeling supports current dosing guidelines for carbamazepine and valproic acid for the treatment of epilepsy in children
Authors: van der Heijden Joyce E.M. , Gijsen Violette , van Uden Anne M. , de Hoop-Sommen Marika , Freriksen Jolien J.M. , Jacobs Elke , Greupink Rick , de Wildt Saskia N.
Published: December 2024

Background

Carbamazepine (CBZ) and valproic acid (VPA) are long-standing treatments for epilepsy in children. Interestingly, they display unique drug disposition characteristics and maturation of drug metabolizing enzymes further complicates personalized dosing. Physiologically-based pharmacokinetic (PBPK) modeling includes these mechanisms and is hence a promising tool to optimize dosing. Our aim is to better support pediatric drug dosing of CBZ and VPA.

Methods

All CBZ and VPA dosing simulations were conducted with Simcyp, using available CBZ and VPA compound models linked with adult and pediatric population models. Current Dutch national dosing strategies were simulated to evaluate their appropriateness to achieve therapeutic levels. Where doses could be optimized, alternative dosing strategies were proposed based on simulations.

Results

Therapeutic levels of CBZ and VPA will be reached after 1 or 2 weeks of treatment with the current dosing strategies. Simulations suggest a CBZ starting dose of 7 mg/kg/day for neonates rather than 10 mg/kg/day. In contrast, children aged 12 to 18 years may receive a higher starting dose (e.g., 400 mg/day instead of 200 mg/day), to reach therapeutic levels more quickly. For VPA, when higher doses are needed (i.e., ≥30 mg/kg/day), measuring unbound VPA concentrations are advised to guide dosing.

Conclusion

We demonstrate that PBPK modeling is a valuable tool to confirm and further optimize dosing recommendations in children. The use of PBPK modeling offers a practical, cost-effective, and swift method to provide valuable comprehensive evidence for guiding clinical practice and potentially informing pediatric drug labeling, thus eliminating the necessity for clinical studies.
Genetic predisposition to raised circulating levels of dietary antioxidants and the association with respiratory health in high-risk populations
Authors: Saied A , Horsfall L. J.
Published: December 2024

Background

Observational studies of raised dietary antioxidants suggest a beneficial effect on health, but the results from interventional studies generally show no effect. There are no robust studies targeting people exposed to high levels of environmental oxidants where any effects of raised antioxidants are plausibly stronger.

Objectives

To examine whether people genetically predisposed to raised dietary serum antioxidants have improved respiratory health.

Methods

We identified single-nucleotide polymorphisms (SNPs) associated with serum ascorbate (vitamin C), retinol (vitamin A), and β-carotene from external data sources. Outcome data on forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), were derived from individual-level data from over 285,000 UK Biobank participants. We used linear regression to explore relationships between the SNPs and lung function. To quantify any relationships, we instrumented the association using exposure beta coefficient from published literature and genome wide association studies (Mendelian randomization).

Results

We found no consistent relationship between genetically raised serum antioxidant levels and respiratory health measures. There was no evidence of effect modification by exposures linked to oxidative stress including cigarette smoke, air pollution and poor diet.

Conclusions

Our findings support interventional studies showing no causal relationship between dietary antioxidants and respiratory disease outcomes. Further, our results do not support interventions to increase serum levels of ascorbate, retinol, or β-carotene in people exposed to high levels of environmental oxidants (Wellcome Grant ID: 209207/Z/17/Z and 225195/Z/22/Z).
Cost-utility analysis of current COVID-19 vaccination program recommendations in Canada
Authors: Simmons Alison E. , Miranda Rafael N. , Li Michael W.Z. , Gebretekle Gebremedhin B. , Xi Min , Salvadori Marina I. , Warshawsky Bryna , Wong Eva , Ximenes Raphael , Andrew Melissa K. , Wilson Sarah , Tunis Matthew , Tuite Ashleigh R.
Published: December 2024

Background

As COVID-19 becomes established as an endemic disease with widespread population immunity, there is uncertainty about the economic benefit of ongoing COVID-19 vaccination programs. We assessed the cost-effectiveness of a COVID-19 vaccination program similar to current Canadian recommendations, modelled as annual vaccination for people aged less than 65 years with chronic medical conditions and biannual vaccination for adults aged 65 years and older.

Methods

Using a static individual-based model of medically attended COVID-19 in a population of 1 million people, we estimated costs (in 2023 Canadian dollars), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). We used health system and societal perspectives and a 1.5% discount rate. Parameters were based on recent COVID-19 epidemiology, vaccine characteristics, and costs.

