bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary biliary cirrhosis and psoriasis: a two-sample Mendelian randomization study
Authors: Zhao Diqian , Zhao Qinyu , Xu Fangwei , Zhang Fang , Bai Wenzhe
Published: January 2024

Background

Primary biliary cirrhosis (PBC) and psoriasis are frequently observed to co-occur in clinical settings. However, the causal associations and underlying mechanisms between PBC and psoriasis remain poorly defined.

Methods

In this study, we conducted bidirectional MR analysis to explore the causal relationship between PBC and psoriasis using four MR methods: inverse-variance weighted, MR-Egger regression, weighted median, and weighted mode. Sensitivity analyses were carried out, employing different models and testing methods for comparison to assess the influence of heterogeneity and pleiotropy on our findings and to confirm the robustness of these results.

Results

A causal relationship between the risk of PBC and psoriasis was identified, as confirmed by IVW analysis (OR: 1.081, 95%CI: 1.028~1.137, P<0.05). The other three MR methods also produced similar results. However, psoriasis did not have a causal effect on PBC risk (OR: 1.022, 95%CI: 0.935~1.118, P>0.05). The intercept of MR-Egger regression was 0.0013 (P>0.05), indicating that genetic pleiotropy did not influence the results. Additionally, the leave-one-out analysis demonstrated the robustness of our MR findings.

Conclusion

This study reveals a causal relationship between PBC and psoriasis, with PBC increasing the risk of psoriasis, but not the reverse. This potential causal relationship offers a new perspective on the etiology of PBC.
MediMer: a versatile do-it-yourself peptide-receptive MHC class I multimer platform for tumor neoantigen-specific T cell detection
Authors: Meyer Marten , Parpoulas Christina , Barthélémy Titouan , Becker Jonas P. , Charoentong Pornpimol , Lyu Yanhong , Börsig Selina , Bulbuc Nadja , Tessmer Claudia , Weinacht Lisa , Ibberson David , Schmidt Patrick , Pipkorn Rüdiger , Eichmüller Stefan B. , Steinberger Peter , Lindner Katharina , Poschke Isabel , Platten Michael , Fröhling Stefan , Riemer Angelika B. , Hassel Jessica C. , Roberti Maria Paula , Jäger Dirk , Zörnig Inka , Momburg Frank
Published: January 2024

Peptide-loaded MHC class I (pMHC-I) multimers have revolutionized our capabilities to monitor disease-associated T cell responses with high sensitivity and specificity. To improve the discovery of T cell receptors (TCR) targeting neoantigens of individual tumor patients with recombinant MHC molecules, we developed a peptide-loadable MHC class I platform termed MediMer. MediMers are based on soluble disulfide-stabilized β2-microglobulin/heavy chain ectodomain single-chain dimers (dsSCD) that can be easily produced in large quantities in eukaryotic cells and tailored to individual patients’ HLA allotypes with only little hands-on time. Upon transient expression in CHO-S cells together with ER-targeted BirA biotin ligase, biotinylated dsSCD are purified from the cell supernatant and are ready to use. We show that CHO-produced dsSCD are free of endogenous peptide ligands. Empty dsSCD from more than 30 different HLA-A,B,C allotypes, that were produced and validated so far, can be loaded with synthetic peptides matching the known binding criteria of the respective allotypes, and stored at low temperature without loss of binding activity. We demonstrate the usability of peptide-loaded dsSCD multimers for the detection of human antigen-specific T cells with comparable sensitivities as multimers generated with peptide-tethered β2m-HLA heavy chain single-chain trimers (SCT) and wild-type peptide-MHC-I complexes prior formed in small-scale refolding reactions. Using allotype-specific, fluorophore-labeled competitor peptides, we present a novel dsSCD-based peptide binding assay capable of interrogating large libraries of in silico predicted neoepitope peptides by flow cytometry in a high-throughput and rapid format. We discovered rare T cell populations with specificity for tumor neoepitopes and epitopes from shared tumor-associated antigens in peripheral blood of a melanoma patient including a so far unreported HLA-C*08:02-restricted NY-ESO-1-specific CD8+ T cell population. Two representative TCR of this T cell population, which could be of potential value for a broader spectrum of patients, were identified by dsSCD-guided single-cell sequencing and were validated by cognate pMHC-I multimer staining and functional responses to autologous peptide-pulsed antigen presenting cells. By deploying the technically accessible dsSCD MHC-I MediMer platform, we hope to significantly improve success rates for the discovery of personalized neoepitope-specific TCR in the future by being able to also cover rare HLA allotypes.
High-throughput CRISPR technology: a novel horizon for solid organ transplantation
Authors: Li Xiaohan , Chen Zhang , Ye Weicong , Yu Jizhang , Zhang Xi , Li Yuan , Niu Yuqing , Ran Shuan , Wang Song , Luo Zilong , Zhao Jiulu , Hao Yanglin , Zong Junjie , Xia Chengkun , Xia Jiahong , Wu Jie
Published: January 2024

