bluuebunny/crossref_metadata_2025 huggingface dataset:
The embryonic role of juvenile hormone in the firebrat,Thermobia domestica,reveals its function before its involvement in metamorphosis
Authors: Truman James W. , Riddiford Lynn M. , Konopová Barbora , Nouzova Marcela , Noriega Fernando G. , Herko Michelle
Published: October 2023

To gain insights into how juvenile hormone (JH) came to regulate insect metamorphosis, we studied its function in the ametabolous firebrat,Thermobia domestica. Highest levels of JH occur during late embryogenesis, with only low levels thereafter. Loss-of-function and gain-of-function experiments show that JH acts on embryonic tissues to suppress morphogenesis and cell determination and to promote their terminal differentiation. Similar embryonic actions of JH on hemimetabolous insects with short germ band embryos indicate that JH’s embryonic role preceded its derived function as the postembryonic regulator of metamorphosis. The postembryonic expansion of JH function likely followed the evolution of flight. Archaic flying insects were considered to lack metamorphosis because tiny, movable wings were evident on the thoraces of young juveniles and their positive allometric growth eventually allowed them to support flight in late juveniles. Like inThermobia, we assume that these juveniles lacked JH. However, a postembryonic reappearance of JH during wing morphogenesis in the young juvenile likely redirected wing development to make a wing pad rather than a wing. Maintenance of JH then allowed wing pad growth and its disappearance in the mature juvenile then allowed wing differentiation. Subsequent modification of JH action for hemi- and holometabolous lifestyles are discussed.

Significance

The likely action of this sesquiterpene hormone as a morphogenesis-to-differentiation switch in archaic embryos preadapted it for later assuming its function as thestatus quoregulator of insect metamorphosis.
Woollymutation withGet02locus overcomes the polygenic nature of trichome-based pest resistance in tomato
Authors: Vendemiatti Eloisa , Hernández-De Lira Inty O. , Snijders Roxane , Torne Tanmayee , Therezan Rodrigo , Prants Gabriela , Lopez-Ortiz Carlos , Reddy Umesh , Bleeker Petra , Schenck Craig A. , Peres Lázaro Eustáquio Pereira , Benedito Vagner Augusto
Published: October 2023

Type-IV glandular trichomes, which only occur in the juvenile phase of tomato development, produce acylsugars (AS) that broadly protect against arthropod herbivory. Previously, we introgressed the capacity to retain type-IV trichomes in the adult phase fromSolanum galapagenseinto the cv. Micro-Tom (MT). The resulting MT-Getline contained five loci associated with enhancing the density of type-IV trichomes in adult plants. We genetically dissected MT-Getand obtained a sub-line containing only the locus on chromosome 2 (MT-Get02). This genotype displayed about half the density of type-IV trichomes compared to the wild progenitor. However, when we stacked the gain-of-function allele ofWOOLLY, which codes for a HD-ZIP IV transcription factor, MT-Get02/Woexhibited double the number of type-IV trichomes compared toS. galapagense. This discovery corroborates previous reports positioningWOOLLYas a master regulator of trichome development. AS levels in MT-Get02/Wowere comparable to the wild progenitor, although the composition of AS types differed, especially regarding less AS with medium-length acyl chains. Agronomical parameters of MT-Get02/Wo, including yield, were comparable to MT. Pest resistance assays showed enhanced protection against whitefly, caterpillar, and the fungusSeptoria lycopersici. However, resistance levels did not reach that of the wild progenitor, suggesting the specificity of particulars AS types in the pest resistance mechanism. Our findings in trichome-mediated resistance advance the development of robust, naturally resistant tomato varieties, harnessing the potential of natural genetic variation. Moreover, by manipulating only two loci, we achieved exceptional results for a highly complex, polygenic trait, such as herbivory resistance in tomato.
Accelerated brain change in healthy adults is associated with genetic risk for Alzheimer’s disease and uncovers adult lifespan memory decline
Authors: Roe James M. , Vidal-Piñeiro Didac , Sørensen Øystein , Grydeland Håkon , Leonardsen Esten H. , Iakunchykova Olena , Pan Mengyu , Mowinckel Athanasia , Strømstad Marie , Nawijn Laura , Milaneschi Yuri , Andersson Micael , Pudas Sara , Bråthen Anne Cecilie Sjøli , Kransberg Jonas , Falch Emilie Sogn , Øverbye Knut , Kievit Rogier A. , Ebmeier Klaus P. , Lindenberger Ulman , Ghisletta Paolo , Demnitz Naiara , Boraxbekk Carl-Johan ,   the Alzheimer‘s Disease Neuroimaging Initiative,   the Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing, Penninx Brenda , Bertram Lars , Nyberg Lars , Walhovd Kristine B. , Fjell Anders M. , Wang Yunpeng
Published: October 2023