Results

Between July 2024 and September 2025, a program similar to current Canadian recommendations was estimated to avert 3.1% (95% credible interval (CrI): 3.0 to 3.2%) of outpatient cases, 8.8% (95% CrI: 7.3 to 10.4%) of inpatient cases, 3.6% (95% CrI: 2.8 to 4.3%) of PCC cases, and 9.4% (95% CrI: 5.6 to 13.8%) of deaths compared to no vaccination. The number needed to vaccinate to prevent one hospitalization and one death was 1,121 (95% CrI: 941 to 1,357) and 8,656 (95% CrI: 5,848 to 14,915), respectively. For the health system perspective, the program would cost an additional $4.695 million but result in 221.17 QALYs gained, leading to an ICER of $21,227 per QALY compared to no vaccination. Vaccine price influenced cost-effectiveness, with higher prices reducing the likelihood the program met common cost-effectiveness thresholds.

Conclusions

A program similar to current COVID-19 recommendations in Canada is likely effective and cost-effective compared to no vaccination. However, unlike some other research studies, alternate vaccination strategies that may offer better value for money were not evaluated.
Going Digital or Stayin’ Clinical?: Modelling Primary Health Care Consultation Types Using Register Data from Sweden
Authors: Ekman Björn
Published: December 2024

Background

Primary health care clinics use several different types of consultations, including on-site visits and remote contacts to see patients. However, it is not clear what factors determine the choice of consultation type taking into consideration the full spectrum of options.

Objectives

This study uses national register data from Sweden on all primary care consultations in the years 2019 to 2022 (N = 15,3 – 19,5 million) to model four types of consultations: office visits, digital contacts (text messages or video), home visits, and telephone/letter contacts.

Methods

The modelling of consultation type takes the cross-sectional, panel, and multilevel structure of the data into consideration fitting multinomial logistic models while controlling for patient, clinic, and context factors.

Results

In the current context, the choice of consultation type is determined by both patient (age, socioeconomic status, diagnosis) and clinic (public or private) factors, as well as context factors (reimbursement mechanism). From a policy perspective, only weak evidence is found to suggest that paying clinics for digital contacts increases those types of consultations.

Conclusions

The findings may inform the development and implementation of policies and regulations to improve the delivery of primary health care in similar contexts.
Genetic downregulation of interleukin-6 signaling and arteriolosclerotic cerebral small vessel disease: a drug target Mendelian randomization analysis
Authors: Tchuisseu-Kwangoua Larissa Ange , Omarov Murad , Shatunov Alexey , Markus Hugh S. , Kamtchum-Tatuene Joseph , Georgakis Marios K.
Published: December 2024

Background

Arteriolosclerotic cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia, yet no disease-modifying therapies exist. Anti-inflammatory strategies targeting IL- 6 signaling have shown efficacy in preventing atherosclerotic cardiovascular disease, but their potential in arteriolosclerotic cSVD remains unexplored. We investigated whether genetically downregulated IL-6 signaling is associated with clinical, imaging, and pathological manifestations of arteriolosclerotic cSVD.

Methods

We applied two-sample Mendelian randomization (MR) using (i) 26 genetic variants nearIL6Rassociated with circulating C-reactive protein (CRP) levels and (ii) rs2228145, a well- characterizedIL6Rmissense variant, as proxies of IL-6 signaling downregulation. Outcomes included clinical (small-vessel stroke, MRI-defined lacunar stroke, non-lobar intracerebral hemorrhage [ICH], vascular dementia), imaging (white matter hyperintensity volume, extensive basal ganglia perivascular space, non-lobar/mixed cerebral microbleeds), and pathological (arteriolosclerosis burden in autopsy) traits of cSVD, as well as atherosclerosis traits (ultrasound- defined carotid plaque, large artery stroke) as positive controls. We used inverse-variance weighting and the Wald ratio estimator for primary analyses. MR-Egger regression, weighted median, and weighted mode estimators were used as sensitivity analyses.

Results

Genetically downregulated IL-6 signaling (30%-decrement in CRP via 26IL6Rvariants) was not associated with small-vessel stroke (OR: 1.02, 95%CI: 0.95–1.10), MRI-confirmed lacunar stroke (OR: 0.95, [0.81–1.11]), non-lobar ICH (OR: 1.04, [0.72–1.50]), or vascular dementia (OR: 1.09, [0.95–1.25]). Similarly, we found no significant association with cSVD imaging biomarkers or pathology-defined arteriolosclerosis. As expected, genetically downregulated IL-6 signaling was associated with lower odds of large artery stroke (OR: 0.79, [0.74-0.84]) and carotid plaque (OR: 0.88, [0.83–0.94]). Results were consistent across sensitivity analyses and when using the rs2228145 missense variant to proxy IL-6 signaling downregulation.

