bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of Th17 immunity
Authors: Lin Chia-Hao , Wu Cheng-Jang , Cho Sunglim , Patkar Rasika , Lin Ling-Li , Chen Mei-Chi , Israelsson Elisabeth , Betts Joanne , Niedzielska Magdalena , Patel Shefali A. , Duong Han G. , Gerner Romana R. , Hsu Chia-Yun , Catley Matthew , Maciewicz Rose A. , Chu Hiutung , Raffatellu Manuela , Chang John T. , Lu Li-Fan
Published: February 2023

Regulatory T (Treg) cells are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, here we show that IL-27 is specifically produced by intestinal Treg cells to regulate Th17 immunity. Selectively increased intestinal Th17 responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+TCF1+Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a novel Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue, and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.
Hypoxia-inducible factor 2 is a key determinant of manganese excess and polycythemia in SLC30A10 deficiency
Authors: Prajapati Milankumar , Zhang Jared Z. , Mercadante Courtney J. , Kowalski Heather L. , Delaney Bradley , Anderson Jessica A. , Guo Shuling , Aghajan Mariam , Bartnikas Thomas B.
Published: February 2023

Manganese is an essential yet potentially toxic metal. Initially reported in 2012, mutations in SLC30A10 are the first known inherited cause of manganese excess. SLC30A10 is an apical membrane transport protein that exports manganese from hepatocytes into bile and from enterocytes into the lumen of the gastrointestinal tract. SLC30A10 deficiency results in impaired gastrointestinal manganese excretion, leading to severe manganese excess, neurologic deficits, liver cirrhosis, polycythemia, and erythropoietin excess. Neurologic and liver disease are attributed to manganese toxicity. Polycythemia is attributed to erythropoietin excess, but the basis of erythropoietin excess in SLC30A10 deficiency has yet to be established. Here we demonstrate that erythropoietin expression is increased in liver but decreased in kidneys in Slc30a10-deficient mice. Using pharmacologic and genetic approaches, we show that liver expression of hypoxia-inducible factor 2 (Hif2), a transcription factor that mediates the cellular response to hypoxia, is essential for erythropoietin excess and polycythemia in Slc30a10-deficient mice, while hypoxia-inducible factor 1 (HIF1) plays no discernible role. RNA-seq analysis determined that Slc30a10-deficient livers exhibit aberrant expression of a large number of genes, most of which align with cell cycle and metabolic processes, while hepatic Hif2 deficiency attenuates differential expression of half of these genes in mutant mice. One such gene downregulated in Slc30a10-deficient mice in a Hif2-dependent manner is hepcidin, a hormonal inhibitor of dietary iron absorption. Our analyses indicate that hepcidin downregulation serves to increase iron absorption to meet the demands of erythropoiesis driven by erythropoietin excess. Finally, we also observed that hepatic Hif2 deficiency attenuates tissue manganese excess, although the underlying cause of this observation is not clear at this time. Overall, our results indicate that HIF2 is a key determinant of pathophysiology in SLC30A10 deficiency.

Graphical abstract
Distinct neurochemical influences on fMRI response polarity in the striatum
Authors: Cerri Domenic H. , Albaugh Daniel L. , Walton Lindsay R. , Katz Brittany , Wang Tzu-Wen , Chao Tzu-Hao Harry , Zhang Weiting , Nonneman Randal J. , Jiang Jing , Lee Sung-Ho , Etkin Amit , Hall Catherine N. , Stuber Garret D. , Shih Yen-Yu Ian
Published: February 2023

The striatum is the primary input nucleus of the basal ganglia, widely studied for its complex roles in health and disease. Functional magnetic resonance imaging (fMRI) studies are essential for discerning striatal function, however the relationship between neuronal and hemodynamic activity, critical for interpreting fMRI signals, has not been rigorously examined in striatum. We find that optogenetic stimulation of striatal neurons or afferents evokes negative striatal fMRI responses in rats that can occur despite broad increases in local neuronal activity. Intra-striatal pharmacological manipulations suggest that opioidergic, but not dopaminergic transmission contributes to negative striatal fMRI signals (the latter instead associated with positive signals). Striatal neuronal activity peaks are also associated with negative hemodynamic signals in behaving rats. Negative fMRI responses are observed in human striatum under conditions of anticipated neuronal activity increases. Our results prompt consideration of local cellular and neurochemical environments along with neuronal activity in fMRI signal interpretation.
Discovery and characterization of a chemical probe targeting the zinc-finger ubiquitin-binding domain of HDAC6
Authors: Harding Rachel J. , Franzoni Ivan , Mann Mandeep K. , Szewczyk Magdalena M. , Mirabi Bijan , Owens Dominic D.G , Ackloo Suzanne , Scheremetjew Alexej , Juarez-Ornelas Kevin A. , Sanichar Randy , Baker Rachel J. , Dank Christian , Brown Peter J. , Barsyte-Lovejoy Dalia , Santhakumar Vijayaratnam , Schapira Matthieu , Lautens Mark , Arrowsmith Cheryl H.
Published: February 2023