Across healthy adult life our brains undergo gradual structural change in a pattern of atrophy that resembles accelerated brain changes in Alzheimer’s disease (AD). Here, using four polygenic risk scores for AD (PRS-AD) in a longitudinal adult lifespan sample aged 30 to 89 years (2-7 timepoints), we show that healthy individuals who lose brain volume faster than expected for their age, have a higher genetic AD risk. We first demonstrate PRS-AD associations with change in early Braak regions, namely hippocampus, entorhinal cortex, and amygdala, and find evidence these extend beyond that predicted byAPOEgenotype. Next, following the hypothesis that brain changes in ageing and AD are largely shared, we performed machine learning classification on brain change trajectories conditional on age in longitudinal AD patient-control data, to obtain a list of AD-accelerated features and model change in these in adult lifespan data. We found PRS-AD was associated with a multivariate marker of accelerated change in many of these features in healthy adults, and that most individuals above ∼50 years of age are on an accelerated change trajectory in AD-accelerated brain regions. Finally, high PRS-AD individuals also high on a multivariate marker of change showed more adult lifespan memory decline, compared to high PRS-AD individuals with less brain change. Our results support a dimensional account linking normal brain ageing with AD, suggesting AD risk genes speed up the shared pattern of ageing- and AD-related neurodegeneration that starts early, occurs along a continuum, and tracks memory change in healthy adults.
Comparison of germline and somatic structural variants in cancers reveal systematic differences in variant generating and selection processes
Authors: Chukwu Wolu , Lee Siyun , Crane Alexander , Zhang Shu , Webster Sophie , Mittra Ipsa , Imielinski Marcin , Beroukhim Rameen , Dubois Frank , Dalin Simona
Published: October 2023

Although several recent studies have characterized structural variants (SVs) in germline and cancer genomes, the features of SVs in these different contexts have not been directly compared. We examined similarities and differences between 2 million germline and 115 thousand tumor SVs from a cohort of 963 patients from The Cancer Genome Atlas (TCGA). We found significant differences in features related to their genomic sequences and localization that suggest differences between SV-generating processes and selective pressures. For example, we found that transposon-mediated processes shape germline much more than somatic SVs, while somatic SVs more frequently show features characteristic of chromoanagenesis. These differences were extensive enough to enable us to develop a classifier-“the great GaTSV”-that accurately distinguishes between germline and cancer SVs in tumor samples that lack a matched normal sample.
Mutations in geneslpxL1, bamAandpmrBimpair the susceptibility of cystic fibrosis strains ofPseudomonas aeruginosato murepavadin
Authors: Ghassani Aya , Triponney Pauline , Bour Maxime , Plesiat Patrick , Jeannot Katy ,   MucoMicrobes study Group
Published: October 2023

Murepavadin is a peptidomimetic exhibiting specific inhibitory activity againstPseudomonasspecies. In the present study, itsin vitroactivity was assessed on 230 cystic fibrosis (CF) strains ofP. aeruginosaisolated from twelve French hospitals, in comparison with twelve other antipseudomonal antibiotics. Although murepavadin is still in pre-clinical stage of development, 9.1% (n=21) of the strains displayed a resistance superior to 4 mg/L, a level at least 128-fold higher than the modal MIC value of the whole collection (≤ 0.06 mg/L). Whole-genome sequencing of these 21 strains along with more susceptible isogenic counterparts coexisting in the same patients revealed diverse mutations in genes involved in the synthesis (lpxL1andlpxL2) or transport of lipopolysaccharides (bamA, lptD, andmsbA), or encoding histidine kinases of two-component systems (pmrBandcbrA). Allelic replacement experiments with wild-type reference strain PAO1 confirmed that alteration of geneslpxL1, bamAand/orpmrBcan increase murepavadin resistance from 8- to 32-fold. Furthermore, we found that specific amino-acid substitutions in histidine kinase PmrB (G188D, Q105P, and D45E) reduce the susceptibility ofP. aeruginosato murepavadin, colistin and tobramycin, three antibiotics used or intended to be used (murepavadin) in aerosols to treat colonized CF patients. Whether colistin or tobramycin may select mutants resistant to murepavadin or the opposite needs to be addressed by clinical studies.
25-hydroxycholesterol mediates brain cytokine production and neutrophil infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation
Authors: Romero Johnathan , Toral-Rios Danira , Yu Jinsheng , Paul Steven M , Cashikar Anil G
Published: October 2023

Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers of neuroinflammation and in response to different inflammatory stimuli overexpress a proinflammatory signature of genes. Among these,Ch25his a gene overexpressed in brain tissue from Alzheimer’s disease as well as various mouse models of neuroinflammation.Ch25hencodes cholesterol 25-hydroxylase, an enzyme that hydroxylates cholesterol to form 25-hydroxycholesterol (25HC). 25HC, an immune-oxysterol primarily produced by activated microglia, is further metabolized to 7α,25-dihydroxycholesterol, which is a potent chemoattractant for leukocytes. We have also previously shown that 25HC increases production and secretion of the proinflammatory cytokine, IL-1β, by mouse microglia treated with lipopolysaccharide (LPS). In the present study, wildtype (WT) andCh25h-knockout (CKO) mice were peripherally administered LPS to induce an inflammatory state in the brain. In LPS-treatedWTmice,Ch25hexpression and 25HC levels increased in brain relative to vehicle-treatedWTmice. Interestingly, 25HC levels were significantly higher in LPS-treatedWTfemale compared to male mice. Activation of microglia and astrocytes in response to systemic LPS was suppressed inCKOmice relative toWTmice. Proinflammatory cytokine production and intra-parenchymal infiltration of neutrophils strongly correlated with brain 25HC levels and were significantly lower inCKOcompared toWTmice. Overall, our results show that 25HC mediates a sex-specific proinflammatory response in the brain characterized by activation of both microglia and astrocytes but also by neutrophil migration into the brain parenchyma presumably due to 7α,25-diHC produced from 25HC.
Sexually dimorphic effects of pexidartinib on nerve injury-induced neuropathic pain in mice
Authors: Saika Fumihiro , Fukazawa Yohji , Hatano Yu , Kishioka Shiroh , Hino Shinjiro , Suzuki Kentaro , Kiguchi Norikazu
Published: October 2023

Background

It is well-established that spinal microglia and peripheral macrophages play critical roles in the etiology of neuropathic pain; however, growing evidence suggests sex differences in pain hypersensitivity owing to microglia and macrophages. Therefore, it is crucial to understand sex- and androgen-dependent characteristics of pain-related myeloid cells in mice with nerve injury-induced neuropathic pain.