Conclusion

Genetically proxied IL-6 signaling downregulation is not associated with clinical, imaging or pathological manifestations of arteriolosclerotic cSVD. Therefore, genetic data suggest that targeting IL-6 signaling is unlikely to prevent cSVD manifestations.
Postpartum Psychosis: could chronic insomnia or short sleep be protective?
Authors: Petrosellini Chiara , Eriksson Sofia , Meyer Nicholas , Protti Olivia , Bass Nicholas , Kuchenbaecker Karoline , Siassakos Dimitrios , McQuillin Andrew
Published: December 2024

Postpartum Psychosis (PP) is a severe and understudied perinatal mental illness which disproportionately affects women with bipolar disorder (BD). A relationship between sleep disturbance and PP is often assumed, but is poorly understood. Data from 2099 BD subjects were screened to identify parous women. Individuals who developed PP and those who had not were compared in our analyses. Polygenic Risk Scores (PRS) for BD, schizophrenia, insomnia, short sleep, long sleep and sleep efficiency were computed using PRS-CS. Logistic regression was used to model the effect of each PRS on PP. Higher PRS for insomnia and short sleep were protective against PP. Individuals in the lowest decile for insomnia PRS (RR 1.96, 95% CI 1.25-3.07, p = 3.50 x 10 -3) and short sleep PRS (RR 2.23, 95% CI 1.40-3.54, p = 7.94 x 10 -4) had approximately double the risk of PP than individuals in the highest decile. BD, schizophrenia, long sleep and sleep efficiency PRS were not associated with PP. Mendelian Randomisation analyses did not support a causal relationship between sleep traits and PP. However, we demonstrate that the integration of PRS with clinical variables can improve prediction accuracy. Individuals with genetic vulnerability to insomnia or short sleep may develop a heightened tolerance to sleep disruption earlier in life, mitigating the impact of childbirth on mood. These findings suggest that genetic susceptibility to sleep disturbance may play a crucial role in the aetiology of PP, offering a new potential avenue for risk stratification and targeted prevention.
EpiInvert, an R application to restore, analyze, compare and forecast epidemiological time series
Authors: Morel Jean-David , Morel Jean-Michel , Alvarez Luis
Published: December 2024

The Covid-19 pandemic produced regional time series of incidence, hospital, ICU admission and death. TheEpiInvertpackage estimates the incidence trend and the daily reproduction numberRtof any infectious disease, compares related time series such as incidence and death, and provides incidence forecasts.EpiInvertis an R package with the following features: (1)EpiInvertinputs raw daily incidence time series and the pandemic time serial interval. It outputs a weekly seasonality, an incidence trend and its reproduction number. (2)EpiIndicatorsinputs two related epidemiological time series such as daily incidence and death count. It outputs a daily ratio and delay between both time series. (3)EpiInvertForecastinputs an incidence trend obtained byEpiInvertand a database of past observed time series. Using the most similar past series, it forecasts the incidence in the next four weeks.EpiInvertis in the CRAN repositoryhttps://cran.r-project.org/web/packages/EpiInvert/index.html.
Probing nanomechanics by direct indentation using Nanoendoscopy-AFM reveals the nuclear elasticity transition in cancer cells
Authors: Ichikawa Takehiko , Kono Yohei , Kudo Makiko , Shimi Takeshi , Miyashita Naoyuki , Maesaka Tomohiro , Ishibashi Kojiro , Yoshida Takeshi , Sivashanmugan Kundan , Hanayama Rikinari , Hirata Eishu , Miyata Kazuki , Kimura Hiroshi , Fukuma Takeshi
Published: December 2024

During cancer invasion and metastasis, the mechanical properties of the nucleus change significantly, with reduced elasticity enhancing nuclear deformability to aid cell migration through tight spaces. Traditional methods of measuring nuclear elasticity, such as using bead-attached cantilevers on cells or isolated nuclei, are limited because they also measure the elasticity of surrounding structures, including cell membranes and cytoskeletons. In this study, we used a Nanoendoscopy-atomic force microscope (AFM) with a nanoneedle probe to directly measure nuclear elasticity in living cells. Our findings show that nuclear elasticity increases with serum depletion but decreases when serum-starved cells are treated with TGF-β, which induces epithelial-mesenchymal transition (EMT). In addition, trimethylation levels of histone H4 at lysine 20 but not the expression levels of nuclear lamins positively correlate with these nuclear elasticities. We propose that changes in nuclear elasticity during cancer progression are associated with alterations in chromatin structure.
Characterization of DNA methylation in PBMCs and donor-matched iPSCs shows methylation is reset during stem cell reprogramming
Authors: Reed Xylena , Weller Cory A. , Saez-Atienzar Sara , Beilina Alexandra , Solaiman Sultana , Portley Makayla , Kaileh Mary , Roy Roshni , Ding Jinhui , Moore A. Zenobia , Whitaker D. Thad , Traynor Bryan J. , Gibbs J. Raphael , Scholz Sonja W. , Cookson Mark R.
Published: December 2024