Histone deacetylase 6 (HDAC6) inhibition is an attractive strategy for treating numerous cancers, and HDAC6 catalytic inhibitors are currently in clinical trials. The HDAC6 zinc-finger ubiquitin-binding domain (UBD) binds free C-terminal diglycine motifs of unanchored ubiquitin polymer chains and protein aggregates, playing an important role in autophagy and aggresome assembly. However, targeting this domain with small molecule antagonists remains an underdeveloped avenue of HDAC6-focused drug discovery. We report SGC-UBD253 (25), a chemical probe potently targeting HDAC6-UBD in vitro with selectivity over nine other UBDs, except for weak USP16 binding. In cells,25is an effective antagonist of HDAC6-UBD at 1 µM, with marked proteome-wide selectivity. We identified SGC-UBD253N (32), a methylated derivative of25which is 300-fold less active, serving as a negative control. Together,25and32could enable further exploration of the biological function of the HDAC6 UBD and investigation of the therapeutic potential of targeting this domain.
Phenotypic and genomic characterization ofPseudomonas aeruginosaisolates recovered from catheter-associated urinary tract infections in an Egyptian hospital
Authors: Eladawy Mohamed , Thomas Jonathan C. , Hoyles Lesley
Published: February 2023

Catheter-associated urinary tract infections (CAUTIs) represent one of the major healthcare-associated infections, andPseudomonas aeruginosais a common Gram-negative bacterium associated with catheter infections in Egyptian clinical settings. The present study describes the phenotypic and genotypic characteristics of 31P. aeruginosaisolates recovered from CAUTIs in an Egyptian hospital over a 3-month period. Genomes of isolates were of good quality and were confirmed to beP. aeruginosaby comparison to the type strain (average nucleotide identity, phylogenetic analysis). Clonal diversity among the isolates was determined; eight different sequence types were found (STs 244, 357, 381, 621, 773, 1430, 1667 and 3765), of which 357 and 773 are considered high-risk clones. Antimicrobial resistance (AMR) testing according to EUCAST guidelines showed the isolates were highly resistant to quinolones [ciprofloxacin (12/31, 38.7 %) and levofloxacin (9/31, 29 %) followed by tobramycin (10/31, 32.5 %)], and cephalosporins (7/31, 22.5 %). Genotypic analysis of resistance determinants predicted all isolates to encode a range of AMR genes, including those conferring resistance to aminoglycosides, β-lactamases, fluoroquinolones, fosfomycin, sulfonamides, tetracyclines and chloramphenicol. One isolate was found to carry a 422,938 bp pBT2436-like megaplasmid encoding OXA-520, the first report from Egypt of this emerging family of clinically important mobile genetic elements. All isolates were able to form biofilms, and were predicted to encode virulence genes associated with adherence, antimicrobial activity, antiphagocytosis, phospholipase enzymes, iron uptake, proteases, secretion systems, and toxins. The present study shows how phenotypic analysis alongside genomic analysis may help us understand the AMR and virulence profiles ofP. aeruginosacontributing to CAUTIs in Egypt.
Emergence of universal computations through neural manifold dynamics
Authors: Vicente Joan Gort
Published: February 2023

There is growing evidence that many forms of neural computation may be implemented by low-dimensional dynamics unfolding at the population scale. However, neither the connectivity structure nor the general capabilities of these embedded dynamical processes are currently understood. In this work, the two most common formalisms of firing-rate models are evaluated using tools from analysis, topology and nonlinear dynamics in order to provide plausible explanations for these problems. It is shown that low-rank structured connectivity predicts the formation of invariant and globally attracting manifolds in both formalisms, which generalizes existing theories to different neural models. Regarding the dynamics arising in these manifolds, it is proved they are topologically equivalent across the considered formalisms.

It is also stated that under the low-rank hypothesis, dynamics emerging in neural models are universal. These include input-driven systems, which broadens previous findings. It is then explored how low-dimensional orbits can bear the production of continuous sets of muscular trajectories, the implementation of central pattern generators and the storage of memory states. It is also proved these dynamics can robustly simulate any Turing machine over arbitrary bounded memory strings, virtually endowing rate models with the power of universal computation. In addition, it is shown how the low-rank hypothesis predicts the parsimonious correlation structure observed in cortical activity. Finally, it is discussed how this theory could provide a useful tool from which to study neuropsychological phenomena using mathematical methods.
Endogenous bystander killing mechanisms enhance the activity of novel FAP-specific CAR-T cells against glioblastoma
Authors: Yu Wenbo , Truong Nga TH , Polara Ruhi , Gargett Tessa , Tea Melinda N , Pitson Stuart M , Cockshell Michaelia P , Bonder Claudine S , Ebert Lisa M , Brown Michael P
Published: February 2023

Objectives

CAR-T cells are being investigated as a novel immunotherapy for glioblastoma, but clinical success has been limited. We recently described fibroblast activation protein (FAP) as an ideal target antigen for glioblastoma immunotherapy, with expression on both tumor cells and tumor blood vessels. However, CAR-T cells targeting FAP have never been investigated as a therapy for glioblastoma.

Methods

We generated a novel FAP targeting CAR with CD3ζ and CD28 signaling domains and tested the resulting CAR-T cells for their lytic activity and cytokine secretion functionin vitro(using real-time impedance, flow cytometry, imaging, and bead-based cytokine assays), andin vivo(using a xenograft mimicking the natural heterogeneity of human glioblastoma).