Methods

The current study was performed using normal male and female mice, as well as gonadectomized (GDX) male mice. To deplete microglia and macrophages, pexidartinib (PLX3397), an inhibitor of the colony-stimulating factor 1 receptor, was orally administered, and mice were subjected to partial sciatic nerve ligation (PSL). Immunohistochemistry was performed to visualize microglia and macrophages, and PSL-induced mechanical allodynia was evaluated using the von Frey test.

Results

Following PSL induction, healthy male and female mice and male GDX mice exhibited similar levels of spinal microglial activation, peripheral macrophage accumulation, and mechanical allodynia. Treatment with PLX3397 significantly suppressed mechanical allodynia in normal males; this was not observed in female and GDX male mice. Sex- and androgen-dependent differences in the PLX3397-mediated preventive effects were observed on spinal microglia and dorsal root ganglia (DRG) macrophages, as well as in expression patterns of pain-related inflammatory mediators in these cells. Conversely, no sex- or androgen-dependent differences were detected in sciatic nerve macrophages, and inhibition of peripheral CC-chemokine receptor 5 prevented neuropathic pain in both sexes.

Conclusion

Collectively, these findings demonstrate the presence of considerable sex- and androgen-dependent differences in the etiology of neuropathic pain in spinal microglia and DRG macrophages but not in sciatic nerve macrophages. Given that the mechanisms of neuropathic pain may differ among experimental models and clinical conditions, accumulating several lines of evidence is crucial to comprehensively clarifying the sex-dependent regulatory mechanisms of pain.
Population of the Paraná AntwrenFormicivora acutirostrisreassessed as being 64% smaller: Revision of its conservation status and assessment of its Green Status, with management proposals
Authors: Bornschein Marcos R. , Sandretti-Silva Giovanna , Sobotka Daiane D. , Corrêa Leandro , Reinert Bianca L. , Vannucchi Fabio Stucchi , Pie Marcio R.
Published: October 2023

Assessing the conservation status of a species is important for designing effective conservation measures. Consequently, it is often vital to review it to update biodiversity management.Formicivora acutirostrisis a bird from coastal marshes and related habitats of Brazil’s southern flood plains. It is considered endangered in Brazil but near threatened globally. In 2007, its area of occupancy (AOO) and population size were estimated based on assessment of aerial photographs from 1978 and 1980. Since the species is threatened and occupies a small area scattered across a coastal pressured region, we aimed to reassess its conservation status and assess its Green Status. We compiled new records, conducted new density estimates, and compared the previous mapping with orbital imagery to estimate the current AOO, habitat loss, population size, and review its conservation status based on the International Union for Conservation of Nature criteria. The species is distributed across 10 populations, including two new populations from the southern coast of Santa Catarina to the northern coast of Rio Grande do Sul. We estimated the AOO at 4,102 ha and the population as 6,284 mature territorial individuals. The previously mapped AOO has decreased by 1,535 ha due to ecological succession. The loss of habitat due to invasion by exotic grasses is the main anthropogenic impact. We recommend that the species be considered vulnerable. The Green Status indicates that the Conservation Legacy of actions taken thus far and the Conservation Dependence of ongoing actions are null, but it highlights the importance of future actions for species conservation. We propose the establishment of exotic-free zones as small geographic areas with a significant amount of minimally invaded environments, which we suggest as priority areas for the conservation of the species due to their cost-effective management potential. We also propose assisted colonization to enhance its long-term conservation.
CEBPA restricts alveolar type 2 cell plasticity during development and injury-repair
Authors: Hassan Dalia , Chen Jichao
Published: October 2023

Cell plasticity theoretically extends to all possible cell types, but naturally decreases as cells differentiate, whereas injury-repair re-engages the developmental plasticity. Here we show that the lung alveolar type 2 (AT2)-specific transcription factor (TF), CEBPA, restricts AT2 cell plasticity in the mouse lung. AT2 cells undergo transcriptional and epigenetic maturation postnatally. Without CEBPA, both neonatal and mature AT2 cells reduce the AT2 program, but only the former reactivate the SOX9 progenitor program. Sendai virus infection bestows mature AT2 cells with neonatal plasticity whereCebpamutant, but not wild type, AT2 cells express SOX9, as well as more readily proliferate and form KRT8/CLDN4+ transitional cells. CEBPA promotes the AT2 program by recruiting the lung lineage TF NKX2-1. The temporal change in CEBPA-dependent plasticity reflects AT2 cell developmental history. The ontogeny of AT2 cell plasticity and its transcriptional and epigenetic mechanisms have implications in lung regeneration and cancer.
A DOMON domain-cytochrome b561 protein acts as a ferric reductase in iron homeostasis and impacts primary root growth under phosphate deficiency
Authors: Clúa Joaquín , Montpetit Jonatan , Poirier Yves
Published: October 2023