DNA methylation is an important epigenetic mechanism that helps define and maintain cellular functions. It is influenced by many factors, including environmental exposures, genotype, cell type, sex, and aging. Since age is the primary risk factor for developing neurodegenerative diseases, it is important to determine if aging-related DNA methylation is retained when cells are reprogrammed to an induced Pluripotent Stem Cell (iPSC) state. Here, we selected peripheral blood mononuclear cells (PBMCs; n = 99) from a cohort of diverse and healthy individuals enrolled in the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (GESTALT) study to convert to iPSCs. After reprogramming we evaluated the resulting iPSCs for DNA methylation signatures to determine if they reflect the confounding factors of age and environmental factors. We used genome-wide DNA methylation arrays in both cell types to show that the epigenetic clock is largely reset to an early methylation age after conversion of PBMCs to iPSCs. We further examined the epigenetic age of each cell type using an Epigenome-wide Association Study (EWAS). Finally, we identified a set of methylation Quantitative Trait Loci (methQTL) in each cell type. Our results show that age-related DNA methylation is largely reset in iPSCs, and each cell type has a unique set of methylation sites that are genetically influenced.

Graphical Abstract

Highlights

Generation of a population-level set of iPSC lines from healthy individuals across the lifespan

Aging-related features were reset based on epigenetic markers of cytosine methylation and telomere length

By comparing methQTLs in iPSC vs. their donor PBMCs, we find that detection of methQTLs reflect biological functions of different cell types
Molecular mechanism of co-transcriptional H3K36 methylation by SETD2
Authors: Walshe James L. , Ochmann Moritz , Neef Ute , Dybkov Olexandr , Dienemann Christian , Oberthür Christiane , Zheenbekova Aiturgan , Urlaub Henning , Cramer Patrick
Published: December 2024

Tri-methylation of histone H3 at residue lysine-36 (H3K36me3) is a hallmark of actively and recently transcribed genes and contributes to cellular memory and identity. The deposition of H3K36me3 occurs co-transcriptionally when the methyltransferase SETD2 associates with RNA polymerase II (Pol II). Here we present three cryo-EM structures of SETD2 bound to Pol II elongation complexes at different states of nucleosome passage. Together with functional probing, our results suggest a 3-step mechanism of transcription-coupled H3K36me3 deposition. First, binding to the elongation factor SPT6 tethers the catalytic SET domain in proximity to the upstream DNA. Second, Pol II nucleosome passage leads to the transfer of a hexasome from downstream to upstream, poised for methylation. Finally, continued transcription leads to upstream nucleosome reassembly, partial dissociation of the histone chaperone FACT and sequential methylation of both H3 tails, completing H3K36me3 deposition of an upstream nucleosome after Pol II passage.
Genomic signatures of island colonization in highly diverse primates
Authors: Colmonero-Costeira I. , Guschanski K. , Djaló M.L. , Fernandes N. , Camará T. , Farh K.K.-H. , Kuderna L. , Rogers J. , Marques-Bonet T. , Bruford M.W. , Russo I-R.M. , Jensen A. , Ferreira da Silva M.J.
Published: December 2024

Understanding how small populations cope with loss of genetic diversity and deleterious variation is crucial to address the current biodiversity crisis. Insular populations are particularly interesting as they have often persisted at low population sizes and higher inbreeding than their mainland counterparts. While the genome-wide consequences of inbreeding in threatened insular species have received some attention, comparative genomics between insular and mainland populations of wide-spread and genetically diverse species have rarely been performed. Yet, they are particularly well suited to inform about the consequences of drastic population declines from initially large populations - a phenomenon that is becoming increasingly common. The spot-nosed monkey (Cercopithecus petaurista), the Campbell’s monkey (Cercopithecus campbelli) and the green monkey (Chlorocebus sabaeus) are common and genetically diverse West African primates. Insular populations can be found at the Bijagós Archipelago, Guinea-Bissau. Here, we assessed the genome-wide diversity, inbreeding, genetic load and adaptive variation using whole genome sequencing data from insular and mainland populations. In the three species, island populations showed lower genome-wide diversity and higher inbreeding. Genetic drift has likely promoted the conversion of masked genetic load into realized load without increased purging of deleterious variation. Additionally, we found no evidence for accumulation of deleterious variation, suggesting that these populations are not yet at risk of extinction by genetic factors and may act as reservoirs of mainland genetic diversity. We highlight, however, that other anthropogenic factors are threatening these insular primates and therefore conservation management should target their immediate threats and safeguard against additional loss of diversity.
Expression screen of TNFR1R347A, MyD88, IRAK4 death domains in E. coli followed by purification and biophysical characterization of TNFR1R347Adeath domain
Authors: Przytulski Kamil , Podkówka Aleksandra , Tomczyk Tomasz , Gajewska Daria , Sypień Magdalena , Jeleń Agnieszka , Dahate Priyanka , Szlachcic Anna , Biśta Michał , Walczak Michał J.
Published: December 2024

Death domains play a crucial role in signaling pathways related to inflammation and programmed cell death, rendering them promising targets for therapeutic interventions. However, their expression as recombinant proteins often pose challenges. Here, we present expression screening of TNFR1, IRAK4, and MyD88 death domains inE. coli, followed by the biophysical characterization of TNFR1 death domain after subsequent construct optimization. The study also discusses the influence of pH and ionic strength on TNFR1R347Astability, providing statistical models to predict optimal conditions of the buffer to achieve the highest protein stability.