Results

FAP-CAR-T cells exhibited target specificity against model cell lines and potent cytotoxicity against patient-derived glioma neural stem cells, even when only a subpopulation expressed FAP, indicating a bystander killing mechanism. Using co-culture assays, we confirmed FAP-CAR-T cells mediate bystander killing of antigen-negative tumor cells, but only after activation by FAP-positive target cells. This bystander killing was at least partially mediated by soluble factors and amplified by IL-2 which activated the non-transduced fraction of the CAR-T product. Finally, a low dose of intravenously administered FAP-CAR-T cells controlled, without overt toxicity, the growth of subcutaneous tumors created using a mixture of antigen-negative and antigen-positive glioblastoma cells.

Conclusions

Our findings advance FAP as a leading candidate for clinical CAR-T therapy of glioblastoma and highlight under-recognized antigen non-specific mechanisms that may contribute meaningfully to the antitumor activity of CAR-T cells.
Tau-Tubulin Kinase 2 restrains microtubule-depolymerizer KIF2A to support primary cilia growth
Authors: Vysloužil David , Bernatík Ondřej , Renzová Tereza , Binó Lucia , Lacigová Andrea , Čajánek Lukáš
Published: February 2023

The initiation of assembly of primary cilia, organelles with crucial functions in development and disease, is under the control of Tau-Tubulin Kinase 2 (TTBK2). Recent work has implicated TTBK2 also in the regulation of primary cilia maintenance and function. However, the mechanisms underlying individual functions of TTBK2 in primary cilia are not fully understood.

Here, to dissect the role of TTBK2 in primary cilia maintenance in human cells, we examined disease related TTBK2 truncations. We demonstrate that these truncated protein moieties show selective activity towards TTBK2 substrates. This creates a semi-permissive condition where partial TTBK2 activity suffices to support the initiation of ciliogenesis but fails to sustain primary cilia length. Subsequently, we show that the defects in primary cilia growth are linked to aberrant turnover of kinesin KIF2A at basal body. Furthermore, we demonstrate that TTBK2 regulates KIF2A by phosphorylation, which in turn restrains its levels at the ciliary base to promote primary cilia elongation and maintenance.

Taken together, our data highlight the regulation of KIF2A by TTBK2 as an important mechanism governing primary cilia in human cells.
Distinguishing examples while building concepts in hippocampal and artificial networks
Authors: Kang Louis , Toyoizumi Taro
Published: February 2023

The hippocampal subfield CA3 is thought to function as an autoassociative network that stores experiences as memories. Information from these experiences arrives via the entorhinal cortex (EC), which projects to CA3 directly as well as indirectly through the dentate gyrus (DG). DG sparsifies and decorrelates the information before also projecting to CA3. The computational purpose for receiving two encodings of the same sensory information has not been firmly established. We model CA3 as a Hopfield-like network that stores both correlated and decorrelated encodings and retrieves them at low and high inhibitory tone, respectively. As more memories are stored, the dense, correlated encodings merge along shared features while the sparse, decorrelated encodings remain distinct. In this way, the model learns to transition between concept and example representations by controlling inhibitory tone. To experimentally test for the presence of these complementary encodings, we analyze the theta-modulated tuning of place cells in rat CA3. In accordance with our model’s prediction, these neurons exhibit more precise spatial tuning and encode more detailed task features during theta phases with sparser activity. Finally, we generalize the model beyond hippocampal architecture and find that feedforward neural networks trained in multitask learning benefit from a novel loss term that promotes hybrid encoding using correlated and decorrelated representations. Thus, the complementary encodings that we have found in CA3 can provide broad computational advantages for solving complex tasks.
Modulation of WNT, Activin/Nodal and MAPK Signaling Pathways Increases Arterial Hemogenic Endothelium and Hematopoietic Stem/Progenitor Cell Formation During Human iPSC Differentiation
Authors: Li Yongqin , Ding Jianyi , Araki Daisuke , Zou Jizhong , Larochelle Andre
Published: February 2023

Several differentiation protocols enable the emergence of hematopoietic stem and progenitor cells (HSPCs) from human induced pluripotent stem cells (iPSCs), yet optimized schemes to promote the development of HSPCs with self-renewal, multilineage differentiation and engraftment potential are lacking. To improve human iPSC differentiation methods, we modulated WNT, Activin/Nodal and MAPK signaling pathways by stage-specific addition of small molecule regulators CHIR99021, SB431542 and LY294002, respectively, and measured the impact on hematoendothelial formation in culture. Manipulation of these pathways provided a synergy sufficient to enhance formation of arterial hemogenic endothelium (HE) relative to control culture conditions. Importantly, this approach significantly increased production of human HSPCs with self-renewal and multilineage differentiation properties, as well as phenotypic and molecular evidence of progressive maturation in culture. Together, these findings provide a stepwise improvement in human iPSC differentiation protocols and offer a framework for manipulating intrinsic cellular cues to enablede novogeneration of human HSPCs with functionalityin vivo.

