bluuebunny/crossref_metadata_2025 huggingface dataset:
METCAM/MUC18 plays a tumor promoter role in the development of nasopharyngeal carcinoma type III
Authors: Liu Yen-Chun , Ko Chun-Chuan , Chen Yu-Jen , Wu Guang-Jer
Published: December 2024

Our previous studies by testing the effects of huMETCAM/MUC18 over-expression on the tumorigenesis of the NPC-TW01 cell line supports the notion that huMETCAM/MUC18 plays a tumor suppressor role in the development of nasopharyngeal carcinoma (NPC) type I. However, it is not clear if this notion also holds true for another NPC cell line, NPC-TW04, which was established from NPC type III. For this purpose, we further investigated the effects of huMETCAM/MUC18 over-expression in the NPC-TW04 cell line on theirin vitrocellular behaviors andin vivotumorigenesis in athymic nude mice. First, the G418-resistant clones were obtained after transfection of the huMETCAM/MUC18 cDNA into the NPC-TW04 cell line. Then, one NPC-TW04 clone, which expressed a high level of huMETCAM/MUC18, and one empty vector (control) clone were used for testing effects of huMETCAM/MUC18 over-expression on theirin vitrobehaviors (intrinsic growth rate, motility, and invasiveness, and growth on three-dimensional basement membrane) andin vivotumorigenesis (via subcutaneous injection) in the athymic nude mice. Time course of tumor proliferation and final tumor volumes/weights were determined. Tumor sections were used for histology and immunohistochemistry (IHC) analyses. Tumor lysates were used to determine levels of huMETCAM/MUC18 and various downstream key effectors. We found that over-expression of huMETCAM/MUC18 increasedin vitromotility and invasiveness, induced the invasive growth in the 3D basement membrane culture assay, and increasedin vivotumorigenicity of NPC-TW04 cell line. The expression levels of downstream effectors, such as an anti-apoptosis index, proliferation index, an index of metabolic switch to aerobic glycolysis, angiogenesis indexes and survival pathway index, were increased, whereas the pro-apoptosis index decreased in the tumors. Thus, contrary to the role of huMETCAM/MUC18 in the NPC-TW01 cells, huMETCAM/MUC18 over-expression in the NPC-TW04 cells increased epithelial-to-mesenchymal transition and alsoin vitroinvasive growth andin vivotumorigenesis, suggesting that it plays a tumor promoter role in the development of NPC type III by reducing apoptosis and increasing anti-apoptosis, angiogenesis, proliferation and metabolic switch to aerobic glycolysis.
Comparison of Transcriptional Activation by Corticosteroids of Human MR (Ile-180) and Human MR Haplotype (Ile180Val)
Authors: Katsu Yoshinao , Zhang Jiawen , Ao Ya , Baker Michael E.
Published: December 2024

While the classical function of human mineralocorticoid receptor (MR) is to regulate sodium and potassium homeostasis through aldosterone activation of the kidney MR, the MR also is highly expressed in the brain, where the MR is activated by cortisol in response to stress. Here, we report the half-maximal response (EC50) and fold-activation by cortisol, aldosterone and other corticosteroids of human MR rs5522, a haplotype containing valine at codon 180 instead of isoleucine found in the wild-type MR (Ile-180). MR rs5522 (Val-180) has been studied for its actions in the human brain involving coping with stress and depression. We compared the EC50 and fold-activation by corticosteroids of MR rs5522 and wild-type MR transfected into HEK293 cells with either the TAT3 promoter or the MMTV promoter. Parallel studies investigated the binding of MR antagonists, spironolactone and progesterone, to MR rs5522. In HEK293 cells with the MMTV promotor, MR rs5522 had a slightly higher EC50 compared to wild-type MR and a similar level of fold-activation for all corticosteroids. In contrast, in HEK293 cells with the TAT3 promoter, MR 5522 had a higher EC50 (lower affinity) and higher fold-activation for cortisol compared to wild-type MR (Ile-180), while compared to wild-type MR, the EC50s of MR rs5522 for aldosterone and corticosterone were slightly lower and fold-activation was higher. Spironolactone and progesterone had similar antagonist activity for MR rs5522 and MR (Ile-180) in the presence of MMTV and TAT3 promoters in HEK293 cells.
Cross-sectional and longitudinal changes in category-selectivity in visual cortex following pediatric cortical resection
Authors: Liu Tina T. , Granovetter Michael C. , Maallo Anne Margarette S. , Robert Sophia , Fu Jason Z. , Patterson Christina , Plaut David C. , Behrmann Marlene
Published: December 2024

The topographic organization of category-selective responses in human ventral occipitotemporal cortex (VOTC) and its relationship to regions subserving language functions is remarkably uniform across individuals. This arrangement is thought to result from the clustering of neurons responding to similar inputs, constrained by intrinsic architecture and tuned by experience. We examined the malleability of this organization in individuals with unilateral resection of VOTC during childhood for the management of drug-resistant epilepsy. In cross-sectional and longitudinal functional imaging studies, we compared the topography and neural representations of 17 category-selective regions in individuals with a VOTC resection, a ‘control patient’ with resection outside VOTC, and typically developing matched controls. We demonstrated both adherence to and deviation from the standard topography and uncovered fine-grained competitive dynamics between word- and face-selectivity over time in the single, preserved VOTC. The findings elucidate the nature and extent of cortical plasticity and highlight the potential for remodeling of extrastriate architecture and function.