Highlights

Optimization of expression conditions for TNFR1R347A, MyD88, IRAK4 death domains inE. coliBL21(DE3) cells.

High-yield production of soluble monomeric TNFR1R347Adeath domain.
Thyroid hormones act as a timer for the postnatal maturation of parvalbumin neurons in mouse neocortex
Authors: Ren Juan , Markossian Suzy , Guyot Romain , Aubert Denise , Brocard Jacques , Wong Jiemin , Flamant Frederic , Richard Sabine
Published: December 2024

Thyroid hormones are crucial for neurodevelopment, but the underlying mechanisms are still unclear. In the neocortex, mutations in thyroid hormone nuclear receptors affect the maturation of GABAergic inhibitory interneurons, and in particular a subset of these neurons that express parvalbumin. We found that, during a defined postnatal development stage, thyroid hormones are essential for the maturation of parvalbumin neurons. They notably promote the formation of the perineuronal net, a specialized extracellular matrix that contributes to the maturation of neocortical networks by stabilizing synapses around parvalbumin neurons. Experimental evidence strongly suggests that thyroid hormones act as a timer to define the temporal boundaries of the well-known critical period of heightened plasticity, during which neuronal networks are shaped by experience.
An age-specific burial practice reflected in ancient DNA preservation in Neolithic Çatalhöyük
Authors: Doğu Ayça Küçükakdağ , Baloğlu Fatma Küçük , Chyleński Maciej , Schotsmans Eline M.J. , Kılıç Muhammed Sıddık , Vural Kıvılcım Başak , Yüncü Eren , Kaptan Damla , Güler Merve N. , Yorulmaz Sevgi , Karabulut Nergis Bilge , Sağlıcan Ekin , Kazancı Duygu Deniz , Milella Marco , Marciniak Arkadiusz , Erdal Yılmaz Selim , Pilloud Marin , Larsen Clark Spencer , Götherström Anders , Hodder Ian , Özer Füsun , Haddow Scott D. , Knüsel Christopher J. , Somel Mehmet
Published: December 2024

Selective funerary practices can inform about social relationships in prehistoric societies but are often difficult to discern. Here we present evidence for an age-specific practice at the Neolithic site of Çatalhöyük in Anatolia, dating to the 7th millennium BCE. Among ancient DNA libraries produced from 362 petrous bone samples, those of subadults contained three times higher average human DNA than those of adults. This difference in organic preservation was also confirmed by FTIR analysis. Studying similar datasets from seven prehistoric and historical sites, we found a similar age-related difference in only one cemetery. We propose that the organic preservation difference with age was caused by the special treatment of chosen corpses before interment, such as defleshing or drying, which was more frequently applied to Çatalhöyük adults and promoted organic decay.
Single neuron diversity supports area functional specialization along the visual cortical pathways
Authors: Feyerabend M , Pommer S , Jimenez-Sosa MS , Rachel J , Sunstrum J , Preuss F , Mestern S , Hinkel R , Mietsch M , Viyajraghavan S , Everling S , Treue S , Arnsten AFT , Lewis DA , Wolf F , Murray J , McCarroll Steve , Muller Lyle , Krienen F , Datta D , Wang XJ , Tripathy SJ , Gonzalez-Burgos G , Inoue W , Neef A , Staiger JF , Martinez-Trujillo J
Published: December 2024

Humans and other primates have specialized visual pathways composed of interconnected cortical areas. The input area V1 contains neurons that encode basic visual features, whereas downstream in the lateral prefrontal cortex (LPFC) neurons acquire tuning for novel complex feature associations. It has been assumed that each cortical area is composed of repeatable neuronal subtypes, and variations in synaptic strength and connectivity patterns underlie functional specialization. Here we test the hypothesis that diversity in the intrinsic make-up of single neurons contributes to area specialization along the visual pathways. We measured morphological and electrophysiological properties of single neurons in areas V1 and LPFC of marmosets. Excitatory neurons in LPFC were larger, less excitable, and fired broader spikes than V1 neurons. Some inhibitory fast spiking interneurons in the LPFC had longer axons and fired spikes with longer latencies and a more depolarized action potential trough than in V1. Intrinsic bursting was found in subpopulations of both excitatory and inhibitory LPFC but not V1 neurons. The latter may favour temporal summation of spikes and therefore enhanced synaptic plasticity in LPFC relative to V1. Our results show that specialization within the primate visual system permeates the most basic processing level, the single neuron.
Pleiotropic function ofDlx5/6in coordinating the development of mammalian vocal and auditory organs
Authors: Sánchez-Garrido Frida , Bouzerand Victoria , Kaiser Markéta , Chaumeton Chloé , Fontaine Anastasia , Zikmund Tomáš , Kaiser Jozef , Heude Églantine
Published: December 2024

