bluuebunny/crossref_metadata_2025_split huggingface dataset:
The oncogenic role of NF1 in gallbladder cancer through regulation of YAP1 stability by direct interaction with YAP1
Authors: Zhang Lingxiao , Jiang Lin , Zeng Ling , Jin Zhaohui , Dong Xuanjia , Zhang Yuhan , Chen Litian , Shu Yijun , Liu Yingbin , Huang Ying 
Published: May 2023

Abstract
Background
Gallbladder cancer (GBC) is the most prevalent and invasive biliary tract malignancy. As a GTPase-activating protein, Neurofibromin 1 (NF1) is a tumor suppressor that negatively regulates the RAS signaling pathway, and its abnormality leads to neurofibromatosis type 1 (NF-1) disease. However, the role of NF1 playing in GBC and the underlying molecular mechanism has not been defined yet.

Methods
A combination of NOZ and EH-GB1 cell lines as well as nude mice, were utilized in this study. mRNA expression and protein levels of NF1 and YAP1 were evaluated by quantitative real-time PCR (qRT-PCR), western blot (WB), and immunohistochemistry (IHC). In vitro and in vivo assays were performed to explore the biological effects of NF1 in NOZ and EH-GB1 cells via siRNA or lv-shRNA mediated knockdown. Direct interaction between NF1 and YAP1 was detected by confocal microscopy and co-immunoprecipitation (Co-IP), and further confirmed by GST pull-down assay and isothermal titration calorimetry assay (ITC). The stability of proteins was measured by western blot (WB) in the presence of cycloheximide.

Results
This study showed that a higher level of NF1 and YAP1 was found in GBC samples than in normal tissues and associated with worse prognoses. The NF1 knockdown impaired the proliferation and migration of NOZ in vivo and in vitro by downregulating YAP1 expression. Moreover, NF1 co-localized with YAP1 in NOZ and EH-GB1 cells, and the WW domains of YAP1 specifically recognized the PPQY motif of NF1. The structural modeling also indicated the hydrophobic interactions between YAP1 and NF1. On the other hand, YAP1 knockdown also impaired the proliferation of NOZ in vitro, phenocopying the effects of NF1 knockdown. Overexpression of YAP1 can partially rescue the impaired proliferation in NF1 stably knockdown cells. In mechanism, NF1 interacted with YAP1 and increased the stability of YAP1 by preventing ubiquitination.

Conclusions
Our findings discovered a novel oncogenic function of NF1 by directly interacting with YAP1 protein and stabilizing YAP1 to protect it from proteasome degradation in NOZ cells. NF1 may serve as a potential therapeutic target in GBC.
Benefits of applying molecular barcoding systems are not uniform across different genomic applications
Authors: Bieler Jonathan , Kubik Slawomir , Macheret Morgane , Pozzorini Christian , Willig Adrian , Xu Zhenyu 
Published: May 2023

Abstract
Background
Despite the wide variety of Next Generation Sequencing (NGS)-based methods, it remains challenging to detect mutations present at very low frequencies. This problem is particularly relevant in oncology, where the limiting amount of input material, and its low quality, often limit the performance of the assays. Unique Molecular Identifiers (UMIs) are a molecular barcoding system often coupled with computational methods of noise suppression to improve the reliability of detection of rare variants. Although widely adopted, UMI inclusion imposes additional technical complexity and sequencing cost. Currently, there are no guidelines on UMI usage nor a comprehensive evaluation of their advantage across different applications.

Methods
We used DNA sequencing data generated by molecular barcoding and hybridization-based enrichment, from various types and quantities of input material (fresh frozen, formaldehyde-treated and cell-free DNA), to evaluate the performance of variant calling in different clinically relevant contexts.

Results
Noise suppression achieved by read grouping based on fragment mapping positions ensures reliable variant calling for many experimental designs even without exogenous UMIs. Exogenous barcodes significantly improve performance only when mapping position collisions occur, which is common in cell-free DNA.