Teaser

After pediatric cortical resection, deviations from the constraints of standard topography in visual cortex reflect plasticity.
Development of Molecular Digital Twins Based on Ambient Ionization Mass Spectrometry Imaging for Application in Cancer Surgery
Authors: Zirem Yanis , Ledoux Léa , Ogrinc Nina , Lagache Laurine , Bourette Roland , Lagadec Chann , Chaillou Paul , Salzet Michel , Fournier Isabelle
Published: December 2024

Cancer surgery is a fundamental component of oncology treatment, its quality significantly impacts patient outcomes, influencing both relapse rates and survival. However, achieving this customization is contingent upon early collection of robust molecular data during surgery, providing accurate information for diagnosis, prognosis, and delineating surgical margins. The introduction of digital twin (DT) technology has recently opened a new era of precision and effectiveness in cancer surgery. Expanding from its successful implementations in the industrial sector, DT concept has evolved into a highly promising breakthrough in healthcare. Therefore, our study goal is on creating DT by using accurate and high-throughput molecular data obtained through mass spectrometry imaging. We developed a machine-learning-based pipeline that allow to depict infiltration of cancer cells into normal tissue that offer precise delineation of tumor margins thanks to SpiderMass. This process also enables the prediction of relative presence of bacterial strains in tumoral and healthy mammary glands.
Motor network activation and white matter connectivity patterns are related to clinical outcomes following perinatal and childhood arterial ischemic stroke
Authors: Curnow SR , Chen J , Warren AEL , Beare R , Mackay MT , Yang JYM
Published: December 2024

Background

Motor outcomes following perinatal and childhood stroke are highly variable and likely reflect complex structural and functional changes within motor-related brain networks. Greater understanding of these network mechanisms is needed to improve patient-specific prognostication and develop targeted therapies to restore motor function. This study explored post-stroke motor-related reorganization patterns through assessment of functional MRI (fMRI) activation and white matter connectivity patterns.

Hypothesis

We hypothesized that activation and connectivity patterns would differ between children with and without hemiparesis following stroke.

Methods

Twelve children (age 9-19 years) with a history of perinatal or childhood stroke underwent 3T MRI with diffusion-weighted imaging and task-related hand-motor fMRI. The Paediatric Stroke Outcome Measure was used to assess motor outcome and dichotomized into two groups. MRI data were processed and analyzed for whole-brain fMRI activation patterns and white matter track-weighted functional connectivity (TW-FC) profiles, in relation to motor outcomes.

Results

Divergent fMRI activation and TW-FC patterns were seen between the two groups. Children in the no hemiparesis group were more likely to retain an ipsilesional fMRI activation pattern while children in the hemiparesis group were more likely to demonstrate bilateral or contralesional patterns. Increased utilization of cortical-subcortical pathways was identified by TW-FC in both groups. Greater TW-FC strength when moving the stroke-affected hand was also seen in the no hemiparesis group compared to the hemiparesis group.

Conclusions

We identified distinct patterns of motor network activation and white matter connectivity relating to clinical outcomes after perinatal and childhood stroke. These patterns have potential to improve prognostic ability and aid identification of infants and children who would most benefit from targeted therapy to improve long-term motor outcomes.
The human RAD52 complex undergoes phase separation and facilitates bundling and end-to-end tethering of RAD51 presynaptic filaments
Authors: Alshareedah Ibraheem , Pangeni Sushil , Dewan Paul A. , Honda Masayoshi , Liao Ting-Wei , Spies Maria , Ha Taekjip
Published: December 2024

Human RAD52 is a prime target for synthetical lethality approaches to treat cancers with deficiency in homologous recombination. Among multiple cellular roles of RAD52, its functions in homologous recombination repair and protection of stalled replication forks appear to substitute those of the tumor suppressor protein BRCA2. However, the mechanistic details of how RAD52 can substitute BRCA2 functions are only beginning to emerge. RAD52 forms an undecameric ring that is enveloped by eleven ∼200 residue-long disordered regions, making it a highly multivalent and branched protein complex that potentiates supramolecular assembly. Here, we show that RAD52 exhibits homotypic phase separation capacity, and its condensates recruit key players in homologous recombination such as single-stranded (ss)DNA, RPA, and the RAD51 recombinase. Moreover, we show that RAD52 phase separation is regulated by its interaction partners such as ssDNA and RPA. Using fluorescence microscopy, we show that RAD52 can induce the formation of RAD51-ssDNA fibrillar structures. To probe the fine structure of these fibrils, we utilized single-molecule super-resolution imaging via DNA-PAINT and atomic force microscopy and showed that RAD51 fibrils are bundles of individual RAD51 nucleoprotein filaments. We further show that RAD52 induces end-to-end tethering of RAD51 nucleoprotein filaments. Overall, we demonstrate unique macromolecular organizational features of RAD52 that may underlie its various functions in the cell.
Secretome analysis of cancer-associated fibroblasts from prostate cancer to identify potential therapeutic targets
Authors: Abikar Apoorva , Subhani Mustafa Mohammad Mehaboob , Athalye Radhika Rajiv , Nadig Namratha , Tamboli Ninad , Babu Vinod , Keshavamurthy Ramaiah , Ranganathan Prathibha
Published: December 2024