Acoustic communication, essential for mammalian social interactions, involves both effector (vocal) and receptor (auditory) organs that present a wide variety of morphologies between species. The molecular mechanisms supporting the harmonious diversification of effector and receptor systems along with the evolution of species-specific acoustic communication are still poorly understood. It is conceivable that common genetic pathways determine the parallel morphogenesis of vocal and auditory systems. Here, we investigated this question by generating mutant mice with targeted invalidation ofDlx5/6genes in the otic placode and cephalic neural crest cells, contributing to the formation of the ear and vocal tract components. We show thatDlx5/6inactivation provokes simultaneous defects of the outer, middle and inner ear and of the jaw, pharynx and larynx musculoskeletal systems. Our findings support the notion thatDlx5/6genes played a pleiotropic role in the co-adaptation of vocal and auditory systems in mammals.
Structural determinants of inverted Alu-mediated backsplicing revealed by -MaP and -JuMP
Authors: Waldern Justin M. , Taylor Colin , Giannetti Catherine A. , Irving Patrick S. , Allen Scott R. , Zhu Mingyi , Backofen Rolf , Mathews Dave , Weeks Kevin M. , Laederach Alain
Published: December 2024

Biogenesis of circular RNA usually involves a backsplicing reaction where the downstream donor site is ligated to the upstream acceptor site by the spliceosome. For this reaction to occur, it is hypothesized that these sites must be in proximity. Inverted repeat sequences, such as Alu elements, in the upstream and downstream introns are predicted to base-pair and represent one mechanism for inducing proximity. Here, we investigate the pre-mRNA structure of the humanHIPK3gene at exon 2, which forms a circular RNA via backsplicing. We leverage multiple chemical probing techniques, including the recently developed SHAPE- JuMP strategy, to characterize secondary and tertiary interactions in the pre- mRNA that govern backsplicing. Our data confirm that the antisense Alu elements, AluSz(-) and AluSq2(+) in the upstream and downstream introns, form a highly- paired interaction. Circularization requires formation of long-range Alu-mediated base pairs but does not require the full-length AluSq2(+). In addition to confirming long-range base pairs, our SHAPE-JuMP data identified multiple long-range interactions between non-pairing nucleotides. Genome-wide analysis of inverted repeats flanking circular RNAs confirm that their presence favors circularization, but the overall effect is modest. Together these results suggest that secondary structure considerations alone cannot fully explain backsplicing and additional interactions are key.
Zero valent sulfur is the product of assimilatory sulfite reductase and a substrate of cysteine synthase
Authors: Cao Qun , Liu Xuanyu , Zhang Xi , Wang Qingda , Xia Yongzhen , Xun Luying , Liu Huaiwei
Published: December 2024

The long process of the assimilatory sulfate-reduction consists of sulfate reduction to H2S and then H2S assimilation for cysteine synthesis. The concept has not been challenged for a long time until now. Herein, phylogenetic analysis grouped assimilatory sulfite reductases into five clusters and we re-examined four representatives from two major clusters. These enzymes produced both zero valent sulfur (S0) and H2S from sulfite. However, S0was more like a direct product, while H2S was just a derivative of S0via chemical reduction. Phylogenetic analysis of cysteine synthases grouped them into six clusters, and we re-examined six representatives from two major clusters. These enzymes used both glutathione persulfide (GSSH, a common intracellular compounds containing a S0atom) and H2S as substrates to synthesize cysteine, but preferred to use GSSH. These findings challenged the long standing concept and supported that S0, other than H2S, is the key intermediate during the process of inorganic sulfur converting to organic sulfur.

IMPORTANCE

First, this study provides new insights into the sulfate reduction process. Representative sulfite reductases were investigated and bothin vitro&in vivotests proved they produce more zero valent sulfur (S0) than H2S from sulfite. S0is the direct product while H2S is derivative of S0. Second, this study provides new insights into cysteine synthesis pathway. Screening and analyses revealed that most cysteine synthases prefer S0-containing compounds (e.g., GSSH) as substrate for cysteine synthesis. Together, the two findings indicate that S0is the key knot connecting sulfate reduction and cysteine synthesis, not the long believed H2S.
Encephalomyocarditis virus non-structural protein 2C degrades NDP52 autophagy protein to promote its own survival
Authors: Mo Rongqian , Cheng Rongrong , Dong Pingan , Ma Tingting , Zhang Yaxin , Xie Jingying , Li Shasha , Li Huixia , Idris Adi , Li Xiangrong , Feng Ruofei
Published: December 2024

Encephalomyocarditis virus (EMCV) is an important zoonotic pathogen that causes encephalitis and myocarditis, primarily in pigs and in some mammals. Nuclear dot protein (NDP) 52 is an important autophagy adaptor protein that is known to target microbial pathogens, including viruses into autophagosomes to facilitate the selective autophagy process. Here, we wanted to investigate how an important zoonotic virus such as EMCV interacts with NDP52. We found that NDP52 negatively regulates the entry and replication phases of EMCV and interacts with EMCV VP1/VP2 proteins to mediate its autophagic degradation. EMCV counteracts this by exerting autophagy induction through its encoded 2C protein. The autophagy machinery then hijacks NDP52 and transports it to lysosomes for subsequent degradation via late endosomal molecules Rab7 and Rab9. Our study describes a novel mechanism by which EMCV escapes the host’s antiviral response to promote its survival by hijacking the autophagy pathway using the non-structural protein 2C of EMCV.