Significance Statement

The ability to produce functional HSPCs by differentiation of human iPSCsex vivoholds enormous potential for cellular therapy of human blood disorders. However, obstacles still thwart translation of this approach to the clinic. In keeping with the prevailing arterial-specification model, we demonstrate that concurrent modulation of WNT, Activin/Nodal and MAPK signaling pathways by stage-specific addition of small molecules during human iPSC differentiation provides a synergy sufficient to promote arterialization of HE and production of HSPCs with features of definitive hematopoiesis. This simple differentiation scheme provides a unique tool for disease modeling, in vitro drug screening and eventual cell therapies.
Self-organization of Long-lasting Human Endothelial Capillary Networks guided by DLP Bioprinting
Authors: Mazari-Arrighi Elsa , Lépine Matthieu , Ayollo Dmitry , Faivre Lionel , Larghero Jérôme , Chatelain François , Fuchs Alexandra
Published: February 2023

Tissue engineering holds great promise for regenerative medicine, drug discovery and as an alternative to animal models. However, as soon as the dimensions of engineered tissue exceed the diffusion limit of oxygen and nutriments, a necrotic core forms leading to irreversible damage. To overcome this constraint, the establishment of a functional perfusion network is essential and is a major challenge to be met. In this work, we explore a promising Digital Light Processing (DLP) bioprinting approach to encapsulate endothelial progenitor cells (EPCs) in 3D photopolymerized hydrogel scaffolds to guide them towards vascular network formation. We observed that EPCs encapsulated in the appropriate photopolymerized hydrogel can proliferate and self-organize within a few days into branched tubular structures with predefined geometry, forming capillary-like vascular tubes or trees of various diameters (in the range of 10 to 100 μm). Presenting a monolayer wall of endothelial cells strongly connected by tight junctions around a central lumen, these structures can be microinjected with fluorescent dye and are stable for several weeksin vitro. Interestingly, our technology has proven to be versatile in promoting the formation of vascular structures using a variety of vascular cell lines, including EPCs, human vascular endothelial cells (HUVECs) and human dermal lymphatic endothelial cells (HDLECs). We have also demonstrated that these vascular structures can be recovered and manipulated in an alginate patch without altering their shape or viability. This opens new opportunities for future applications, such as stacking these endothelial vascular structures with other cell sheets or multicellular constructs to yield bioengineered tissue with higher complexity and functionality.
Regional Gene Expression in the Retina, Optic Nerve Head, and Optic Nerve of Mice with Experimental Glaucoma and Optic Nerve Crush
Authors: Keuthan Casey J. , Schaub Julie , Wei Meihan , Fang Weixiang , Quillen Sarah , Kimball Elizabeth , Johnson Thomas V. , Ji Hongkai , Zack Donald J. , Quigley Harry A.
Published: February 2023

A major risk factor for glaucomatous optic neuropathy is the level of intraocular pressure (IOP), which can lead to retinal ganglion cell axon injury and cell death. The optic nerve has a rostral unmyelinated portion at the optic nerve head followed by a caudal myelinated region. The unmyelinated region is differentially susceptible to IOP-induced damage in rodent models and in human glaucoma. While several studies have analyzed gene expression changes in the mouse optic nerve following optic nerve injury, few were designed to consider the regional gene expression differences that exist between these distinct areas. We performed bulk RNA-sequencing on the retina and on separately micro-dissected unmyelinated and myelinated optic nerve regions from naïve C57BL/6 mice, mice after optic nerve crush, and mice with microbead-induced experimental glaucoma (total = 36). Gene expression patterns in the naïve unmyelinated optic nerve showed significant enrichment of the Wnt, Hippo, PI3K-Akt, and transforming growth factor β pathways, as well as extracellular matrix–receptor and cell membrane signaling pathways, compared to the myelinated optic nerve and retina. Gene expression changes induced by both injuries were more extensive in the myelinated optic nerve than the unmyelinated region, and greater after nerve crush than glaucoma. Changes three and fourteen days after injury largely subsided by six weeks. Gene markers of reactive astrocytes did not consistently differ between injury states. Overall, the transcriptomic phenotype of the mouse unmyelinated optic nerve was significantly different from immediately adjacent tissues, likely dominated by expression in astrocytes, whose junctional complexes are inherently important in responding to IOP elevation.
choros: correction of sequence-based biases for accurate quantification of ribosome profiling data
Authors: Mok Amanda , Tunney Robert , Benegas Gonzalo , Wallace Edward W. J. , Lareau Liana F.
Published: February 2023