Tumor microenvironment (TME) is a complex entity comprising of several cell types secreted factors as well as an extracellular matrix. A dynamic interaction between tumor cells and their environment profoundly influences tumor survival, aggressiveness, and progression. Cancer- associated fibroblasts (CAFs) are one of the major cellular components of TME and serve as a major source of various secreted factors. These factors are known to modulate tumor survival and progression, as well as their response to therapy. Despite the importance of the TME factors on various aspects of tumor cell behavior, to date factors unique to CAFs that could be potential therapeutic targets are not identified in most systems. This study was aimed at identifying such factors from CAFs which may impact tumor behavior such as the ability to metastasize, response to therapy, relapse, etc. This would aid in identifying therapeutic targets originating from the TME. Furthermore, targeting those factors along with conventional chemotherapeutic drugs is likely to enhance the overall efficacy of the therapy. This study has used fibroblasts derived from Benign Prostatic Hyperplasia (BPH) and prostate cancer for comparing the secretome using a quantitative proteomics approach. 66 proteins unique to CAFs and 24 unique to control (BPH) fibroblasts have been identified. Besides 236 proteins are differentially expressed between control and cancer- associated fibroblasts. Using in-silico approaches the potential processes that may be influenced by the differentially expressed proteins have also been identified. This study has identified both qualitative and quantitative differences between the secretomes of normal and cancer-associated fibroblasts with further validation, this paves the way for identifying therapeutic targets.
Patient-Derived Xenografts of Triple-Negative Breast Cancer Enable Deconvolution and Prediction of Chemotherapy Responses
Authors: Lei Jonathan T. , Dobrolecki Lacey E. , Huang Chen , Srinivasan Ramakrishnan R. , Vasaikar Suhas V. , Lewis Alaina N. , Sallas Christina , Zhao Na , Cao Jin , Landua John D. , Moon Chang In , Liao Yuxing , Hilsenbeck Susan G. , Osborne C. Kent , Rimawi Mothaffar F. , Ellis Matthew J. , Petrosyan Varduhi , Wen Bo , Li Kai , Saltzman Alexander B. , Jain Antrix , Malovannaya Anna , Wulf Gerburg M. , Marangoni Elisabetta , Li Shunqiang , Kraushaar Daniel C. , Wang Tao , Damodaran Senthil , Zheng Xiaofeng , Meric-Bernstam Funda , Echeverria Gloria V. , Anurag Meenakshi , Chen Xi , Welm Bryan E. , Welm Alana L. , Zhang Bing , Lewis Michael T.
Published: December 2024

Combination chemotherapy remains essential for clinical management of triple-negative breast cancer (TNBC). Consequently, responses to multiple single agents cannot be delineated at the single patient level, even though some patients might not require all drugs in the combination. Herein, we conduct multi-omic analyses of orthotopic TNBC patient-derived xenografts (PDXs) treated with single agent carboplatin, docetaxel, or the combination. Combination responses were usually no better than the best single agent, with enhanced response in only ∼13% of PDX, and apparent antagonism in a comparable percentage. Single-omic comparisons showed largely non-overlapping results between genes associated with single agent and combination treatments that could be validated in independent patient cohorts. Multi-omic analyses of PDXs identified agent-specific biomarkers/biomarker combinations, nominating high Cytokeratin-5 (KRT5) as a general marker of responsiveness. Notably, integrating proteomic with transcriptomic data improved predictive modeling of pathologic complete response to combination chemotherapy. PDXs refractory to all treatments were enriched for signatures of dysregulated mitochondrial function. Targeting this process indirectly in a PDX with HDAC inhibition plus chemotherapyin vivoovercomes chemoresistance. These results suggest possible resistance mechanisms and therapeutic strategies in TNBC to overcome chemoresistance, and potentially allow optimization of chemotherapeutic regimens.

Highlights

Minable multi-omic resource of baseline TNBC PDX tumors matched with single and combination chemotherapy responses yields candidate resistance mechanisms and potentially targetable processes

Combination carboplatin/docetaxel is largely ineffective at enhancing response versus the best single agent in TNBC PDXs, and they can antagonize one another in some PDXs

Proteomics data enhances predictions of platinum- and taxane-based chemotherapy response

Targeted agents can enhance chemotherapy response in TNBC PDXs
Perivascular Macrophages Convert Physical Wound Signals Into Rapid Vascular Responses
Authors: Gelashvili Zaza , Shen Zhouyang , Ma Yanan , Jelcic Mark , Niethammer Philipp
Published: December 2024

Leukocytes detect distant wounds within seconds to minutes, which is essential for effective pathogen defense, tissue healing, and regeneration. Blood vessels must detect distant wounds just as rapidly to initiate local leukocyte extravasation, but the mechanism behind this immediate vascular response remains unclear. Using high-speed imaging of live zebrafish larvae, we investigated how blood vessels achieve rapid wound detection. We monitored two hallmark vascular responses: vessel dilation and serum exudation. Our experiments—including genetic, pharmacologic, and osmotic perturbations, along with chemogenetic leukocyte depletion—revealed that the cPla2nuclear shape sensing pathway in perivascular macrophages converts a fast (∼50 μm/s) osmotic wound signal into a vessel-permeabilizing, 5-lipoxygenase (Alox5a) derived lipid within seconds of injury.