Iron (Fe) and phosphate (Pi) are essential nutrients for plant growth. Several interactions between Fe and Pi homeostasis have been described, such as the Fe-dependent inhibition of primary root growth under Pi deficiency. This response involves the formation of apoplastic Fe+3-malate complexes in the root meristem which implicates the oxidation of Fe+2by the LPR1 ferroxidase. However, how is the reduced Fe+2generated in the root meristem and the Fe+3/Fe+2ratio regulated is unknown. Here, we have identified a gene inArabidopsis thaliana, namedCRR, that is implicated in primary root growth under Pi deficiency. Under low-Pi conditions, thecrrmutant showed an enhanced reduction of primary root growth that was associated with increased accumulation of apoplastic Fe in the root meristem and a reduction in meristematic cell division. Conversely, CRR overexpression rendered primary root growth insensitive to low-Pi inhibition, reduced root apoplastic Fe deposition, and impacted the expression of genes involved in Fe and redox homeostasis. CRR is a member of an uncharacterized CYBDOM protein family possessing a cytochrome b561 (CYB561) with an N-terminal DOMON domain. We demonstrated that CRR localizes to the plasma membrane and possesses ascorbate-dependent ferric reductase activity. Thecrrsingle mutant and thecrr hyp1double mutant, which harbored a null allele in another member of the CYDOM family, showed increased tolerance to high-Fe stress upon germination and seedling growth. In contrast, CRR overexpression was associated with increased uptake and translocation of Fe to the shoot and resulted in plants highly sensitive to Fe excess toxicity. Our results thus identify a ferric reductase implicated in root Fe acquisition and homeostasis and reveal a biological role for CYBDOM proteins in plants.
Interaction of GAT1 with sodium ions: from efficient recruitment to stabilisation of substrate and conformation
Authors: Lazzarin Erika , Gradisch Ralph , Skopec Sophie M.C. , Alves da Silva Leticia , Sebastianelli-Schoditsch Chiara , Szöllősi Dániel , Maier Julian , Sucic Sonja , Roblek Marko , Kanner Baruch I. , Sitte Harald H. , Stockner Thomas
Published: October 2023

The human GABA transporter (GAT1) is a membrane transporter that mediates the reuptake of the neurotransmitter GABA from the synaptic cleft into neurons and glial cells. Dysregulation of the transport cycle has been associated with epilepsy and neuropsychiatric disorders, highlighting the crucial role of the transporter in maintaining homeostasis of brain GABA levels. GAT1 is a secondary active transporter that couples the movement of substrate to the simultaneous transport of sodium and chloride ions along their electrochemical gradients. Using MD simulations, we identified a novel sodium recruiting site at the entrance to the outer vestibule, which attracts positively charged ions and increases the local sodium concentration, thereby indirectly increasing sodium affinity. Mutations of negatively charged residues at the recruiting site slowed the binding kinetics, while experimental data revealed a change in sodium dependency of GABA uptake and a reduction of sodium affinity. Simulation showed that sodium displays a higher affinity for the sodium binding site NA2, which plays a role in stabilisation of the outward-open conformation. We directly show that the presence of a sodium ion bound to NA2 increases the stability of the closed inner gate and restrains motions of TM5. We find that sodium is only weakly bound to NA1 in the absence of GABA, while the presence of the substrate strengthens the interaction due to the completed ion coordinating shell, explaining cooperativity between GABA and sodium.
Increased circulating CD39+FoxP3+CD4+ regulatory T cells in Early Rheumatoid Arthritis facilitate the antiinflammatory action of methotrexate and associate with the clinical response
Authors: Villalba Alejandro , Nuño Laura , Benito-Miguel Marta , Nieto-Carvalhal Beatriz , Novella-Navarro Marta , Monjo Irene , Peiteado Diana , García-Carazo Sara , Balsa Alejandro , Miranda-Carús María-Eugenia
Published: October 2023

OBJECTIVES

FoxP3+ regulatory T cells (Tregs) are key to the immune system homeostasis; their CD39+ subset (Treg39+) hydrolises adenine nucleotides released by stressed cells, rendering the antiinflammatory adenosine. Methotrexate (MTX), inhibiting AICAR transformylase (ATIC), enhances the extrusion of adenine nucleotides and hence may help Treg39+ cells control inflammation. Therefore, we examined the relation of CD39 expression on Tregs of early RA (ERA) patients with the effect of MTX.

METHODS

Freshly isolated lymphocytes from 72 untreated ERA patients (duration <24 weeks) and 72 healthy controls (HCs) were examined by cytometry. Treg cell potency was assessed in cocultures of CD4+CD25+CD127- Treg with CD4+CD25- CD127+ responder T cells (Tresp).

RESULTS

ERA patients demonstrated a superior frequency of circulating Tregs containing increased proportions of Treg39+ cells. Total ERA Tregs were more potent than HC Tregs and MTX further heightened their potency, with greater amplification in ERA vs HC; differences were reduced by adenosine pathway blockade. The potency of isolated Treg39+ and its enhancement by MTX were comparable for ERA and HC suggesting that the differences seen with total Tregs are due to the increased ERA Treg39+ frequency. Basal Treg39+ cell proportions > 39.3 associated with a good 12 month EULAR response [RR 13.4 (2.9-75.6)]. At 12 months, the ERA Treg39+ frequency had decreased to HC levels but its association with the clinical response remained.