Importance

EMCV is an important zoonotic pathogen that can induce autophagy, but the regulatory role of autophagy receptors in EMCV infection has been rarely reported. Herein, we show that NDP52 is a novel host limiting factor for EMCV, which not only inhibits early EMCV endocytosis, but also restricts EMCV replication in vitro by controlling autophagic degradation of EMCV structural proteins VP1 and VP2. In order to counteract this, EMCV uses the N-terminal region of its non-structural protein 2C to interact with NDP52, and hijacks the autophagy machine to transport NDP52 to lysosomes for degradation, which weakens NDP52-mediated degradation of VP1 and VP2. Importantly, we reveal a novel mechanism by which EMCV evades the host antiviral response, contributing to a deeper understanding of the infectious mechanism of EMCV and providing new ideas for the design of antiviral drug targets.
Regulation of Fungal Morphology, Conidiogenesis and Violet Pigment Synthesis by the Betalain Biosynthesis Pathway Genes inAspergillus sydowiiH-1
Authors: Ran Yulu , Cao Yu , Guo Yihan , Zeng Jie , Wang Jiale , Xiang Dongyou , Xu Hui , Cao Yi
Published: December 2024

The biosynthesis of antioxidant pigments, namely, betalains, has predominantly been found in Caryophyllales. The potential betalains biosynthesis was firstly explored inAspergillus sydowiiH-1 under controlled culture conditions. This study identified, knocked out, and overexpressed genes involved in the betanin biosynthesis and assessed the activities of tyrosinase, 4’5-DOPA dioxygenase and LigB. The results indicated these betanin biosynthesis pathway was crucial for colony morphology, conidiogenesis, stress response, and violet pigment synthesis. Moreover, AsDODA and AsLigB catalyzed the conversion of L-DOPA into 4’5-seco-DOPA, a key intermediate in the formation of betalamic acid in vitro. Additionally, transcription factors such as AsbHLH, AsMYB1R, and AsWD40 positively regulated the expression of betalain biosynthesis genes. This research provides new insights into the evolutionary origins of betalain-producing species, expanding the scope of betalain biosynthesis to includeAspergillusspecies.

Importance

To date, betalains were restricted to plants of the order Caryophyllales, fungi of Basidiomycota and several types of bacteria. This study is the first to demonstrate the potential of AscomycetesA. sydowiiH-1 to synthesize betalains under controlled culture conditions, providing a detailed genetic and biological characterization of the associated genes and metabolic pathways. This finding demonstrates that betalain biosynthesis can be expanded to otherAspergillus.
Differentiation and co-occurrence of obsessive-compulsive disorder and autism spectrum disorder in people with intellectual developmental disorder: a case series on symptoms specificities
Authors: Andreini Nicole , Boniotti Veronica , Scuticchio Daniela , Bianco Annamaria , Bertelli Marco O.
Published: December 2024

Purpose

In persons with an intellectual developmental disorder, obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD) are often difficult to differentiate, particularly when patients present major communication difficulties and low accessibility to subjective symptoms and clinicians are poorly trained in the specific psychopathological phenomenology. OCD and ASD share some important symptoms such as repetitiveness of behaviours, low flexibility to contextual variations or a narrow range of interests. The purpose of this study is to identify and describe symptomatological specificities, including how they manifest at behavioural level.

Design/methodology/approach

The present study is a retrospective case series study (n = 3) focusing on in-depth assessment, detection and comprehension of symptomatological specificities as well as on the direct observation of behavioural symptoms.

Findings

Some symptoms such as signs of sudden autonomous nervous system activation or behavioural equivalents of obsessive thoughts are crucial in achieving an effective differential or comorbidity diagnosis. These symptoms can be identified through a multidisciplinary and comprehensive evaluation, integrating present clinical and test findings with a thorough developmental and medical history. Symptoms should also be interpreted in the light of antecedent, contextual and personal factors.