These findings demonstrate that perivascular macrophages act as physicochemical relays, bridging osmotic wound signals and vascular responses. By uncovering this novel type of communication, we provide new insights into the coordination of immune and vascular responses to injury.
What challenges remain in harmonizing cytomegalovirus viral load quantification across laboratories?
Authors: Boutolleau D. , L’Honneur A-S. , Germi R. , Chanzy B. , Archimbaud-Jallat C. , Rzadkowolski C. , Raimbourg J.B. , Gauthier D. , Thibault V.
Published: December 2024

Cytomegalovirus (CMV) infection monitoring is a key element in the management of immunocompromised patients. CMV DNA quantification in plasma or whole blood is the best indicator for clinicians to adjust immunosuppressive or antiviral therapies. Despite the availability of internationally standardized material, the commutability of CMV quantification results across laboratories remains inadequate. To assess inter-laboratory variability in CMV DNA quantification, we conducted a blinded study in seven independent laboratories. Each participant received a panel of 92 specimens for CMV quantification using their routinely used standard platform. While quantifications were highly correlated and reproducible, large discrepancies were observed with differences up to 1.45 log10IU/mL between techniques for identical specimens. However, quantification scattering was lower for the WHO international standard or a commercially tested control (IQR=0.129) than for clinical specimens (0.469; p=0.0142). Blind quantification of the WHO or the commercial standard indicated that all techniques, except for fully integrated platforms, did not align well with the expected values and most platforms tended to quantify specimens and standards differently. Recalibration of all platforms against the same standard improved the spread of results, but differences of up to 1.19 log10IU/mL remained for the same specimens. Achieving commutability in CMV quantification remains an elusive goal. Efforts should focus on improving both the assay calibrators and the run controls, which currently do not appear to simulate the unique characteristics of circulating CMV in patients. Until this is resolved, each transplanted patient should be consistently monitored by the same laboratory on the same platform.
Pervasive divergence in protein thermostability is mediated by both structural changes and cellular environments
Authors: Walunjkar Nilima , Lai Timothy Y. , Akhter Nasima , Miller James H. , Bettinger John Q. , Marcus Erin , Phizicky Eric M. , Ghaemmaghami Sina , Fay Justin C.
Published: December 2024

Temperature is a universal environmental constraint and organisms have evolved diverse mechanisms of thermotolerance. A central feature of thermophiles relative to mesophiles is a universal shift in protein stability, implying that it is a major constituent of thermotolerance. However, organisms have also evolved extensive buffering systems, such as those that disaggregate and refold denatured proteins and enable survival of heat shock. Here, we show that both cellular and protein structural changes contribute to divergence in protein thermostability between two closely relatedSaccharomycesspecies that differ by 8°C in their thermotolerance. Using thermal proteomic profiling we find that 85% ofS. cerevisiaeproteins are more stable than theirS. uvarumhomologs and there is an average shift of 1.6°C in temperature induced protein aggregation. In an interspecific hybrid of the two species,S. cerevisiaeproteins retain their thermostability, while the thermostability of theirS. uvarumhomologs is enhanced, indicating that cellular context contributes to protein stability differences. By purifying orthologous proteins we show that amino acid substitutions underlie melting temperature differences for two proteins, Guk1 and Aha1. Amino acid substitutions are also computationally predicted to contribute to stability differences for most of the proteome. Our results imply that coordinated changes in protein thermostability impose a significant constraint on the time scales over which thermotolerance can evolve.
H3.1K27M-induced misregulation of the TSK/TONSL-H3.1 pathway causes genomic instability
Authors: Yuan Wenxin , Huang Yi-Chun , LeBlanc Chantal , Poulet Axel , Valsakumar Devisree , van Wolfswinkel Josien C. , Voigt Philipp , Jacob Yannick
Published: December 2024

The oncomutation lysine 27-to-methionine in histone H3 (H3K27M) is frequently identified in tumors of patients with diffuse midline glioma-H3K27 altered (DMG-H3K27a). H3K27M inhibits the deposition of the histone mark H3K27me3, which affects the maintenance of transcriptional programs and cell identity. Cells expressing H3K27M are also characterized by defects in genome integrity, but the mechanisms linking expression of the oncohistone to DNA damage remain mostly unknown. In this study, we demonstrate that expression of H3.1K27M in the model plantArabidopsis thalianainterferes with post-replicative chromatin maturation mediated by the H3.1K27 methyltransferases ATXR5 and ATXR6. As a result, H3.1 variants on nascent chromatin remain unmethylated at K27 (H3.1K27me0), leading to ectopic activity of TONSOKU (TSK), which induces DNA damage and genomic alterations. Elimination of TSK activity suppresses the genome stability defects associated with H3.1K27M expression, while inactivation of specific DNA repair pathways prevents survival of H3.1K27M-expressing plants. Overall, our results suggest that H3.1K27M disrupts the chromatin-based mechanisms regulating TSK/TONSL activity, which causes genomic instability and may contribute to the etiology of DMG-H3K27a.
Ctenophores and parahoxozoans independently evolved complex and functionally diverse sets of voltage-gated K+channels
Authors: Simonson Benjamin T. , Jiang Zhaoyang , Ryan Joseph F. , Jegla Timothy
Published: December 2024