CONCLUSION

MTX cooperates with Treg39+ cells and the basal Treg39+ frequency is a predictor of clinical response. The increased circulating Treg39+ cells in untreated ERA would further facilitate the action of MTX thereby providing a slot for prompt MTX initiation.
Phosphorylation Promotes DELLA Activity by Enhancing Its Binding to Histone H2A at Target Chromatin inArabidopsis
Authors: Huang Xu , Zentella Rodolfo , Park Jeongmoo , Reser Larry , Bai Dina L. , Ross Mark M. , Shabanowitz Jeffrey , Hunt Donald F. , Sun Tai-ping
Published: October 2023

DELLA proteins are conserved master growth regulators that play a central role in controlling plant development in response to internal and environmental cues. DELLAs function as transcription regulators, which are recruited to target promoters by binding to transcription factors (TFs) and histone H2A via its GRAS domain. Recent studies showed that DELLA stability is regulated post-translationally via two mechanisms, phytohormone gibberellin-induced polyubiquitination for its rapid degradation, and Small Ubiquitin-like Modifier (SUMO)- conjugation to alter its accumulation. Moreover, DELLA activity is dynamically modulated by two distinct glycosylations: DELLA-TF interactions are enhanced byO-fucosylation, but inhibited byO-linkedN-acetylglucosamine (O-GlcNAc) modification. However, the role of DELLA phosphorylation remains unclear. Here, we identified phosphorylation sites in REPRESSOR OFga1-3(RGA, an AtDELLA) purified fromArabidopsisby tandem mass spectrometry analysis, and showed that phosphorylation of the RGA LKS-peptide in the poly- S/T region enhances RGA-H2A interaction and RGA association with target promoters. Interestingly, phosphorylation does not affect RGA-TF interactions. Our study has uncovered that phosphorylation is a new regulatory mechanism of DELLA activity.
Full genome sequence analysis of African swine fever virus isolates from Cameroon
Authors: Goatley Lynnette C , Freimanis Graham , Tennakoon Chandana , Foster Thomas J , Quershi Mehnaz , Dixon Linda K , Batten Carrie , Forth Jan Hendrik , Wade Abel , Netherton Christopher L
Published: October 2023

African swine fever is a devastating disease of domestic pigs that has spread across the globe since its introduction into Georgia in 2007. The etiological agent is a large double-stranded DNA virus with a genome of 170 to 180 kb in length depending on the isolate. Much of the differences in genome length between isolates are due to variations in the copy number of five different multigene families that are encoded in repetitive regions that are towards the termini of the covalently closed ends of the genome. Molecular epidemiology of ASFV is primarily based on Sanger sequencing of a few conserved and variable regions, but due to the stability of the dsDNA genome changes in the variable regions occur relatively slowly. Observations in Europe and Asia have shown that changes in other genetic loci can occur and that this could be useful in molecular tracking. ASFV has been circulating in Western Africa for at least forty years. It is therefore reasonable to assume that changes may have accumulated in regions of the genome other than the standard targets over the years. At present only one full genome sequence is available for an isolate from Western Africa, that of a highly virulent isolate collected from Benin during an outbreak in 1997. In Cameroon, ASFV was first reported in 1981 and outbreaks have been reported to the present day and is considered endemic. Here we report three full genome sequences from Cameroon isolates of 1982, 1994 and 2018 outbreaks and identify novel single nucleotide polymorphisms and insertion-deletions that may prove useful for molecular epidemiology studies in Western Africa and beyond.
Multigenerational inheritance of parasitic stress memory inDrosophila melanogaster
Authors: Khan Shagufta , Saini Ravina , Hamid Runa , Mishra Rakesh K
Published: October 2023

Organisms sense harmful environmental conditions and employ strategies to safeguard themselves. Moreover, they can communicate this experience to the next generation or beyond via non-DNA sequence-based mechanisms, referred to as intergenerational or transgenerational epigenetic inheritance, respectively. Using a specialist larval parasitoid,Leptopilina boulardi, and its host,Drosophila melanogaster, we show that the parental experience of parasitic stress results in an increased survivability of the immediate offspring of the host. Furthermore, we observe that the increased survivability in response to the parasitic stress is transmitted transgenerationally where the grandparents have been exposed to the parasitoid but not the parents. The increased survivability is primarily inherited through male parents, and at least one of the forms of the memory is better immune priming at larval stage. Our study suggests that the stress exposure during the pre-adult stage of the host has lifetime benefits for its progeny to deal with the future parasitic attack.
Prolonged metaphase II arrest weakens Aurora B/C- dependent error correction in mouse oocytes
Authors: Langeoire Antoine , Kem-Seng Alison , Cladière Damien , Wassmann Katja , Buffin Eulalie
Published: October 2023