Organ transplantation is the gold standard therapy for end-stage organ failure. However, the shortage of available grafts and long-term graft dysfunction remain the primary barriers to organ transplantation. Exploring approaches to solve these issues is urgent, and CRISPR/Cas9-based transcriptome editing provides one potential solution. Furthermore, combining CRISPR/Cas9-based gene editing with an ex vivo organ perfusion system would enable pre-implantation transcriptome editing of grafts. How to determine effective intervention targets becomes a new problem. Fortunately, the advent of high-throughput CRISPR screening has dramatically accelerated the effective targets. This review summarizes the current advancements, utilization, and workflow of CRISPR screening in various immune and non-immune cells. It also discusses the ongoing applications of CRISPR/Cas-based gene editing in transplantation and the prospective applications of CRISPR screening in solid organ transplantation.
Immunological and virological triggers of type 1 diabetes: insights and implications
Authors: Lemos Joana R. N. , Hirani Khemraj , von Herrath Matthias
Published: January 2024

Type 1 diabetes (T1D) is caused by an autoimmune process which culminates in the destruction of insulin-producing beta cells in the pancreas. It is widely believed that a complex and multifactorial interplay between genetic and environmental factors, such as viruses, play a crucial role in the development of the disease. Research over the past few decades has shown that there is not one single viral culprit, nor one single genetic pathway, causing the disease. Rather, viral infections, most notably enteroviruses (EV), appear to accelerate the autoimmune process leading to T1D and are often seen as a precipitator of clinical diagnosis. In support of this hypothesis, the use of anti-viral drugs has recently shown efficacy in preserving beta cell function after onset of diabetes. In this review, we will discuss the various pathways that viral infections utilize to accelerate the development of T1D. There are three key mechanisms linking viral infections to beta-cell death: One is modulated by the direct infection of islets by viruses, resulting in their impaired function, another occurs in a more indirect fashion, by modulating the immune system, and the third is caused by heightened stress on the beta-cell by interferon-mediated increase of insulin resistance. The first two aspects are surprisingly difficult to study, in the case of the former, because there are still many questions about how viruses might persist for longer time periods. In the latter, indirect/immune case, viruses might impact immunity as a hit-and-run scenario, meaning that many or all direct viral footprints quickly vanish, while changes imprinted upon the immune system and the anti-islet autoimmune response persist. Given the fact that viruses are often associated with the precipitation of clinical autoimmunity, there are concerns regarding the impact of the recent global coronavirus-2019 (COVID-19) pandemic on the development of autoimmune disease. The long-term effects of COVID-19 infection on T1D will therefore be discussed, including the increased development of new cases of T1D. Understanding the interplay between viral infections and autoimmunity is crucial for advancing our knowledge in this field and developing targeted therapeutic interventions. In this review we will examine the intricate relationship between viral infections and autoimmunity and discuss potential considerations for prevention and treatment strategies.
Coastal upwelling systems as dynamic mosaics of bacterioplankton functional specialization
Authors: Delgadillo-Nuño Erick , Teira Eva , Pontiller Benjamin , Lundin Daniel , Joglar Vanessa , Pedrós-Alió Carlos , Fernández Emilio , Pinhassi Jarone , Martínez-García Sandra
Published: January 2024

Coastal upwelling areas are extraordinarily productive environments where prokaryotic communities, the principal remineralizers of dissolved organic matter (DOM), rapidly respond to phytoplankton bloom and decay dynamics. Nevertheless, the extent of variability of key microbial functions in such dynamic waters remains largely unconstrained. Our metatranscriptomics analyses of 162 marker genes encoding ecologically relevant prokaryotic functions showed distinct spatial-temporal patterns in the NW Iberian Peninsula upwelling area. Short-term (daily) changes in specific bacterial functions associated with changes in biotic and abiotic factors were superimposed on seasonal variability. Taxonomic and functional specialization of prokaryotic communities, based mostly on different resource acquisition strategies, was observed. Our results uncovered the potential influence of prokaryotic functioning on phytoplankton bloom composition and development (e.g., Cellvibrionales and Flavobacteriales increased relative gene expression related to vitamin B12 and siderophore metabolisms during Chaetoceros and Dinophyceae summer blooms). Notably, bacterial adjustments to C- or N-limitation and DMSP availability during summer phytoplankton blooms and different spatial-temporal patterns of variability in the expression of genes with different phosphate affinity indicated a complex role of resource availability in structuring bacterial communities in this upwelling system. Also, a crucial role of Cellvibrionales in the degradation of DOM (carbohydrate metabolism, TCA cycle, proteorhodopsin, ammonium, and phosphate uptake genes) during the summer phytoplankton bloom was found. Overall, this dataset revealed an intertwined mosaic of microbial interactions and nutrient utilization patterns along a spatial-temporal gradient that needs to be considered if we aim to understand the biogeochemical processes in some of the most productive ecosystems in the world´s oceans.
Blue carbon development in China: realistic foundation, internal demands, and the construction of blue carbon market trading mode
Authors: Li Ping , Liu Dahai , Liu Chao , Li Xiaoxuan , Liu Zhenhang , Zhu Yanjing , Peng Bo
Published: January 2024