Ribosome profiling quantifies translation genome-wide by sequencing ribosome-protected fragments, or footprints. Its single-codon resolution allows identification of translation regulation, such as ribosome stalls or pauses, on individual genes. However, enzyme preferences during library preparation lead to pervasive sequence artifacts that obscure translation dynamics. Widespread over- and under-representation of ribosome footprints can dominate local footprint densities and skew estimates of elongation rates by up to five fold. To address these biases and uncover true patterns of translation, we presentchoros, a computational method that models ribosome footprint distributions to provide bias-corrected footprint counts.chorosuses negative binomial regression to accurately estimate two sets of parameters: (i) biological contributions from codon-specific translation elongation rates; and (ii) technical contributions from nuclease digestion and ligation efficiencies. We use these parameter estimates to generate bias correction factors that eliminate sequence artifacts. Applyingchorosto multiple ribosome profiling datasets, we are able to accurately quantify and attenuate ligation biases to provide more faithful measurements of ribosome distribution. We show that a pattern interpreted as pervasive ribosome pausing near the beginning of coding regions is likely to arise from technical biases. Incorporatingchorosinto standard analysis pipelines will improve biological discovery from measurements of translation.
Differentially Expressed Heterogeneous Overdispersion Genes Testing for Count Data*
Authors: Yuan Yubai , Xu Qi , Wani Agaz , Dahrendor Jan , Wang Chengqi , Donglasan Janelle , Burgan Sarah , Graham Zachary , Uddin Monica , Wildman Derek , Qu Annie
Published: February 2023

The mRNA-seq data analysis is a powerful technology for inferring information from biological systems of interest. Specifically, the sequenced RNA fragments are aligned with genomic reference sequences, and we count the number of sequence fragments corresponding to each gene for each condition. A gene is identified as differentially expressed (DE) if the difference in its count numbers between conditions is statistically significant. Several statistical analysis methods have been developed to detect DE genes based on RNA-seq data. However, the existing methods could suffer decreasing power to identify DE genes arising from overdispersion and limited sample size. We propose a new differential expression analysis procedure: heterogeneous overdispersion genes testing (DEHOGT) based on heterogeneous overdispersion modeling and a post-hoc inference procedure. DEHOGT integrates sample information from all conditions and provides a more flexible and adaptive overdispersion modeling for the RNA-seq read count. DEHOGT adopts a gene-wise estimation scheme to enhance the detection power of differentially expressed genes. DEHOGT is tested on the synthetic RNA-seq read count data and outperforms two popular existing methods, DESeq and EdgeR, in detecting DE genes. We apply the proposed method to a test dataset using RNAseq data from microglial cells. DEHOGT tends to detect more differently expressed genes potentially related to microglial cells under different stress hormones treatments.
Life stage and vaccination shape the gut microbiome of hatchery-reared Atlantic salmon (Salmo salar)
Authors: Andres Kara J. , Liu Bingdi , Johnson Lauren E. , Kapuscinski Kevin L. , Moerke Ashley H. , Ling Fangqiong , Knouft Jason H.
Published: February 2023

Microbiomes play an essential role in promoting host health and fitness, but the factors affecting variation in gut microbiomes among individuals are not fully understood. Investigating the microbiome under different conditions is needed to link gut microbiomes to host physiology and potentially design manipulations to improve rearing success of captive species. In this study, we characterized the gut microbiomes of Atlantic salmon (Salmo salar) in individuals at different life stages, vaccination status, and hatchery origin. Microbiomes differed between age-0 sub-adults and adults, with sub-adults exhibiting higher diversity and more similar communities when compared to adults. We also found that vaccines against bacterial kidney disease reduced gut microbial diversity within individual sub-adult salmon, resulting in dissimilar gut microbial communities among individuals. The diversity and structure of microbiomes did not differ between groups of adults that were reared in two different hatcheries and sampled from the wild. Sub-adults, particularly unvaccinated sub-adults, displayed a strong core microbiome present in the majority of individuals. Our results suggest that life stage and vaccination status are essential factors in the gut microbiome development of salmon. Conditions experienced during early life stages appear to have a strong influence on the microbiome, but differences among individuals at early life stages may be lost due to environmental factors experienced later in life. The plasticity of the microbiome throughout the life of individuals may have important implications for understanding host health, with potential applications for improving the rearing and reintroduction success of the ecologically and economically important Atlantic salmon.

IMPORTANCE

The Atlantic salmon (Salmo salar) is a globally important fisheries and aquaculture species, but the factors affecting gut microbiomes of hatchery-reared fish are not fully understood. Our study explores the influence of life stage, vaccination status, and hatchery origin on the composition and structure of the Atlantic salmon gut microbiome. We found that life stage is an important driver of gut microbiome diversity, likely driven by differences in habitat and diet.

Vaccination against bacterial kidney disease led to marked declines in gut microbial diversity within individuals, resulting in highly distinct gut microbial communities among individuals. Hatchery origin did not have a strong influence on adult Atlantic salmon captured from the wild. These findings suggest that life stage and vaccination drive variation in Atlantic salmon microbiomes, but the stability and long-term implications of such variation on host health should be considered in future microbiome research.
The autotransporter BafA contributes to the proangiogenic potential of Bartonella elizabethae
Authors: Suzuki Natsumi , Kumadaki Kayo , Tatematsu Kaoru , Doi Yohei , Tsukamoto Kentaro
Published: February 2023