The ctenophore speciesMnemiopsis leidyiis known to have a large set of voltage-gated K+channels, but little is known about the functional diversity of these channels or the evolutionary history of this gene family in other ctenophore species. Here, we searched the genomes of two additional ctenophore species,Beroe ovataandHormiphora californensis, for voltage-gated K+channels and functionally expressed a subset ofM. leidyichannels. We found that the last common ancestor of these three disparate ctenophore lineages probably had at least 33 voltage-gated K+channels. Two of these genes belong to the EAG family, and the remaining 31 belong to the Shaker family and form a single clade within the animal/choanoflagellate Shaker phylogeny. We additionally found evidence for 10 of these Shaker channels in a transcriptome of the early branching ctenophore lineageEuplokamis dunlapae, suggesting that the diversification of these channels was already underway early in ctenophore evolution. We functionally expressed 16MnemiopsisShakers and found that they encode a functionally diverse array of voltage-gated K+conductances with functional orthologs for many classic Shaker family subtypes found in cnidarians and bilaterians. Ctenophores therefore appear to have independently evolved much of the voltage-gated K+channel diversity that is shared between cnidarians and bilaterians.
Predicting plant traits using large conglomerate RNA-seq datasets
Authors: Hadish John Anthony , Honaas Loren A. , Ficklin Stephen Patrick
Published: December 2024

RNA-seq datasets offer potential for predicting phenotypic traits, but the optimal dataset size for reliable predictions remains unclear. To explore this question, we compiled large-scale transcriptomic datasets across 12 plant species and used them to predict the phenotypic variables of tissue type and age. Predictions were made using random forest models. We created these models using an increasing number of samples to create performance curves.

These curves show that only a few hundred samples are required to achieve maximum accuracy for tissue classification, while predicting age demands a few thousand samples. Acceptable prediction accuracy can be achieved at even lower numbers of samples. Our findings provide a benchmark for designing transcriptomic studies aimed at phenotype prediction and highlight the differing complexities involved in predicting simple versus more complex traits.

CORE IDEAS

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Plant transcriptomes are highly dynamic in response to internal and external conditions

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There is interest in using transcriptomes for predicting phenotypic traits and disorders

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It is unknown how many samples are required for accurate phenotype prediction

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We created 12 massive RNA-seq datasets and corresponding phenotypic data and used these to create prediction models

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Performance curves from our models provide insight into the required number of samples for accurate prediction
Participatory Development of a Speech-Language Telerehabilitation Intervention combined with Home-based Transcranial Direct Current Stimulation for Primary Progressive Aphasia: a Qualitative Study
Authors: Rysop Anna Uta , Schiwek Roxana , Grewe Tanja , Breitenstein Caterina , Binkofski Ferdinand , Roheger Mandy , Unger Nina , Flöel Agnes , Meinzer Marcus
Published: December 2024

Purpose

Intensive speech-language therapy (SLT) delivered as telerehabilitation in combination with transcranial direct current stimulation (tDCS) may be an effective treatment option for people with primary progressive aphasia (pwPPA). However, such combined treatment approaches are technically challenging and feasibility for pwPPA has not yet been established.

We aimed to involve stakeholders in the development of a novel approach combining remotely-supervised but independently self-administered home-based tDCS with an intensive aphasia telerehabilitation (naming and communicative-pragmatic therapy).

Method

Eight pwPPA and 16 caregivers participated in two semi-structured interviews to identify the needs, preferences, and perceived barriers and challenges with regard to SLT, telerehabilitation and tDCS, and the combination of all components. Based on the results, a step-by-step manual was developed and tested by means of home-based usability tests and follow-up interviews involving four dyads. Interview data were transcribed and analysed qualitatively and quantitatively. Competency checklists used in the usability tests were analysed quantitatively.

Results

PwPPA and their caregivers provided valuable insights into all aspects of the planned treatment programme. Overall, the findings suggest a high level of acceptance and perceived need for an intensive telerehabilitation SLT approach combined with tDCS. Using the developed step-by-step manual and training, pwPPA were able to independently perform more than half of the actions required for telerehabilitation but needed assistance with technically more demanding aspects of tDCS. To ensure feasibility, caregiver-assistance is needed to support pwPPA during technically challenging interventions.