Promoting the inclusion of blue carbon in market trading is crucial for recognizing its value and protecting the marine ecological environment. However, China currently does not have an internationally influential blue carbon market trading platform, which hampers the transmission of supply and demand in the blue carbon market and prevents the realization of blue carbon value. In this study, we analyze the feasibility and necessity of establishing a trading mode for the blue carbon market in China. The introduction of futures trading in the blue carbon market’s trading mode allows for the use of futures pricing methods and multiple financial instruments to address the challenges of income cost mismatch in blue carbon project development. The paper also discusses key strategies for the development of China’s blue carbon market, including the creation of a blue carbon trading methodology, the improvement of preservation and appreciation mechanisms, and the establishment of a unified trading platform. These strategies aim to provide intellectual support and decision-making reference for the construction of the market.
The two salinity peaks mode of marine salt supply to coastal underground brine during a single tidal cycle
Authors: Xiao Xiaoteng , Zhang Yufeng , Fu Tengfei , Sun Zengbing , Lei Bingxiao , Li Mingbo , Guo Xiujun
Published: January 2024

Seawater salt is constantly supplied from the marine environment to coastal underground brine deposits, meaning that brine has the potential for continuous extraction. There is currently a lack of information about the processes that drive the fluxes of seawater salt to underground brine deposits in tidal-driven brine mining areas. We chose the Yangkou salt field on the southern coast of Laizhou Bay, a brine mining area, as our study site. We monitored the spatial and temporal distribution of the underground brine reserve and the changes in water level and salinity in the mining area and adjacent tidal flats using electrical resistivity tomography and hydrogeological measurements. We monitored cross-sections along two survey lines and observed that the underground brine reserve receives a stable supply of seawater salt, and calculated that the rate of influx into the brine body in the mining area near the boundary of the precipitation funnel was 0.226−0.232 t/h. We calculated that a total salt flux of approximately 5.50 t enters the underground brine body every day through a 150 m long shoreline and a 1322.3 m2 window, which is sufficient to sustain the daily extraction of one brine well. During tidal cycles, there are two peaks in the salinity of the water supplied to the underground brine reserve, which means that the brine supply is from at least two high-salinity salt sources in different tidal stages. The first salinity peak occurs during the initial stage of the rising tide after seawater inundates the tidal flat. At this time, seawater, which is a solution and carries a large amount of evaporated salt, is transported into the brine layer through highly permeable areas or biological channels and replenishes the brine in the mining area. The second salinity peak occurs during the early stage of the falling tide. Influenced by hysteresis-driven tidal pumping, high-salinity brine from the lower intertidal zone is rapidly transported into the mining area, thereby increasing the salinity of the underground brine.
Reduction of retinal vessel density in non-exudative macular neovascularization: a retrospective study
Authors: Gao Yang , Zhang Su , Zhao Yue , Yang Tingting , Moreira Paulo , Sun Guangli
Published: January 2024

Purpose

The purpose of this study is to identify predictive activation biomarkers in retinal microvascular characteristics of non-exudative macular neovascularization (MNV) and avoid delayed treatment or overtreatment of subclinical MNV. The main objective is to contribute to the international debate on a new understanding of the role of retinal vessel features in the pathogenesis and progression of non-exudative MNV and age-related macular degeneration (AMD). A discussion on revising-related clinical protocols is presented.

Methods

In this retrospective study, the authors included eyes with non-exudative MNV, eyes with exudative AMD, and normal eyes of age-matched healthy subjects. The parameters were obtained by optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA).

Results

In total, 21 eyes with exudative AMD, 21 eyes with non-exudative MNV, and 20 eyes of 20 age-matched healthy subjects without retinal pathology were included. Vessel density (VD) of the deep vascular complex (DVC) in eyes with non-exudative MNV was significantly greater than that in eyes with exudative AMD (p = 0.002), while for superficial vascular plexus (SVP) metrics, no VD differences among sectors were observed between eyes with non-exudative MNV and eyes with exudative AMD.

Conclusion

The reduction in retinal vessel density, especially in the DVC, seems to be involved in or be accompanied by non-exudative MNV activation and should be closely monitored during follow-up visits in order to ensure prompt anti-angiogenic therapy. A discussion on applicable clinical protocols is presented aiming to contribute to new insights into ophthalmology service development which is directed to this specific type of patient and diagnosis.
Citrate metabolism in lactic acid bacteria: is there a beneficial effect for Oenococcus oeni in wine?
Authors: Eicher Camille , Coulon Joana , Favier Marion , Alexandre Hervé , Reguant Cristina , Grandvalet Cosette
Published: January 2024

Lactic acid bacteria (LAB) are Gram positive bacteria frequently used in the food industry for fermentation, mainly transformation of carbohydrates into lactic acid. In addition, these bacteria also have the capacity to metabolize citrate, an organic acid commonly found in food products. Its fermentation leads to the production of 4-carbon compounds such as diacetyl, resulting in a buttery flavor desired in dairy products. Citrate metabolism is known to have several beneficial effects on LAB physiology. Nevertheless, a controversial effect of citrate has been described on the acid tolerance of the wine bacterium Oenococcus oeni. This observation raises questions about the effect of citrate on the capacity of O. oeni to conduct malolactic fermentation in highly acidic wines. This review aims to summarize the current understanding of citrate metabolism in LAB, with a focus on the wine bacterium O. oeni. Metabolism with the related enzymes is detailed, as are the involved genes organized in cit loci. The known systems of cit locus expression regulation are also described. Finally, the beneficial effects of citrate catabolism on LAB physiology are reported and the negative impact observed in O. oeni is discussed.
Nutrient-dependent cross-kingdom interactions in the hyphosphere of an arbuscular mycorrhizal fungus
Authors: Faghihinia Maede , Halverson Larry J. , Hršelová Hana , Bukovská Petra , Rozmoš Martin , Kotianová Michala , Jansa Jan
Published: January 2024

Introduction

The hyphosphere of arbuscular mycorrhizal (AM) fungi is teeming with microbial life. Yet, the influence of nutrient availability or nutrient forms on the hyphosphere microbiomes is still poorly understood.