Bartonella elizabethae is a rat‐borne zoonotic bacterium that causes human infectious endocarditis or neuroretinitis. Recently, a case of bacillary angiomatosis (BA) resulting from this organism was reported, leading to speculation that B. elizabethae may also trigger vasoproliferation. However, there are no reports of B. elizabethae promoting human vascular endothelial cell (EC) proliferation or angiogenesis, and to date, the effects of this bacterium on ECs are unknown. We recently identified a proangiogenic autotransporter, BafA, secreted from B. henselae and B. quintana, which are recognized as Bartonella spp. responsible for BA in humans. Here, we hypothesized that B. elizabethae also harbored a functional bafA gene and examined the proangiogenic activity of recombinant B. elizabethae–derived BafA. The bafA gene of B. elizabethae, which was found to share a 51.1% amino acid sequence identity with BafA of B. henselae and 52.5% with that of B. quintana in the passenger domain, was located in a syntenic region of the genome. The recombinant protein of the N‐terminal passenger domain of B. elizabethae‐BafA facilitated EC proliferation and capillary structure formation. Furthermore, it upregulated the receptor signaling pathway of vascular endothelial growth factor, as observed in B. henselae‐BafA. Taken together, B. elizabethae–derived BafA stimulates human EC proliferation and may contribute to the proangiogenic potential of this bacterium. So far, functional bafA genes have been found in all BA‐causing Bartonella spp., supporting the key role BafA may play in BA pathogenesis.
Predictors of clinical experience performance in occupational therapy and physiotherapy: A scoping review
Authors: Horwitz Heidi M. , Struckmeyer Linda R. , MacPherson Kevin L. , Morgan‐Daniel Jane , Gerry Grace , Myers Christine
Published: February 2023

Introduction

Successful completion of clinical education experiences is a graduation requirement for students in occupational therapy and physical therapy programmes. A scoping review was conducted to determine what is known about possible clinical experience performance predictors and to find associated research gaps.

Methods

The search included one hand‐searched journal and seven databases, which were used to identify related relevant studies: CINAHL, Education Database, Education Source, Education Resources Information Center (ERIC), PubMed, REHABDATA, and Web of Science. A research librarian guided the search process, and the review's reporting is structured by the Preferred Reporting Items for Systematic reviews and Meta‐Analyses extension for Scoping Reviews (PRISMA‐ScR) Checklist. Studies were included if they contained predictors of clinical experience success indicated by validated performance evaluation tools that were scored by clinical instructors. A multidisciplinary team reviewed the title, abstract, and full text for inclusion and conducted thematic data synthesis to categorise findings.

Findings

Twenty‐six articles met the inclusion criteria. The majority of articles were of correlational design and included single institutions. Seventeen articles included occupational therapy, eight included physical therapy, with only one article including both programmes. Four categories of predictors of clinical experience success were identified: pre‐admission variables, academic preparation, learner characteristics, and demographics. Each of the main categories included three to six subcategories. Key findings included the following: (a) The most common cited predictors in clinical experiences are academic preparation and learner characteristics, (b) more experimental design studies are needed to determine the causal relationship between predictors and clinical experience success, and (c) future research is needed on ethnic disparities and clinical experience success.

Conclusion

Findings from this review show that possible predictors of clinical experience success include a wide range of factors when correlating success with a standardised tool. Academic preparation and learner characteristics were the most investigated predictors. There were only a small number of studies that found a correlation with pre‐admission variables. The findings of this study suggest that students' academic achievement may be a critical element of clinical experience preparation. Future research using experimental designs and across institutions is needed to determine the main predictors for student success.
Transformation or tumor heterogeneity: Mutations in EGFR, SOX2, TP53, and RB1 persist in the histological rapid conversion from lung adenocarcinoma to small‐cell lung cancer
Authors: Hao Lidan , Chen Haiyang , Wang Lili , Zhou Hanqiong , Zhang Zhe , Han Jing , Hou Jiabao , Zhu Yichen , Zhang He , Wang Qiming
Published: February 2023

The transformation from non‐small‐cell lung cancer (NSCLC) to small‐cell lung cancer (SCLC) is one of the mechanisms of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) resistance. Previous studies exhibited that the median transformation time was 17.8 months for NSCLC to SCLC. Here we introduced a case of lung adenocarcinoma (LADC) with EGFR19 exon deletion mutation in which the pathological transformation emerged only 1 month after lung cancer surgery and receiving EGFR‐TKI inhibitor. Eventually, the pathological examination confirmed the patient experienced a transformation from LADC to SCLC with EGFR, tumor protein p53 (TP53), RB transcriptional corepressor 1 (RB1), and SRY‐box transcription factor 2 (SOX2) mutation. Although the transformation of LADC with EGFR‐mutant into SCLC after targeted therapy was frequent, the pathological results of most patients were only biopsy specimens, which cannot rule out the existence of mixed pathological components of the primary tumor. In this case, the patient's postoperative pathology was sufficient to exclude the probability of mixed tumor components, confirming that the patient's pathological change was indeed transformation from LADC to SCLC. In addition, primary drug resistance in such a short time after surgery and osimertinib‐targeted therapy has not been reported before. We detected the molecular state of this patient before and after SCLC transformation through targeted gene capture and high‐throughput sequencing, and also found for the first time that the mutations of EGFR, TP53, RB1, and SOX2 continue to exist before and after transformation, but the mutation abundance is different. In our paper, the occurrence of small‐cell transformation is affected largely by these gene mutations.
Machine‐reeling technology diffusion in early Meiji Japan's silk industry
Authors: Moriwaki Shota
Published: February 2023