Conclusions

This mixed-methods study identified needs and preferences of pwPPA and their caregivers with regard to speech-language telerehabilitation, as well as barriers and challenges regarding telerehabilitation and home-based tDCS. We demonstrate high acceptability and initial feasibility of such combined programmes. Our findings highlight the importance of stakeholder involvement in intervention development, which will inform future development and optimisation of technologically demanding intervention programmes.
Cell-type-resolved chromatin accessibility in the human intestine identifies complex regulatory programs and clarifies genetic associations in Crohn’s disease
Authors: Zhao Yu , Zhou Ran , Mu Zepeng , Carbonetto Peter , Zhong Xiaoyuan , Xie Bingqing , Luo Kaixuan , Cham Candace M , Koval Jason , He Xin , Dahl Andrew W. , Liu Xuanyao , Chang Eugene B , Basu Anindita , Pott Sebastian
Published: December 2024

Crohn’s disease (CD) is a complex inflammatory bowel disease resulting from an interplay of genetic, microbial, and environmental factors. Cell-type-specific contributions to CD etiology and genetic risk are incompletely understood. Here we built a comprehensive atlas of cell-type- resolved chromatin accessibility comprising 557,310 candidate cis-regulatory elements (cCREs) in terminal ileum and ascending colon from patients with active and inactive CD and healthy controls. Using this atlas, we identified cell-type-, anatomic location-, and context-specific cCREs and characterized the regulatory programs underlying inflammatory responses in the intestinal mucosa of CD patients. Genetic variants that disrupt binding motifs of cell-type-specific transcription factors significantly affected chromatin accessibility in specific mucosal cell types. We found that CD heritability is primarily enriched in immune cell types. However, using fine- mapped non-coding CD variants we identified 29 variants located within cCREs several of which were accessible in epithelial and stromal cells implicating cell types from additional lineages in mediating CD risk in some loci. Our atlas provides a comprehensive resource to study gene regulatory effects in CD and health, and highlights the cellular complexity underlying CD risk.
An Individually Tailored, Home-Based Supervised Exercise Programme for People with Early Dementia: An RCT-informed Health Economic Evaluation
Authors: Ezeofor Victory ‘Segun , Hartfiel Ned , Doungsong Kodchawan , Goldberg Sarah , van der Wardt Veronika , Howe Louise , Gladman John , Harwood Rowan H , Edwards Rhiannon T.
Published: December 2024

Background

The effectiveness of exercise interventions to improve activities of daily living function in people with dementia is inconclusive. This study aimed to assess the long-term cost-effectiveness of the PrAISED intervention from a National Health Service (NHS) perspective.

Method

This novel robust economic analysis used a Markov model to evaluate the incremental cost-effectiveness ratio (ICER) over a lifetime horizon of 15 years for a cohort of patients. Sensitivity analyses were conducted to investigate the uncertainty and robustness of high-impacting parameters and results.

Results

This study included 365 adults, aged 65 years and above with 183 and 182 randomised to the PrAISED and standard care groups respectively. The PrAISED intervention had mean per-patient cost of £60,465 for the PrAISED arm and £54,604 for standard care. The Praised intervention gained an incremental QALYs of 0.05 resulting in an ICER of £129,614 per QALY. The sensitivity analysis of the intervention cost varied the ICER value between £68,173 and £191,054/QALY. To achieve the recommended NICE willingness to pay threshold value of less than £30,000/QALYs would require the intervention cost to be reduced from £1,236 (current cost) to £263 to break even and be cost-effective. The sensitivity analyses revealed that there was a 40% probability of standard care dominating the PrAISED treatment.

Conclusions

Although the PrAISED intervention was a low-cost intervention, it did not produce a cost-effective intervention in this analysis. The flexibility of the PrAISED program to adapt to government policy during the COVID-19 pandemic was positive.

Trial registration

ISRCTN15320670
Algorithm Refinement of the National Early Warning Score 2 (NEWS2): Study Protocol
Authors: Plummer Chris , Milne-Ives Madison , Cong Cen , Threlfall Lynsey , Meinert Edward
Published: December 2024

Introduction

The second iteration of the National Early Warning Score (NEWS2) has been widely adopted for predicting patient deterioration in healthcare settings using routinely collected physiological observations. The use of NEWS2 has been shown to reduce in-hospital mortality, but it has limited accuracy in the prediction of clinically important outcomes, especially over longer time periods. The increasing implementation of digital patient observations and health records presents an opportunity to investigate whether the addition of individual patient characteristics and information about their care-setting, would improve the predictive accuracy of the score.

Methods and analysis

This protocol describes the work to determine whether the performance of the current NEWS2 system could be improved by the use of additional variables. The project has been designed after an extensive scoping review of existing literature on NEWS2 and an exploration of retrospective cohort data in The Newcastle upon Tyne Hospitals NHS Foundation Trust, with input from key clinical stakeholders.

Ethics and dissemination

The project has received competitive funding following peer-review, from the NIHR Newcastle Biomedical Research Centre as an Interdisciplinary Research Award. Ethical approval has been requested. Findings are expected to be produced by June 2025, and will be disseminated at symposia, conferences and in journal publications.