Methods

Here, we examined how the microbial community (prokaryotic, fungal, protistan) was affected by the presence of the AM fungus Rhizophagus irregularis in the rhizosphere and the root-free zone, and how different nitrogen (N) and phosphorus (P) supplements into the root-free compartment influenced the communities.

Results

The presence of AM fungus greatly affected microbial communities both in the rhizosphere and the root-free zone, with prokaryotic communities being affected the most. Protists were the only group of microbes whose richness and diversity were significantly reduced by the presence of the AM fungus. Our results showed that the type of nutrients AM fungi encounter in localized patches modulate the structure of hyphosphere microbial communities. In contrast we did not observe any effects of the AM fungus on (non-mycorrhizal) fungal community composition. Compared to the non-mycorrhizal control, the root-free zone with the AM fungus (i.e., the AM fungal hyphosphere) was enriched with Alphaproteobacteria, some micropredatory and copiotroph bacterial taxa (e.g., Xanthomonadaceae and Bacteroidota), and the poorly characterized and not yet cultured Acidobacteriota subgroup GP17, especially when phytate was added. Ammonia-oxidizing Nitrosomonas and nitrite-oxidizing Nitrospira were significantly suppressed in the presence of the AM fungus in the root-free compartment, especially upon addition of inorganic N. Co-occurrence network analyses revealed that microbial communities in the root-free compartment were complex and interconnected with more keystone species when AM fungus was present, especially when the root-free compartment was amended with phytate.

Conclusion

Our study showed that the form of nutrients is an important driver of prokaryotic and eukaryotic community assembly in the AM fungal hyphosphere, despite the assumed presence of a stable and specific AM fungal hyphoplane microbiome. Predictable responses of specific microbial taxa will open the possibility of using them as co-inoculants with AM fungi, e.g., to improve crop performance.
Analysis of α-syn and parkin interaction in mediating neuronal death in Drosophila model of Parkinson's disease
Authors: Narwal Sonia , Singh Amit , Tare Meghana
Published: January 2024

One of the hallmarks of Parkinson's Disease (PD) is aggregation of incorrectly folded α-synuclein (SNCA) protein resulting in selective death of dopaminergic neurons. Another form of PD is characterized by the loss-of-function of an E3-ubiquitin ligase, parkin. Mutations in SNCA and parkin result in impaired mitochondrial morphology, causing loss of dopaminergic neurons. Despite extensive research on the individual effects of SNCA and parkin, their interactions in dopaminergic neurons remain understudied. Here we employ Drosophila model to study the effect of collective overexpression of SNCA along with the downregulation of parkin in the dopaminergic neurons of the posterior brain. We found that overexpression of SNCA along with downregulation of parkin causes a reduction in the number of dopaminergic neuronal clusters in the posterior region of the adult brain, which is manifested as progressive locomotor dysfunction. Overexpression of SNCA and downregulation of parkin collectively results in altered mitochondrial morphology in a cluster-specific manner, only in a subset of dopaminergic neurons of the brain. Further, we found that SNCA overexpression causes transcriptional downregulation of parkin. However, this downregulation is not further enhanced upon collective SNCA overexpression and parkin downregulation. This suggests that the interactions of SNCA and parkin may not be additive. Our study thus provides insights into a potential link between α-synuclein and parkin interactions. These interactions result in altered mitochondrial morphology in a cluster-specific manner for dopaminergic neurons over a time, thus unraveling the molecular interactions involved in the etiology of Parkinson's Disease.
Impact of cholesterol homeostasis within cochlear cells on auditory development and hearing loss
Authors: Wu Jichang , Ji Peilin , Zhang Andi , Hu Haixia , Shen Yilin , Wang Quan , Fan Cui , Chen Kaili , Ding Rui , Huang Weiyi , Xiang Mingliang , Ye Bin
Published: January 2024

Cholesterol is the most abundant sterol molecule in mammalian cells, which not only constitutes the cell membrane but also plays essential roles in the synthesis of important hormones, synapse formation, and cell signal transduction. The effect of hypercholesterolemia on hearing has been studied extensively, and multiple studies have demonstrated that hypercholesterolemia is a risk factor for hearing loss. However, the impact of cholesterol homeostasis within auditory cells on peripheral auditory development and maintenance has not been evaluated in detail. Mutations in certain cholesterol metabolism-related genes, such as NPC1, SERAC1, DHCR7, and OSBPL2, as well as derivatives of cholesterol metabolism-related ototoxic drugs, such as β-cyclodextrin, can lead to disruptions of cholesterol homeostasis within auditory cells, resulting in hearing loss. This article aims to review the impact of cholesterol homeostasis within auditory cells on the peripheral auditory function from the following two perspectives: (1) changes in cholesterol homeostasis regulatory genes in various hearing loss models; (2) mechanisms underlying the effects of some drugs that have a therapeutic effect on hearing loss via regulating cholesterol homeostasis. This article aims to summarize and analyze the impact of disruption of cellular cholesterol homeostasis within auditory cells on hearing, in order to provide evidence regarding the underlying mechanisms.
Case report: Clinically mild encephalitis/encephalopathy with a reversible splenial lesion: an autopsy case
Authors: Hayashi Maho , Ueda Midori , Hayashi Koji , Kawahara Ei , Azuma Shin-ichiro , Suzuki Asuka , Nakaya Yuka , Asano Rei , Sato Mamiko , Miura Toyoaki , Hayashi Hiromi , Hayashi Kouji , Kobayashi Yasutaka
Published: January 2024