Originality/value

Differential diagnosis between OCD and ASD in persons with major cognitive and communication issues is a rather neglected research area, although it has significant implications for treatment planning and implementation.
Driving resiliency and digitalization in the sourcing process: integration of blockchain technology and smart contracts
Authors: Meafa Azz-Eddine , Chaouni Benabdellah Abla , Zekhnini Kamar , Belhadi Amine , Kamble Sachin
Published: December 2024

Purpose

Under the current untrusted business environment, digital technologies, such as blockchain technology (BT), show the potential to digitally transform SC processes particularly the sourcing process (SP). Indeed, this process suffers from a lack of digitalization, a lack of trust and a high workload in the automotive supply chain (ASC). Therefore, BT coupled with smart contracts can deal with such issues by fostering trust, transparency, reliability and traceability as a digital solution.

Design/methodology/approach

This paper conducts multiple case studies in the automotive sector and interviews 11 managers from two firms. It follows the managers’ perspective to identify and analyze the main issues that occurred while conducting this process using the existing technology.

Findings

It proposes a new architecture for the smart sourcing process (SSP) that uses BT & smart contracts to mitigate the identified issues, enable traceability, improve resilience, eliminate intermediaries, automate tasks, and enhance trust and data management. Also, the paper provides a decision tree to help determine which blockchain platform is needed for adopting the SSP solution.

Practical implications

This study is useful for both academics and practitioners as it demonstrates the digitalization of one of the SC processes using BT and smart contracts, as well as develops a roadmap for digitalizing the SP of the ASC, and solves its vulnerabilities.

Originality/value

BT has been used by researchers to digitalize the sourcing process only in the public procurement area. Considering all the faced challenges by the private procurement area, this paper aims to present a new architecture for the digitalization of the SP using BT and smart contracts in the ASC as a private SC.
Are developmental performance management systems inclusive? An intersectional analysis for age and gender
Authors: Nepoti Francesca , Curzi Ylenia , Ferrarini Filippo
Published: December 2024

Purpose

Rooted in Joan Acker’s “gendered organisations” framework, this paper aims to explore the impact of employee’s developmental performance management systems (DPMSs) on occupational wellbeing, highlighting gender and age-based intersectional disparities within organisations.

Design/methodology/approach

This study uses data from a sample of more than 600 Italian employees and investigates with a three-way interaction, the effect that DPMS have on employee’s occupational wellbeing by considering the intersectionality between gender and ages’ categories.

Findings

The findings dismiss the idea that DPMS can be regarded as a practice for inclusion. Moreover, the analysis discloses the need for intersectional perspective as the authors do reveal different effects of developmental performance system adoption on occupational wellbeing for people in diverse intersections of genders and ages.

Originality/value

This paper expands on Acker’s tradition with a focus on age, dismissing the possible inclusive outcome of competency based employee performance systems.
The effects of the different dimensions of social capital on situated learning processes in projects
Authors: Guribie Francis Lanme , Owusu-Manu Dr. De-Graft , Badu Edward , Edwards David John
Published: December 2024

Purpose

The purpose of the study is to demonstrate the influences of three dimensions of social capital (the structural, relational and cognitive dimensions) on five situated learning processes (institutionalization, socialization, knowledge articulation, experience accumulation and knowledge reuse) in projects.

Design/methodology/approach

Drawing on a cross sectional survey, data were drawn from 203 construction professionals in Ghana who have hands-on experience in managing projects. Partial least square structural equation modeling was used to conduct both confirmatory factor analysis and path analysis of the structural model of the relationship between these two constructs.

Findings

In relation to the research questions, all three dimensions of social capital have effects of the situating learning processes. However, the research’s key finding is that the relational dimension of social capital exerts much influence on the situated learning processes in projects, with the structural and cognitive dimensions of social capital exerting medium and small effects, respectively.

Practical implications

The study’s key finding implies that – addressing the “relational” conditioners that moderate project participants’ behaviour in social relationships is critical for increasing situated learning activity in projects. These must, however, be complemented by both structural and cognitive factors.

Originality/value

The research findings expand existing frontiers of knowledge by addressing the gap in the literature on the lack of practical demonstration of the influences exerted by the various dimensions of social capital on a situated learning activity in projects.
Digitalization and bank performance: the mediator effect of financial stability and moderator effect of nonperforming loans
Authors: Saadaoui Amir , Chouchene Issam
Published: December 2024

Purpose

Digitalization is a keyword not only mentioned in recent years but also strongly applied by financial institutions. However, the benefits of digitalization for banks remain an issue that needs to be investigated.

Design/methodology/approach

Therefore, this study is conducted to determine the role of digitalization in improving the financial performance of banks in the presence of financial stability as a mediating variable and nonperforming loans (NPLs) as a moderating variable. The research was conducted by African banks between 2000 and 2021.

Findings

Using panel data, the results showed that digitalization has a positive and significant effect on the performance of African banks. Similarly, the results showed that the financial stability of African banks plays a mediating role between digitalization and performance.

Originality/value

However, the effect of digitalization on the performance of African banks goes through their financial stability, which verifies its mediating role. Similarly, this study’s results showed that NPLs have a moderating role between digitalization and bank performance. Indeed, this paper found that NPLs play a braking role that minimizes the effect of digitalization on improving the financial performance of banks.