Strengths and limitations of this study

Strengths

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This work highlights the importance of investigating the use of additional clinical variables to those used in NEWS2, in the development of a new early warning score

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The study design was informed by an evidence synthesis of the literature

Limitations

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Some retrospective data sets may be of low quality and/or incomplete

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External validation will be needed to test algorithm generalisability
Heterogeneity in and correlation between host transmissibility and susceptibility can greatly impact epidemic dynamics
Authors: Tuschhoff Beth M. , Kennedy David A.
Published: December 2024

While it is well established that host heterogeneity in transmission and host heterogeneity in susceptibility each individually impact disease dynamics in characteristic ways, it is generally unknown how disease dynamics are impacted when both types of heterogeneity are simultaneously present. Here we explore this question. We first conducted a systematic review of published studies from which we determined that the effects of correlations have been drastically understudied. We then filled in the knowledge gaps by developing and analyzing a stochastic, individual-based SIR model that includes both heterogeneity in transmission and susceptibility and flexibly allows for positive or negative correlations between transmissibility and susceptibility. We found that in comparison to the uncorrelated case, positive correlations result in major epidemics that are larger, faster, and more likely, whereas negative correlations result in major epidemics that are smaller and less likely. We additionally found that, counter to the conventional wisdom that heterogeneity in susceptibility always reduces outbreak size, heterogeneity in susceptibility can lead to major epidemics that are larger and more likely than the homogeneous case when correlations between transmissibility and susceptibility are positive, but this effect only arises at small to moderateR0. Moreover, positive correlations can frequently lead to major epidemics with subcriticalR0. Ultimately, we show that correlations between transmissibility and susceptibility profoundly impact disease dynamics.

Highlights

Systematic review finds that effects of correlations on epidemics are understudied

Positive correlations lead to larger, faster, more likely epidemics

Negative correlations lead to smaller, less likely epidemics

Positive correlations consistently lead to major epidemics with subcriticalR0
Distinct genetic architecture for trait mean and plasticity in chickpea
Authors: Alagarasan Ganesh , Varshney Rajeev K. , Ramireddy Eswarayya
Published: December 2024

Crop plants often face rapid environmental changes, and their ability to adapt to novel conditions depends on whether specific traits can adjust to match these changes. This capacity for adjustment, known as phenotypic plasticity, is frequently regarded as a mere “response” rather than a distinct trait with its own genetic basis, particularly in agricultural science. As a result, plasticity is often oversimplified and viewed as an undesirable phenomenon when the goal is to achieve trait stability. In this study, we present a quantitative metric to measure phenotypic plasticity and provide evidence, through genome-wide association studies (GWAS) in chickpea, that plasticity is indeed a genetically based trait, comparable to any other agronomic trait. This foundational study paves the way for future GWAS efforts to harness phenotypic plasticity, offering new insights for crop improvement strategies.
Gut Microbiome Signatures During Acute Infection Predict Long COVID
Authors: Comba Isin Y. , Mars Ruben A. T. , Yang Lu , Dumais Mitchell , Chen Jun , Van Gorp Trena M. , Harrington Jonathan J. , Sinnwell Jason P. , Johnson Stephen , Holland LaRinda A. , Khan Adam K. , Lim Efrem S. , Aakre Christopher , Athreya Arjun P. , Gerber Georg K. , O’Horo Jack C. , Lazaridis Konstantinos N. , Kashyap Purna C.
Published: December 2024

Long COVID (LC), manifests in 10-30% of non-hospitalized individuals post-SARS-CoV-2 infection leading to significant morbidity. The predictive role of gut microbiome composition during acute infection in the development of LC is not well understood, partly due to the heterogeneous nature of disease. We conducted a longitudinal study of 799 outpatients tested for SARS-CoV-2 (380 positive, 419 negative) and found that individuals who later developed LC harbored distinct gut microbiome compositions during acute infection, compared with both SARS-CoV-2–positive individuals who did not develop LC and negative controls with similar symptomatology. However, the temporal changes in gut microbiome composition between the infectious (0–1 month) and post-infectious (1–2 months) phases was not different between study groups. Using machine learning, we showed that microbiome composition alone more accurately predicted LC than clinical variables. Including clinical data only marginally enhanced this prediction, suggesting that microbiome profiles during acute infection may reflect underlying health status and immune responses thus, help predicting individuals at risk for LC. Finally, we identified four LC symptom clusters, with gastrointestinal and fatigue-only groups most strongly linked to gut microbiome alterations.
Muscle length modulates recurrent inhibition and post-activation depression differently according to contraction type
Authors: Colard Julian , Duclay Julien , Betus Yohan , Cattagni Thomas , Jubeau Marc
Published: December 2024

It is well documented that, in soleus, motoneuron output and the effectiveness of activated Ia afferents to discharge α-motoneurons both decrease during eccentric contractions. Evidence suggests that these regulations can be explained by (1) recurrent inhibition and (2) greater post-activation depression by primary afferent depolarization. However, the influence of muscle length on the regulation of the effectiveness of Ia afferents to discharge α-motoneurons observed during eccentric contractions remains unclear. We conducted a study on 16 healthy young individuals. We used simple and conditioned Hoffmann reflex with different conditioning techniques such as paired H reflex, D1 method and heteronymous Ia facilitation coupled with electromyography during eccentric, isometric and concentric contractions at long, intermediate and short soleus muscle lengths. Our results confirm that during eccentric contraction the effectiveness of Ia afferents to dischargeU-motoneurons decreases only at intermediate and short muscle lengths but is similar between all contraction types at long muscle length. Findings are similar for recurrent inhibition. Post-activation depression is significantly more pronounced during eccentric contractions compared with isometric and concentric contractions at long muscle length. Our analysis also shows that recurrent inhibition and post-activation depression are greater at long muscle length compared with short muscle length, whatever the contraction type. These new findings demonstrate an important influence of muscle length on the activity of spinal regulatory mechanisms and the effectiveness of activated Ia afferents to discharge α-motoneurons during eccentric contractions.
Toxicity and Biodegradation of Two Different Hydrothermal Liquefaction Process Waters to Anaerobic Digestion and the Effect of Microaeration
Authors: Zhou Mei , Usack Joseph G. , Smith Aidan Mark , Angenent Largus T.
Published: December 2024