Clinically mild encephalitis/encephalopathy with a reversible splenial lesion is a clinicoradiological syndrome characterized by transient neuropsychiatric symptoms and hyperintensity of the splenium of the corpus callosum on diffusion-weighted MRI. Although intramyelinic edema and inflammatory cell infiltration can be predicted by MRI, the pathology of the splenium of the corpus callosum remains unknown. We encountered a case of clinically mild encephalitis/encephalopathy with a reversible splenial lesion and hypoglycemia in a patient who died of sepsis, and an autopsy was performed. The postmortem pathological findings included intramyelinic edema, myelin pallor, loss of fibrous astrocytes, microglial reactions, and minimal lymphocytic infiltration in the parenchyma. Based on these findings, transient demyelination following cytotoxic edema in the splenium of corpus callosum was strongly considered a pathogenesis of “clinically mild encephalitis/encephalopathy with a reversible splenial lesion” associated with hypoglycemia, and it could be generalized for the disease associated with the other causes. As cytotoxic edema could be the central pathology of the disease, the recently proposed term cytotoxic lesions of the corpus callosum may be applicable to this syndrome.
Stratified predictions of upper limb motor outcomes after stroke
Authors: Park Chang-hyun , Kim Min-Su
Published: January 2024

Introduction

Longitudinal observations of upper limb motor recovery after stroke have suggested that certain subgroups may exhibit distinct recovery patterns. Here we sought to examine whether the predictive ability for post-stroke upper limb motor outcomes could be enhanced by applying conventional stratification strategies.

Method

For 60 individuals who suffered the first stroke, upper limb motor impairment was assessed with the upper extremity Fugl-Meyer assessment (UE-FMA) at 2 weeks as a baseline and then 3 months post-stroke. Brain structural damage at baseline was assessed by MRI data-derived markers ranging from traditional lesion size to the lesion load and to the disconnectome. Linear regression models for predicting upper limb motor outcomes (UE-FMA score at 3 months post-stroke) based on baseline upper limb motor impairment (UE-FMA score at 2 weeks post-stroke), brain structural damage, and their combinations were generated, and those with the best predictive performance were determined for individual subgroups stratified according to initial impairment (severe and non-severe), lesion location (cortical and non-cortical), and neurophysiological status (motor evoked potential-positive and motor evoked potential-negative).

Results

The best predictions were made by baseline upper limb motor impairment alone for subgroups with less functional impairment (non-severe) or less structural involvement (non-cortical), but by the combination of baseline upper limb motor impairment and brain structural damage for the other subgroups. The predictive models tailored for subgroups determined according to initial impairment and neurophysiological status yielded a smaller overall error than that for the whole group in upper limb motor outcome predictions.

Discussion

The predictive ability for upper limb motor outcomes could be enhanced beyond the one-size-fits-all model for all individuals with stroke by applying specific stratification strategies, with stratification according to initial impairment being the most promising. We expect that predictive models tailored for individual subgroups could lead closer to the personalized prognosis of upper limb motor outcomes after stroke.
Exploratory analysis on the relationship between dietary live microbe intake and arthritis: a national population based cross-sectional study
Authors: Liu Yiping , Xing Yida , Kong Xiaodan
Published: January 2024

Objective

The pathogenesis of arthritis such as rheumatoid arthritis (RA) and osteoarthritis (OA) remains unclear. This study aims to investigate whether the intake of live dietary microbes can be used as an auxiliary means for the treatment of arthritis.

Methods

Data used in the present research were originated from the US National Health and Nutrition Examination Survey (NHANES) from 2003–2018. Participants involved in the present study were categorized into three groups based on the dietary live microbe classification system, namely low, medium, and high dietary live microbe groups. The analyses utilized weighted univariate and multivariate logistic regression. The restricted cubic spline plot was used to explore the relationship between the high dietary live microbe group and the odds of arthritis.

Results

12,844 participants were included in the present study. The intake of high live dietary microbes in RA group was lower than that in healthy control group and OA group. The proportion of RA patients in the high live dietary microbe group was lower than that in the low and medium live dietary microbe group. Following the comprehensive adjustment for covariates, it was observed that participants in both the high and medium dietary live microbe groups exhibited lower odds of RA compared to those in the low dietary live microbe group (High OR: 0.71, 95% CI: 0.53–0.96; Medium OR: 0.77, 95% CI: 0.59–1.00, p = 0.02). A restricted cubic spline plot indicates a negative correlation between the quantity of dietary live microbes and the occurrence of RA within the high dietary live microbe group.