Chromosome segregation during meiosis is highly error-prone in mammalian oocytes. The mechanisms controlling chromosome attachments and the Spindle Assembly Checkpoint (SAC) have been extensively studied in meiosis I, but our knowledge of these mechanisms during meiosis II is rather limited. Although mammalian oocytes arrest in metaphase II for an extended period awaiting fertilization, some misattached chromosomes may persist. This suggests that the mechanism correcting misattachments is not fully functional during the arrest. In this study, we investigated whether low inter-kinetochore tension, which characterizes incorrect attachments, can be detected by Aurora B/C-dependent error correction in meiosis II. We found that low tension in early metaphase II does indeed mediate microtubule detachment by Aurora B/C and consequently, anaphase II delay through SAC activation. Surprisingly, we also found that during prolonged metaphase II arrest, Aurora B/C activity is no longer sufficient to detach low-tension attachments, concomitantly with high accumulation of PP2A at kinetochores. As a result, the SAC is not activated and sister chromatids segregate in anaphase II without delay even in the presence of low tension. Hence, during the prolonged metaphase II arrest to await fertilization, oocytes become unable to discriminate between correct and incorrect attachments and may allow errors to persist.
An exploration of mechanisms underlyingDesemzia incertacolonization resistance to methicillin-resistantStaphylococcus aureuson the skin
Authors: Wei Monica , Knight Simon AB , Fazelinia Hossein , Spruce Lynn , Roof Jennifer , Chu Emily , Walsh Jasmine , Flowers Laurice , Kim Daniel Y. , Zhu Jun , Grice Elizabeth A.
Published: October 2023

Colonization of human skin and nares by methicillin-resistantStaphylococcus aureus(MRSA) leads to community spread of MRSA. This spread is exacerbated by transfer of MRSA between humans and livestock, particularly swine. Here we capitalized on the shared features between human and porcine skin, including shared MRSA colonization, to study novel bacterial mediators of MRSA colonization resistance. We focused on the poorly studied bacterial speciesDesemzia incerta, which we found to exert antimicrobial activity through a secreted product and exhibited colonization resistance against MRSA in anin vivomurine skin model. Using parallel genomic and biochemical investigation, we discovered thatD. incertasecretes an antimicrobial protein. Sequential protein purification and proteomics analysis identified 24 candidate inhibitory proteins, including a promising peptidoglycan hydrolase candidate. Aided by transcriptional analysis ofD. incertaand MRSA cocultures, we found that exposure toD. incertaleads to decreased MRSA biofilm production. These results emphasize the value in exploring microbial communities across a spectrum of hosts, which can lead to novel therapeutic agents as well as increased understanding of microbial competition.

IMPORTANCE

Methicillin-resistantStaphylococcus aureuscauses significant healthcare burden and can be spread to the human population via livestock transmission. Members of the skin microbiome can prevent MRSA colonization via a poorly-understood phenomenon known as colonization resistance. Here, we studied colonization resistance ofS. aureusby bacterial inhibitors previously identified from a porcine skin model. We identify a pig skin commensal,Desemzia incerta, that reduced MRSA colonization in a murine model. We employ a combination of genomic, proteomic, and transcriptomic analyses to explore the mechanisms of inhibition betweenD. incertaandS. aureus. We identify 24 candidate antimicrobial proteins secreted byD. incertathat could be responsible for its antimicrobial activity. We also find that exposure toD. incertaleads to decreasedS. aureusbiofilm formation. These findings show that the livestock transmission of MRSA can be exploited to uncover novel mechanisms of MRSA colonization resistance.
Laser Desorption Rapid Evaporative Ionisation Mass Spectrometry (LD-REIMS) demonstrates a direct impact of hypochlorous acid stress on PQS-mediated quorum sensing inPseudomonas aeruginosa
Authors: Bradley Rob , Simon Daniel , Spiga Livia , Xiang Yuchen , Takats Zoltan , Williams Huw
Published: October 2023

To establish infections in human hosts,Pseudomonas aeruginosamust overcome innate immune generated oxidative stress, such as the hypochlorous acid (HOCl) produced by neutrophils. We set out to find specific biomarkers of oxidative stress through the development of a protocol for the metabolic profiling ofP. aeruginosacultures grown in the presence of different oxidants using a novel ionisation technique for mass spectrometry, laser desorption rapid evaporative ionisation mass spectrometry (LD-REIMS). We demonstrated the ability of LD-REIMS to classify samples as untreated or treated with a specific oxidant with 100 % accuracy and identified a panel of 54 metabolites with significantly altered concentrations after exposure to one or more of the oxidants. Key metabolic changes were conserved inP. aeruginosaclinical strains isolated from patients with cystic fibrosis lung infections. These data demonstrated that HOCl stress impacted the Pseudomonas Quinolone Signal (PQS) quorum sensing system. Ten 2-alkyl-4-quinolones (AHQs) associated with the PQS system were significantly lower in concentration in HOCl-stressedP. aeruginosacultures, including 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS), the most active signal molecule of the PQS system. The PQS system regulates the production of virulence factors, including pyocyanin and elastase, and their levels were markedly affected by HOCl stress. No pyocyanin was detectable and elastase concentrations were significantly reduced in cultures grown with sub-lethal concentrations of HOCl, suggesting that this neutrophil-derived oxidant may disrupt the ability ofP. aeruginosato establish infections through interference with production of PQS-associated virulence factors.