Conclusions
We demonstrate that UMI usage is not universally beneficial across experimental designs and that it is worthwhile to critically consider the comparative advantage of UMI usage for a given NGS application prior to experimental design.
Neuroinflammatory CSF biomarkers MIF, sTREM1, and sTREM2 show dynamic expression profiles in Alzheimer’s disease
Authors: Hok-A-Hin Yanaika S. , del Campo Marta , Boiten Walter A. , Stoops Erik , Vanhooren Melanie , Lemstra Afina W. , van der Flier Wiesje M. , Teunissen Charlotte E. 
Published: May 2023

Abstract
Background
There is a need for novel fluid biomarkers tracking neuroinflammatory responses in Alzheimer’s disease (AD). Our recent cerebrospinal fluid (CSF) proteomics study revealed that migration inhibitory factor (MIF) and soluble triggering receptor expressed on myeloid cells 1 (sTREM1) increased along the AD continuum. We aimed to assess the potential use of these proteins, in addition to sTREM2, as CSF biomarkers to monitor inflammatory processes in AD.

Methods
We included cognitively unimpaired controls (n = 67, 63 ± 9 years, 24% females, all amyloid negative), patients with mild cognitive impairment (MCI; n = 92, 65 ± 7 years, 47% females, 65% amyloid positive), AD (n = 38, 67 ± 6 years, 8% females, all amyloid positive), and DLB (n = 50, 67 ± 6 years, 5% females, 54% amyloid positive). MIF, sTREM1, and sTREM2 levels were measured by validated immunoassays. Differences in protein levels between groups were tested with analysis of covariance (corrected for age and sex). Spearman correlation analysis was performed to evaluate the association between these neuroinflammatory markers with AD-CSF biomarkers (Aβ42, tTau, pTau) and mini-mental state examination (MMSE) scores.

Results
MIF levels were increased in MCI (p < 0.01), AD (p < 0.05), and DLB (p > 0.05) compared to controls. Levels of sTREM1 were specifically increased in AD compared to controls (p < 0.01), MCI (p < 0.05), and DLB patients (p > 0.05), while sTREM2 levels were increased specifically in MCI compared to all other groups (all p < 0.001). Neuroinflammatory proteins were highly correlated with CSF pTau levels (MIF: all groups; sTREM1: MCI, AD and DLB; sTREM2: controls, MCI and DLB). Correlations with MMSE scores were observed in specific clinical groups (MIF in controls, sTREM1 in AD, and sTREM2 in DLB).

Conclusion
Inflammatory-related proteins show diverse expression profiles along different AD stages, with increased protein levels in the MCI stage (MIF and sTREM2) and AD stage (MIF and sTREM1). The associations of these inflammatory markers primarily with CSF pTau levels indicate an intertwined relationship between tau pathology and inflammation. These neuroinflammatory markers might be useful in clinical trials to capture dynamics in inflammatory responses or monitor drug–target engagement of inflammatory modulators.
Armed conflict and household food insecurity: evidence from war-torn Tigray, Ethiopia
Authors: Weldegiargis Aregawi Weldegebreal , Abebe Haftom Temesgen , Abraha Hiluf Ebuy , Abrha Meron Micheale , Tesfay Tsegay Berihu , Belay Rieye Esayas , Araya Alemnesh Abraha , Gebregziabher Mengish Bahresilassie , Godefay Hagos , Mulugeta Afework 
Published: May 2023

Abstract
Background
Exposure to armed conflicts result in strongly adverse and often irreversible short- and long-term effects which may transmit across generations. Armed conflicts directly cause food insecurity and starvation by disruption and destruction of food systems, reduce farming populations, destroying infrastructure, reducing resilience, and increasing vulnerabilities, disruptions in access to market, increasing food price or making goods and services unavailable altogether. The objective of the present study was to determine the status of household food insecurity in the armed conflict affected communities of Tigray in terms of Access, Experience and Hunger scale.

Method
Community-based cross-sectional study was conducted to assess impact of armed conflict on household food insecurity among households with children with under one year. FHI 360 and FAO guidelines were used to quantify household food insecurity and Household hunger status.

Results
Three-fourth of the households had anxiety about food supply and eat undesired monotonous diet due to lack of resources. Households were obliged to eat few kinds of foods, eat smaller meals, eat foods they do not want to eat, or went a whole day without eating any food. Household food insecurity access, food insecurity experience, and hunger scales significantly increased by 43.3 (95% CI: 41.9–44.7), 41.9 (95% CI: 40.5–43.3) and 32.5 (95% CI: 31.0-33.9) percentage points from the prewar period.