Conclusion

The results of our study revealed a significant difference in dietary live microbe intake between healthy and RA patients. Higher dietary intake was correlated with a decreased odds of RA. However, no significant association was found between the occurrence of OA and the quantity of dietary live microbes.
Case report: ex vivo tumor organoid drug testing identifies therapeutic options for stage IV ovarian carcinoma
Authors: Al-Aloosi Marwah , Prechtl Amanda M. , Chatterjee Payel , Bernard Brady , Kemp Christopher J. , Rosati Rachele , Diaz Robert L. , Appleyard Lauren R. , Pereira Shalini , Rajewski Alex , McDonald Amber , Gordon Eva J. , Grandori Carla
Published: January 2024

Patients presenting with stage 4 ovarian carcinoma, including low-grade serous disease, have a poor prognosis. Although platinum-based therapies can offer some response, these therapies are associated with many side effects, and treatment resistance often develops. Toxic side effects along with disease progression render patients unable to receive additional lines of treatment and limit their options to hospice or palliative care. In this case report, we describe a patient with an unusual case of metastatic low-grade serous ovarian cancer with some features of high-grade disease who had received four previous lines of treatment and was suffering from atelectasis, pulmonary embolism, and hydronephrosis. A CLIA-certified drug sensitivity assay of an organoid culture derived from the patient’s tumor (PARIS® test) identified several therapeutic options, including the combination of fulvestrant with everolimus. On this treatment regimen, the patient experienced 7 months of stable disease and survived nearly 11 months before succumbing to her disease. This case emphasizes the clinical utility of ex vivo drug testing as a new functional precision medicine approach to identify, in real-time, personalized treatment options for patients, especially those who are not benefiting from standard of care treatments.
Development of a cancer metastasis-on-chip assay for high throughput drug screening
Authors: Ozer Lutfiye Yildiz , Fayed Hend Salah , Ericsson Johan , Al Haj Zen Ayman
Published: January 2024

Metastasis is the cause of most triple-negative breast cancer deaths, yet anti-metastatic therapeutics remain limited. To develop new therapeutics to prevent metastasis, pathophysiologically relevant assays that recapitulate tumor microenvironment is essential for disease modeling and drug discovery. Here, we have developed a microfluidic metastasis-on-chip assay of the early stages of cancer metastasis integrated with the triple-negative breast cancer cell line (MDA-MB-231), stromal fibroblasts and a perfused microvessel. High-content imaging with automated quantification methods was optimized to assess the tumor cell invasion and intravasation within the model. Cell invasion and intravasation were enhanced when fibroblasts co-cultured with a breast cancer cell line (MDA-MB-231). However, the non-invasive breast cancer cell line, MCF7, remained non-invasive in our model, even in the presence of fibroblasts. High-content screening of a targeted anti-cancer therapy drug library was conducted to evaluate the drug response sensitivity of the optimized model. Through this screening, we identified 30 compounds that reduced the tumor intravasation by 60% compared to controls. Multi-parametric phenotypic analysis was applied by combining the data from the metastasis-on-chip, cell proliferation and 2D cell migration screens, revealing that the drug library was clustered into eight distinct groups with similar drug responses. Notably, MEK inhibitors were enriched in cluster cell invasion and intravasation. In contrast, drugs with molecular targets: ABL, KIT, PDGF, SRC, and VEGFR were enriched in the drug clusters showing a strong effect on tumor cell intravasation with less impact on cell invasion or cell proliferation, of which, Imatinib, a multi-kinase inhibitor targeting BCR-ABL/PDGFR/KIT. Further experimental analysis showed that Imatinib enhanced endothelial barrier stability as measured by trans-endothelial electrical resistance and significantly reduced the trans-endothelial invasion activity of tumor cells. Our findings demonstrate the potential of our metastasis-on-chip assay as a powerful tool for studying cancer metastasis biology, drug discovery aims, and assessing drug responses, offering prospects for personalized anti-metastatic therapies for triple-negative breast cancer patients.
Clinical utility of square-wave jerks in neurology and psychiatry
Authors: Zachou Athena , Armenis Georgios , Stamelos Ioannis , Stratigakou-Polychronaki Eirini , Athanasopoulos Fotios , Anagnostou Evangelos
Published: January 2024

Human eye fixation is steadily interrupted by small, physiological or abnormal, eye movements. Square-wave jerks (SWJ) are the most common saccadic intrusion which can be readily seen at the bedside and also quantified using oculographic techniques. Various neurological, neuropsychiatric and psychiatric disorders display abnormal fixational eye movement patterns characterized by frequent SWJ. For the clinician, SWJ are particularly important because they can be readily observed at the bedside. Here, we will discuss the pathological conditions that present with SWJ and explore the expanding body of literature suggesting that SWJ may serve as a potential indicator for various clinical conditions.
Trends in research related to fetal therapy from 2012 to 2022: a bibliometric analysis
Authors: Jia Yang , Liang Xiaoling , Liu Lini , Ma Huixi , Xu Chenhao , Zeng Jingyuan , Xu Rong , Ye Lu , Xie Linjun
Published: January 2024

Background

The development of prenatal diagnosis technology allows prompt detection of severe fetal diseases. To address adverse factors that threaten fetal survival, fetal therapy came into existence, which aims to preserve the function after birth to a higher degree and improve the quality of life.