Hydrothermal liquefaction (HTL) can convert a considerable portion of the carbon in complex feedstocks into renewable bio-oil, but it also generates a liquid byproduct (i.e., HTL process water) that retains 15 – 55% of the carbon from the HTL feedstock. Feeding HTL process water to anaerobic digestion (AD) is a promising approach for maximizing resource recovery, enabling the conversion of the retained carbon into biogas. However, various toxic and poorly biodegradable compounds in HTL process water make its treatment with AD challenging. Presently, the underlying mechanisms remain often unclear. We investigated the impact of HTL process water from two different feedstocks – a food-waste proxy (i.e., dog food, rich in proteins) and wheat straw (rich in lignocellulose) – on the different trophic groups in the food web of AD. We found that methanogens rather than acidogens were inhibited by HTL process water. Comparative toxicity and biodegradability analyses showed that wheat-straw process water had a higher biodegradability regardless of its higher toxicity to acetoclastic methanogens than food-waste process water, due to its higher content in toxic but easily degradable aromatic compounds. Microaeration enhanced the biodegradation and methane yields of food-waste process water, particularly under anoxic conditions. However, microaeration was ineffective for wheat-straw process water. These findings highlight the importance of feedstock-specific strategies to optimize AD for biogas production from HTL process water.
Near-infrared real time non-destructive monitoring of sugar accumulation reveals that single berries ripen two times faster than previously documented on standard asynchronous samples
Authors: Tavernier Flora , Motelica-Heino Elias , Thomas Miguel , Herbold Theresa , Shi Mengyao , Cunff Loïc Le , Romieu Charles , Segura Vincent
Published: December 2024

Understanding how climate change impacts berry ripening physiology is essential for selecting genotypes that balance sugars and acids under warming conditions. In this context, we used a portable near-infrared spectrometer in the vineyard, to monitor sugar and acid evolution in individual berries from 10 grapevine varieties over two years. Spectra were periodically acquired on the same berries all along ripening, and a subset of these berries was also collected for sugars and organic acids quantification by HPLC, to train partial least square regression models. Prediction models for glucose, fructose, and malic acid concentrations were fairly accurate with validation R² of 0.71, 0.64, and 0.55, respectively. We further used these models to study sugar accumulation in individual berries and observed that the single berries ripen two times faster than average samples. Our results pave avenues toward precise quantitative approaches on sugar and acid fluxes in berry ripening studies.
Identification of novel prophages and variants of Integrative and Conjugative Elements in Elizabethkingia anophelis clinical isolates from Seremban, Malaysia
Authors: Zajmi Asdren , Md Zoqratt Muhammad Zarul Hanifah , Loganathan Aswini Leela , A. Rahman Nor Iza , Mohd Yusof Nurul Hafizah , Tang Soo Nee , Ayub Qasim , Yeo Chew Chieng
Published: December 2024

Elizabethkingia anophelis is an emerging multidrug-resistant pathogen that has been identified globally, including in Malaysia. In this study, we used the Oxford Nanopore Technologies (ONT) long-read platform to generate the complete genome sequences of seven clinical isolates of E. anophelis from a tertiary hospital in the city of Seremban, located in the state of Negeri Sembilan in Peninsular Malaysia. These sequences were analysed alongside over 400 publicly available E. anophelis genomes from other countries. Three of the seven E. anophelis isolates, Eli4, Eli5, and Eli6, were almost identical and their isolation over a period of six weeks from the same hospital was suggestive of nosocomial transmission. Besides these three isolates, the other E. anophelis isolates were genetically diverse and related to distinct isolates from other countries. No plasmids were identified in the genomes of all seven E. anophelis isolates. A novel 39,686 bp prophage was identified in the genome of E. anophelis Eli4 while a presumptive incomplete prophage was found in the genomes of Eli2, Eli4, Eli5 and Eli6. E. anophelis genomes are notable for possessing integrative and conjugative elements (ICEs), which enable the bacterium to acquire new genes, including those encoding antimicrobial resistance or virulence. Several novel ICE sequences were discovered in the Seremban E. anophelis genomes, and this includes an ICE found in Eli8, designated Eli8_ICE1, which encodes phage defence genes such as type I restriction-modification systems, a bacterial cyclic oligonucleotide-based anti-phage signalling system (CBASS) and prokaryotic argonaute systems. The latter two phage defence genes have so far not been reported in the E. anophelis genome. This study demonstrates the utility of long-read sequencing in assessing the diversity and plasticity of E. anophelis genomes and emphasises further research into the role of ICEs in phage defence systems and their potential impact on antimicrobial treatment and phage therapy.