IMPORTANCE

This work demonstrates that a high-throughput ambient ionisation mass spectrometry method can be used successfully to study a bacterial stress response. Its application to the opportunistic pathogenPseudomonas aeruginosaled to the identification of specific oxidative stress biomarkers, and demonstrated that hypochlorous acid, an oxidant specifically produced by human neutrophils during infection, affects quorum sensing and markedly reduces production of the virulence factors pyocyanin and elastase in this bacterium. This approach has the potential to be widely applicable to the characterisation of the stress responses of bacteria.
Variation in monitoring: Glucose measurement in the ICU as a case study to preempt spurious correlations
Authors: Teotia Khushboo , Jia Yueran , Woite Naira Link , Celi Leo Anthony , Matos João , Struja Tristan
Published: October 2023

Objective

Health inequities can be influenced by demographic factors such as race and ethnicity, proficiency in English, and biological sex. Disparities may manifest as differential likelihood of testing which correlates directly with the likelihood of an intervention to address an abnormal finding. Our retrospective observational study evaluated the presence of variation in glucose measurements in the Intensive Care Unit (ICU).

Methods

Using the MIMIC-IV database (2008-2019), a single-center, academic referral hospital in Boston (USA), we identified adult patients meeting sepsis-3 criteria. Exclusion criteria were diabetic ketoacidosis, ICU length of stay under 1 day, and unknown race or ethnicity. We performed a logistic regression analysis to assess differential likelihoods of glucose measurements on day 1. A negative binomial regression was fitted to assess the frequency of subsequent glucose readings. Analyses were adjusted for relevant clinical confounders, and performed across three disparity proxy axes: race and ethnicity, sex, and English proficiency.

Results

We studied 24,927 patients, of which 19.5% represented racial and ethnic minority groups, 42.4% were female, and 9.8% had limited English proficiency. No significant differences were found for glucose measurement on day 1 in the ICU. This pattern was consistent irrespective of the axis of analysis, i.e. race and ethnicity, sex, or English proficiency. Conversely, subsequent measurement frequency revealed potential disparities. Specifically, males (incidence rate ratio (IRR) 1.06, 95% confidence interval (CI) 1.01 - 1.21), patients who identify themselves as Hispanic (IRR 1.11, 95% CI 1.01 - 1.21), or Black (IRR 1.06, 95% CI 1.01 - 1.12), and patients being English proficient (IRR 1.08, 95% CI 1.01 - 1.15) had higher chances of subsequent glucose readings.

Conclusion

We found disparities in ICU glucose measurements among patients with sepsis, albeit the magnitude was small. Variation in disease monitoring is a source of data bias that may lead to spurious correlations when modeling health data.
Emulating a target trial to assess effect modification: an application to obesity in the comparative effectiveness and safety of apixaban versus warfarin in non-valvular atrial fibrillation using electronic health records
Authors: Bin Hammad Turki M , Powell Emma , Baptiste Paris J , Douglas Ian , Wing Kevin
Published: October 2023

Anticoagulation therapy is recommended for patients with non-valvular atrial fibrillation (NVAF) and an increased risk of stroke. Although apixaban showed superiority over warfarin in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study, little is known about their effects in overweight and obese patients, with concerns that obesity might undermine apixaban’s effects due to the fixed dosing across body mass index (BMI) groups. We emulated a target trial similar to the ARISTOTLE study using Clinical Practice Research Datalink (CPRD) linked data to estimate the 36-month risk ratios (RR) and risk differences of the effects of apixaban compared to warfarin in NVAF patients in a composite of stroke/systemic embolism (SE), major bleeding and all-cause mortality. In 55,826 patients, apixaban did not differ across groups of BMI in stroke/SE with RR (95% CI) of 1.15 (0.81, 1.62) in normal weight, 1.06 (0.70, 1.61) in overweight and 1.23 (0.69, 2.17) in obese patients. In major bleeding, apixaban was not superior to warfarin in the normal weight group (RR (95% CI) 1.10 (0.76, 1.60) but superior in overweight (RR (95% CI) 0.73 (0.57, 0.93) and obese (RR (95 % CI) 0.67 (0.52, 0.87) groups. In NVAF, the effectiveness and safety of apixaban compared to warfarin were consistent across BMI groups.
Virtual Simulated Placements in Healthcare Education: A scoping review
Authors: Samson Juliana , Gilbey Marc , Taylor Natasha , Kneafsey Rosie
Published: October 2023

Introduction

A virtual simulated placement (VSP) is a computer-generated version of a practice placement. COVID-19 drove increased adoption of virtual technology in clinical education. Accordingly, the number of VSP publications increased from 2020. This review aims to determine the scope of this literature to inform future research questions.

Objective

Assess the range and types of evidence related to VSPs across the healthcare professions.

Inclusion criteria

Studies that focussed on healthcare students participating in VSPs. Hybrid, augmented reality (AR) and mixed reality (MR) placements were excluded.

Methods

Fourteen databases were searched, limited to English, and dated from 1stJanuary 2020. Supplementary searches were employed, and an updated search was conducted on 9thJuly 2023. Themes were synthesised using the PAGER framework to highlight patterns, advances, gaps, evidence for practice and research recommendations.

Results

Twenty-eight papers were reviewed. All VSPs were designed in response to pandemic restrictions. Students were primarily from medicine and nursing. Few publications were from developing nations. There was limited stakeholder involvement in the VSP designs and a lack of robust research designs, consistent outcome measures, conceptual underpinnings, and immersive technologies. Despite this, promising trends for student experience, knowledge, communication, and critical thinking skills using VSPs have emerged.

Conclusion

This review maps the VSP evidence across medicine, nursing, midwifery and allied health. Before a systematic review is feasible across healthcare, allied health and midwifery research require greater representation. Based on the highlighted gaps, other areas for future research are suggested.