Objective

To conduct a comprehensive bibliometric analysis of studies on fetal therapy in the past decade and explore the research trends and hotspots in this field.

Methods

We conducted a systematic search on the Web of Science Core Collection to retrieve studies related to fetal therapy published from 2012 to 2022. VOSviewer and CiteSpace were used to analyze the key features of studies, including annual output, countries/regions, institutions, authors, references, research hotspots, and frontiers.

Results

A total of 9,715 articles were included after eliminating duplicates. The annual distribution of the number of articles showed that the number of articles published in fetal therapy had increased in the past decade. Countries and institutions showed that fetal therapy is more mature in the United States. Author analysis showed the core investigators in the field. Keyword analysis showed the clustering and emergence frequency, which helped summarize the research results and frontier hotspots in this field. The cocited references were sorted out to determine the literature with a high ranking of fetal therapy in recent years, and the research trend in recent years was analyzed.

Conclusions

This study reveals that countries, institutions, and researchers should promote wider cooperation and establish multicenter research cooperation in fetal therapy research. Moreover, fetal therapy has been gradually explored from traditional surgical treatment to gene therapy and stem cell therapy. In recent years, fetoscopic laser surgery, guideline, and magnetic resonance imaging have become the research hotspots in the field.
A minimal PBPK model to accelerate preclinical development of drugs against tuberculosis
Authors: Reali Federico , Fochesato Anna , Kaddi Chanchala , Visintainer Roberto , Watson Shayne , Levi Micha , Dartois Véronique , Azer Karim , Marchetti Luca
Published: January 2024

Introduction: Understanding drug exposure at disease target sites is pivotal to profiling new drug candidates in terms of tolerability and efficacy. Such quantification is particularly tedious for anti-tuberculosis (TB) compounds as the heterogeneous pulmonary microenvironment due to the infection may alter lung permeability and affect drug disposition. Murine models have been a longstanding support in TB research so far and are here used as human surrogates to unveil the distribution of several anti-TB compounds at the site-of-action via a novel and centralized PBPK design framework.

Methods: As an intermediate approach between data-driven pharmacokinetic (PK) models and whole-body physiologically based (PB) PK models, we propose a parsimonious framework for PK investigation (minimal PBPK approach) that retains key physiological processes involved in TB disease, while reducing computational costs and prior knowledge requirements. By lumping together pulmonary TB-unessential organs, our minimal PBPK model counts 9 equations compared to the 36 of published full models, accelerating the simulation more than 3-folds in Matlab 2022b.

Results: The model has been successfully tested and validated against 11 anti-TB compounds—rifampicin, rifapentine, pyrazinamide, ethambutol, isoniazid, moxifloxacin, delamanid, pretomanid, bedaquiline, OPC-167832, GSK2556286 - showing robust predictability power in recapitulating PK dynamics in mice. Structural inspections on the proposed design have ensured global identifiability and listed free fraction in plasma and blood-to-plasma ratio as top sensitive parameters for PK metrics. The platform-oriented implementation allows fast comparison of the compounds in terms of exposure and target attainment. Discrepancies in plasma and lung levels for the latest BPaMZ and HPMZ regimens have been analyzed in terms of their impact on preclinical experiment design and on PK/PD indices.

Conclusion: The framework we developed requires limited drug- and species-specific information to reconstruct accurate PK dynamics, delivering a unified viewpoint on anti-TB drug distribution at the site-of-action and a flexible fit-for-purpose tool to accelerate model-informed drug design pipelines and facilitate translation into the clinic.
P2X4 signalling contributes to hyperactivity but not pain sensitization comorbidity in a mouse model of attention deficit/hyperactivity disorder
Authors: Bou Sader Nehme Sarah , Sanchez-Sarasua Sandra , Adel Ramy , Tuifua Marie , Ali Awatef , Essawy Amina E. , Abdel Salam Sherine , Hleihel Walid , Boué-Grabot Eric , Landry Marc
Published: January 2024

Introduction: Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by hyperactivity, inattention, and impulsivity that often persist until adulthood. Frequent comorbid disorders accompany ADHD and two thirds of children diagnosed with ADHD also suffer from behavioural disorders and from alteration of sensory processing. We recently characterized the comorbidity between ADHD-like symptoms and pain sensitisation in a pharmacological mouse model of ADHD, and we demonstrated the implication of the anterior cingulate cortex and posterior insula. However, few studies have explored the causal mechanisms underlying the interactions between ADHD and pain. The implication of inflammatory mechanisms has been suggested but the signalling pathways involved have not been explored.

Methods: We investigated the roles of purinergic signalling, at the crossroad of pain and neuroinflammatory pathways, by using a transgenic mouse line that carries a total deletion of the P2X4 receptor.

Results: We demonstrated that P2X4 deletion prevents hyperactivity in the mouse model of ADHD. In contrast, the absence of P2X4 lowered thermal pain thresholds in sham conditions and did not affect pain sensitization in ADHD-like conditions. We further analysed microglia reactivity and the expression of inflammatory markers in wild type and P2X4KO mice. Our results revealed that P2X4 deletion limits microglia reactivity but at the same time exerts proinflammatory effects in the anterior cingulate cortex and posterior insula.