Using 1880 s panel data from Yamanashi and Gifu prefectures in Japan, we estimated the diffusion factors and total factor productivity (TFP) in machine‐reeling technology in Japan's silk‐reeling sector. While the cost of distance through the traditional highway from the Shimosuwa‐shuk post town in the Nagano Prefecture has a negative correlation with technology diffusion, the correlation of silk production per population is positive. Machine‐reeling technology is raw‐material‐intensive and does not show increasing returns to scale. While the TFP in Yamanashi is higher than in Gifu, machine‐reeling output expansion is larger in the latter.
Colonial companies and the cost of introducing Indian immigrants into Fiji, 1884–1916
Authors: Persaud Alexander
Published: February 2023

Using Fiji as a case study, I conduct the first cost accounting of government‐run Indian indentureship in the nineteenth and twentieth centuries. I analyse multiple official data sources and estimate the total cost of bringing Indians to Fiji was £926,851, roughly a fifth of Fiji's reported expenditure. Businesses funded 92.6% of this cost. However, business payments to the government do not appear in official Blue Books. Incorporating business payments shows that both official revenue and expenditure were underestimated by 15%. My results show how one part of colonialism was funded and how colonial fiscal capacity may be underestimated more broadly.
Effects of dietary organic or inorganic iron concentrations on productive performance, egg quality, blood measurements, and tissue iron concentrations in aged laying hens
Authors: Kim Jong Hyuk , Kim Hyun Woo , Kwon Chan Ho , Kwon Sung Hoon , Kil Dong Yong
Published: February 2023

The objective of the current experiment was to investigate the effects of dietary organic or inorganic iron (Fe) concentrations on productive performance, egg quality, blood measurements, and tissue Fe concentrations in aged laying hens. A total of three hundred fifty 60‐week‐old Hy‐Line Brown laying hens were allotted to one of five dietary treatments with seven replicates. Each replicate had 10 consecutive cages. Organic Fe (Fe‐Gly) or inorganic Fe (FeSO4) was added to the basal diet at the levels of 100 or 200 mg/kg Fe. Diets were fed on an ad libitum basis for 6 weeks. Results indicated that supplementation of organic or inorganic Fe in diets increased (p < 0.05) eggshell color and feather Fe concentrations compared with no supplementation of Fe in diets. An interaction was found (p < 0.05) between Fe sources and supplemental levels in diets for egg weight, eggshell strength, and Haugh unit. Hens fed diets supplemented with organic Fe had greater (p < 0.05) eggshell color and hematocrit than those fed diets supplemented with inorganic Fe. In conclusion, dietary supplementation of organic Fe increases the eggshell color of aged laying hens. High supplemental levels of organic Fe in diets improve egg weight in aged laying hens.
The Informative Value of Key Audit Matters in the Audit Report: Understanding the Impact of the Audit Firm and KAM Type
Authors: Gambetta Nicolás , Sierra‐García Laura , García‐Benau María Antonia , Novejarque‐Civera Josefina
Published: February 2023

This paper examines whether the readability (and hence informative value) of key audit matters (KAM) varies according to the audit firm and the KAM type disclosed, a question of vital importance for stakeholders, whose effective decision‐making depends on the quality of information received. Our analysis shows that the informative value of KAM matter and KAM audit procedures varies according to the audit firm responsible. This informative value also depends on whether the KAM is related to entity‐ or accounting‐level risks. This study contributes to the KAM and audit quality literature by showing how these factors impact on the informative value of the expanded audit report. Furthermore, in the context of the agency, institutional and self‐presentation theories and the real effects hypothesis, we discuss auditors’ incentives to increase or decrease the informative value of the expanded audit report.
A qualitative study of young people's lived experiences of suicide and self‐harm: intentionality, rationality and authenticity
Authors: Marzetti Hazel , McDaid Lisa , O'Connor Rory
Published: February 2023

Background

Suicide is a leading cause of death amongst young people and a major public health concern. Although increasing research has identified contributory and protective factors affecting youth suicide, less is known about how young people make sense of suicidal distress themselves.

Methods

Using semi‐structured interview methods and reflexive thematic analysis, this study explores how 24 young people aged 16–24 in Scotland, UK made sense of their lived experiences of suicidal thoughts and feelings, self‐harm, and suicide attempts.

Results

Intentionality, rationality, and authenticity formed our central themes. Suicidal thoughts were categorised by participants dependent on their intention to act on them; a distinction often used to downplay the significance of early suicidal thoughts. Escalating suicidal feelings were then described as almost rational responses to adversities; whereas suicide attempts appeared to be described as more impulsive. These narratives seemed to be somewhat shaped by dismissive attitudes participants experienced in response to their suicidal distress, both from professionals and within their close networks. This impacted how participants articulated distress and asked for support.