WHAT IS ALREADY KNOWN ON THIS TOPIC

Digital placements in undergraduate nursing and medicine have been studied in one existing systematic review, providing evidence that learning outcomes for knowledge and practice were equivalent to traditional placements.

VSPs are a subset of digital placements that are computer-generated. With the increasing trend towards VSPs, an updated scoping review across a wider range of professions was justified.

WHAT THIS STUDY ADDS

Scoping the literature on VSPs across healthcare for undergraduate and postgraduate students, provides a map across professions, specialities, countries, designs, content, and outcomes.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

Gaps in allied health and midwifery VSP research highlight populations of focus. Future VSPs should consider Interprofessional Education (IPE) and resource sharing with developing countries. The benefits of immersive technologies are yet to be considered, and improvements to VSP design and research methodology are recommended.
Association between Clauss fibrinogen concentration and ROTEM® FIBTEM A5 in women with postpartum haemorrhage: validation of cut-off points
Authors: Gillissen Ada , Golyardi Bahar , van den Akker Thomas , Caram-Deelder Camila , Henriquez Dacia D.C.A. , Bloemenkamp Kitty W.M. , Duvekot Johannes J. , de Maat Moniek P. M. , Eikenboom Jeroen , van der Bom Johanna G.
Published: October 2023

Objective

Point-of-care tests like FIBTEM A5 have been proposed to guide the treatment of patients who might have low fibrinogen concentrations (≤2 g/L). The aim of this study was to describe fibrinogen concentrations according to previously proposed FIBTEM A5 cut-off points in blood samples collected from women during postpartum haemorrhage.

Design and setting

Prospective multicentre cohort study

Population

511 women sustaining postpartum haemorrhage. A total of 637 blood samples were drawn during haemorrhage.

Methods

Clauss fibrinogen concentrations and ROTEM® FIBTEM A5 values were studied to assess the diagnostic properties of previously proposed FIBTEM A5 cut-off points for the detection of low fibrinogen concentrations.

Main outcome measures

Youden index, sensitivity and specificity

Results

Of 511 women with a median total volume of blood loss of 1500 mL (IQR 1200 to 2000) 31 women (6%) developed Clauss fibrinogen concentrations below 2 g/L. Using FIBTEM A 5 cut-off of ≤ 7 mm: 48% of cases with Clauss fibrinogen ≤2 g/L were missed (FIBTEM A5 > 7mm), and of the 28 samples with FIBTEM A5 ≤ 7mm, 12 (43%) samples had Clauss fibrinogen >2 g/L. Using FIBTEM A5 cut-off of ≤12mm: 13% of cases with Clauss fibrinogen ≤2 g/L were missed and of the 145 samples with a FIBTEM A5 ≤12 mm, 118 had Clauss fibrinogen >2 g/L, resulting in false positive selection of 81% of women. Using FIBTEM A5 ≤ 15 mm: 97% (30/31) of the samples with Clauss fibrinogen ≤2 g/L were accurately selected; yet 89% (248/278) of samples that were selected had a fibrinogen concentration of >2 g/L. Based on the Youden index, the optimal cut-off point in our cohort was a FIBTEM A5 of 12mm with sensitivity 87% and specificity 81%.

Conclusions

Our findings suggest that if FIBTEM A5 lower than 12 mm would have been used to detect women with fibrinogen concentrations below 2 g/L in order to treat them with fibrinogen concentrate, 87 % of the women with fibrinogen below 2 g/L would correctly have received fibrinogen. However, most women (81%) receiving fibrinogen concentrate would not have needed it, because they had plasma fibrinogen concentrations above 2 g/L.

Funding

no funding was obtained to conduct this research
Associations between life course longitudinal growth and hip shapes at ages 60 to 64 years: evidence from the MRC National Survey of Health and Development
Authors: Staines Katherine A. , Saunders Fiona R. , Ireland Alex , Aspden Richard M. , Gregory Jenny S. , Hardy Rebecca , Cooper Rachel
Published: October 2023

We sought to examine associations between height gain across childhood and adolescence with hip shape in individuals aged 60-64 years from the MRC National Survey of Health and Development, a nationally representative British birth cohort. Height was measured at ages 2, 4, 6, 7, 11 and 15 years, and self-reported at age 20 years. Ten modes of variation in hip shape (HM1-10), described by statistical shape models, were previously ascertained from DXA images taken at ages 60-64 years. Associations between (1) height at each age (2) Super-Imposition by Translation And Rotation (SITAR) growth curve variables of height size, tempo and velocity, and (3) height gain during specific periods of childhood and adolescence, and HM1-10 were tested. Faster growth velocity was associated with a wider, flatter femoral head and neck, as described by positive scores for HM6 (regression coefficient 0.014; 95%CI, 0.08–0.019; P<0.001) and HM7 (regression coefficient 0.07; 95%CI, 0.002-0.013; P=0.009), and negative scores for HM10 (regression coefficient –0.006; 95%CI, – 0.011-0.00, P=0.04) and HM2 (males only, regression coefficient –0.017; 95%CI, –0.026 – – 0.09; P<0.001). Similar associations were observed with greater height size and later height tempo. Examination of height gains during specific periods of childhood and adolescence identified those during the adolescence period as being most consistently associated. Our analyses suggest that individual growth patterns, particularly in the adolescent period, are associated with modest variations in hip shape at 60-64 years, which are consistent with features seen in osteoarthritis.