Conclusion: This dual role of P2X4 could be responsible for the differential effects noted on ADHD-like symptoms and pain sensitization and calls for further studies to investigate the therapeutic benefit of targeting the P2X4 receptor in ADHD patients.
Representative QRS loop of the VCG record evaluation
Authors: Kijonka Jan , Vavra Petr , Penhaker Marek , Kubicek Jan
Published: January 2024

Introduction: This study proposes an algorithm for preprocessing VCG records to obtain a representative QRS loop.

Methods: The proposed algorithm uses the following methods: Digital filtering to remove noise from the signal, wavelet-based detection of ECG fiducial points and isoelectric PQ intervals, spatial alignment of QRS loops, QRS time synchronization using root mean square error minimization and ectopic QRS elimination. The representative QRS loop is calculated as the average of all QRS loops in the VCG record. The algorithm is evaluated on 161 VCG records from a database of 58 healthy control subjects, 69 patients with myocardial infarction, and 34 patients with bundle branch block. The morphologic intra-individual beat-to-beat variability rate is calculated for each VCG record.

Results and Discussion: The maximum relative deviation is 12.2% for healthy control subjects, 19.3% for patients with myocardial infarction, and 17.2% for patients with bundle branch block. The performance of the algorithm is assessed by measuring the morphologic variability before and after QRS time synchronization and ectopic QRS elimination. The variability is reduced by a factor of 0.36 for healthy control subjects, 0.38 for patients with myocardial infarction, and 0.41 for patients with bundle branch block. The proposed algorithm can be used to generate a representative QRS loop for each VCG record. This representative QRS loop can be used to visualize, compare, and further process VCG records for automatic VCG record classification.
Hamstrings mechanical properties profiling in football players of different competitive levels and positions after a repeated sprint protocol
Authors: Pimenta Ricardo , Antunes Hugo , Bruno Paula , Veloso A. P.
Published: January 2024

Purpose: This study compares the average speed, knee flexor peak torque and shear modulus of the hamstrings after a repeated sprint task, in football players of different competitive levels and playing positions.

Methods: Fifty-four football field players without hamstring strain injury history participated, 15 being categorized as professional (2nd league) and 39 as semi-professional (17 in 3rd and 22 in 4th league). Muscle shear modulus was assessed using ultrasound-based shear wave elastography at rest and at 20% of maximal voluntary isometric effort before and immediately after the repeated sprint protocol.

Results: No significant differences were seen in average sprint speed between competitive levels (p = 0.07; η2p = 0.28) and positions (p = 0.052; η2p = 0.29). Moreover, the sprint fatigue index showed no significant differences between competitive levels (p = 0.14; η2p = 0.08) and playing positions (p = 0.89; η2p = 0.05). No significant differences were observed in hamstring shear modulus changes between competitive levels (p = 0.94; η2p = 0.03) and positions (p = 0.92; η2p = 0.03). Peak torque changes also showed non-significant association with competitive levels (p = 0.46; η2p = 0.03) and positions (p = 0.60; η2p = 0.02).

Conclusion: The results of this study suggest that the average sprint speed performance parameter and mechanical parameters are not able to distinguish football players of different competitive levels and positions.
Phylogenomic analyses and chromosome ploidy identification reveal multiple cryptic species in Allium sikkimense complex (Amaryllidaceae)
Authors: Huang De-Qing , Ma Xiang-Guang , Sun Hang
Published: January 2024

Polyploidization is a process that typically leads to instantaneous reproductive isolation and has, therefore, been considered as one of the major evolutionary forces in the species-rich Hengduan Mountains (HM), yet this topic remains poorly studied in the region. Allium sikkimense and its relatives (about eight species) compose a natural diploid–polyploid complex with the highest diversity in the HM and adjacent areas. A combination of nuclear ribosomal DNA (nrDNA), plastome, transcriptome, and ploidy identification through chromosome counting and flow cytometry is employed to reconstruct the phylogenetic relationships in this complex and to investigate the frequency and the evolutionary significance of polyploidy in the complex. The plastome failed to resolve the phylogenetic relationships of the different species in the A. sikkimense complex, and the phylogenetic tree based on nrDNA also has limited resolution. However, our study reveals a well-resolved phylogenetic framework for species in the A. sikkimense complex using more than 1,000 orthologous genes from the transcriptome data. Previously recognized morphospecies A. sikkimense are non-monophyletic and comprise at least two independently evolved lineages (i.e., cryptic species), each forming a clade with different diploid species in this complex. The embedded pattern of octoploid A. jichouense and tetraploid A. sp. nov. within different polyploid samples of A. sikkimense supports a possible scenario of budding speciation (via niche divergence). Furthermore, our results reveal that co-occurring species in the A. sikkimense complex usually have different ploidy levels, suggesting that polyploidy is an important process for reproductive isolation of sympatric Allium species. Phylogenetic network analyses suggested that the phylogenetic relationships of the A. sikkimense complex, allowing for reticulation events, always fit the dataset better than a simple bifurcating tree. In addition, the included or exserted filaments, which have long been used to delimit species, are highly unreliable taxonomically due to their extensive parallel and convergent evolution.