Conclusion

Suicidal thoughts that participants articulated as lacking the intention to act could represent key opportunities for early clinical intervention to prevent suicide. In contrast, stigma, difficulties communicating suicidal distress and dismissive attitudes could serve as barriers to seeking help, and, therefore, additional efforts should be made to ensure young people feel comfortable seeking help.
The 5C model: A proposed continuous quality improvement framework for volunteer dental services in remote Australian Aboriginal communities
Authors: Patel Jilen , Nattabi Barbara , Long Robyn , Durey Angela , Naoum Steven , Kruger Estie , Slack‐Smith Linda
Published: February 2023

Objectives

Aboriginal and Torres Strait Islander communities in remote parts of Australia are some of the most underserviced communities in regard to oral health care. These communities rely on volunteer dental programmes such as the Kimberley Dental Team to fill the gaps in care, however, there are no known continuous quality improvement (CQI) frameworks to guide such organizations to ensure that they are delivering high‐quality, community‐centred, culturally appropriate care. This study proposes a CQI framework model for voluntary dental programmes providing care to remote Aboriginal communities.

Methods

Relevant CQI models wherein the (i) behaviour of interest was quality improvement, and (ii) the health context was volunteer services in Aboriginal communities were identified from the literature. The conceptual models were subsequently augmented using a ‘best fit’ framework and the existing evidence synthesized to develop a CQI framework that aims to guide volunteer dental services to develop local priorities and enhance current dental practice.

Results

A cyclical five‐phase model is proposed starting with consultation and moving through the phases of data collection, consideration, collaboration and celebration.

Conclusions

This is the first proposed CQI framework for volunteer dental services working with Aboriginal communities. The framework enables volunteers to ensure that the quality of care provided is commensurate with the community needs and informed by community consultation. It is anticipated that future mixed methods research will enable formal evaluation of the 5C model and CQI strategies focusing on oral health among Aboriginal communities.
Dietary nitrate improves jaw bone remodelling in zoledronate‐treated mice
Authors: Pan Wen , Gu Jianyu , Xu Shihan , Zhang Chunmei , Wang Jinsong , Wang Songlin , Xu Junji
Published: February 2023

Bisphosphonate‐related osteonecrosis of the jaw (BRONJ) is a serious complication that occurs in patients with osteoporosis or metastatic bone cancer treated with bisphosphonate. There is still no effective treatment and prevention strategy for BRONJ. Inorganic nitrate, which is abundant in green vegetables, has been reported to be protective in multiple diseases. To investigate the effects of dietary nitrate on BRONJ‐like lesions in mice, we utilized a well‐established mouse BRONJ model, in which tooth extraction was performed. Specifically, 4 mM sodium nitrate was administered in advance through drinking water to assess the short‐ and long‐term effects on BRONJ. Zoledronate injection could induce severe healing inhibition of the tooth extraction socket, while addition of pretreating dietary nitrate could alleviate the inhibition by reducing monocyte necrosis and inflammatory cytokines production. Mechanistically, nitrate intake increased plasma nitric oxide levels, which attenuated necroptosis of monocytes by downregulating lipid and lipid‐like molecule metabolism via a RIPK3 dependent pathway. Our findings revealed that dietary nitrate could inhibit monocyte necroptosis in BRONJ, regulate the bone immune microenvironment and promote bone remodelling after injury. This study contributes to the understanding of the immunopathogenesis of zoledronate and supports the feasibility of dietary nitrate for the clinical prevention of BRONJ.
Prediction of movement difficulties at 5 years from parent report at 2 years in children born extremely preterm
Authors: Costa Raquel , Aubert Adrien M. , Seppänen Anna‐Veera , Ådén Ulrika , Sarrechia Iemke , Zemlin Michael , Cuttini Marina , Männamaa Mairi , Pierrat Véronique , van Heijst Arno , Barros Henrique , Zeitlin Jennifer , Johnson Samantha ,   the SHIPS research group
Published: February 2023

Aim

To assess the predictive validity of parent‐reported gross motor impairment (GMI) at age 2 years to detect significant movement difficulties at age 5 years in children born extremely preterm.

Method

Data were from 556 children (270 males, 286 females) born at less than 28 weeks' gestation in 2011 to 2012 in 10 European countries. Parent report of moderate/severe GMI was defined as walking unsteadily or unable to walk unassisted at 2 years corrected age. Examiners assessed significant movement difficulties (score ≤ 5th centile on the Movement Assessment Battery for Children, Second Edition) and diagnoses of cerebral palsy (CP) were collected by parent report at 5 years chronological age.

Results

At 2 years, 66 (11.9%) children had moderate/severe GMI. At 5 years, 212 (38.1%) had significant movement difficulties. Parent reports of GMI at age 2 years accurately classified CP at age 5 years in 91.0% to 93.2% of children. Classification of moderate/severe GMI at age 2 years had high specificity (96.2%; 95% confidence interval 93.6–98.0) and positive predictive value (80.3%; 68.7–89.1) for significant movement difficulties at age 5 years. However, 74.5% of children with significant movement difficulties at 5 years were not identified with moderate/severe GMI at age 2 years, resulting in low sensitivity (25.1%; 19.4–31.5).

Interpretation

This questionnaire may be used to identify children born extremely preterm who at age 2 years have a diagnosis of CP or movement difficulties that are likely to have a significant impact on their functional outcomes at age 5 years.
Sudden unexpected death in epilepsy: The need for age‐specific evidence‐based prevention
Authors: Mastrangelo Mario , Esposito Dario , Pisani Francesco
Published: February 2023

This commentary is on the invited review by Whitney et al. on pages 1150–1156 of this issue.