Conclusions
Household food insecurity levels and household hunger status of the study communities was unacceptably high. The armed conflict has significant negative effect on food security in Tigray. It is recommended that the study communities need to be protected from the immediate and long-term consequences of conflict-induced household food insecurity.
Systematic screening identifies ABCG2 as critical factor underlying synergy of kinase inhibitors with transcriptional CDK inhibitors
Authors: van der Noord Vera E. , van der Stel Wanda , Louwerens Gijs , Verhoeven Danielle , Kuiken Hendrik J. , Lieftink Cor , Grandits Melanie , Ecker Gerhard F. , Beijersbergen Roderick L. , Bouwman Peter , Le Dévédec Sylvia E. , van de Water Bob 
Published: May 2023

Abstract
Background
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with limited treatment options and poor clinical prognosis. Inhibitors of transcriptional CDKs are currently under thorough investigation for application in the treatment of multiple cancer types, including breast cancer. These studies have raised interest in combining these inhibitors, including CDK12/13 inhibitor THZ531, with a variety of other anti-cancer agents. However, the full scope of these potential synergistic interactions of transcriptional CDK inhibitors with kinase inhibitors has not been systematically investigated. Moreover, the mechanisms behind these previously described synergistic interactions remain largely elusive.

Methods
Kinase inhibitor combination screenings were performed to identify kinase inhibitors that synergize with CDK7 inhibitor THZ1 and CDK12/13 inhibitor THZ531 in TNBC cell lines. CRISPR-Cas9 knockout screening and transcriptomic evaluation of resistant versus sensitive cell lines were performed to identify genes critical for THZ531 resistance. RNA sequencing analysis after treatment with individual and combined synergistic treatments was performed to gain further insights into the mechanism of this synergy. Kinase inhibitor screening in combination with visualization of ABCG2-substrate pheophorbide A was used to identify kinase inhibitors that inhibit ABCG2. Multiple transcriptional CDK inhibitors were evaluated to extend the significance of the found mechanism to other transcriptional CDK inhibitors.

Results
We show that a very high number of tyrosine kinase inhibitors synergize with the CDK12/13 inhibitor THZ531. Yet, we identified the multidrug transporter ABCG2 as key determinant of THZ531 resistance in TNBC cells. Mechanistically, we demonstrate that most synergistic kinase inhibitors block ABCG2 function, thereby sensitizing cells to transcriptional CDK inhibitors, including THZ531. Accordingly, these kinase inhibitors potentiate the effects of THZ531, disrupting gene expression and increasing intronic polyadenylation.

Conclusion
Overall, this study demonstrates the critical role of ABCG2 in limiting the efficacy of transcriptional CDK inhibitors and identifies multiple kinase inhibitors that disrupt ABCG2 transporter function and thereby synergize with these CDK inhibitors. These findings therefore further facilitate the development of new (combination) therapies targeting transcriptional CDKs and highlight the importance of evaluating the role of ABC transporters in synergistic drug–drug interactions in general.
Probing pathways by which rhynchophylline modifies sleep using spatial transcriptomics
Authors: Ballester Roig Maria Neus , Leduc Tanya , Dufort-Gervais Julien , Maghmoul Yousra , Tastet Olivier , Mongrain Valérie 
Published: May 2023

Abstract
Background
Rhynchophylline (RHY) is an alkaloid component of Uncaria, which are plants extensively used in traditional Asian medicines. Uncaria treatments increase sleep time and quality in humans, and RHY induces sleep in rats. However, like many traditional natural treatments, the mechanisms of action of RHY and Uncaria remain evasive. Moreover, it is unknown whether RHY modifies key brain oscillations during sleep. We thus aimed at defining the effects of RHY on sleep architecture and oscillations throughout a 24-h cycle, as well as identifying the underlying molecular mechanisms. Mice received systemic RHY injections at two times of the day (beginning and end of the light period), and vigilance states were studied by electrocorticographic recordings.

Results
RHY enhanced slow wave sleep (SWS) after both injections, suppressed paradoxical sleep (PS) in the light but enhanced PS in the dark period. Furthermore, RHY modified brain oscillations during both wakefulness and SWS (including delta activity dynamics) in a time-dependent manner. Interestingly, most effects were larger in females. A brain spatial transcriptomic analysis showed that RHY modifies the expression of genes linked to cell movement, apoptosis/necrosis, and transcription/translation in a brain region-independent manner, and changes those linked to sleep regulation (e.g., Hcrt, Pmch) in a brain region-specific manner (e.g., in the hypothalamus).

Conclusions
The findings provide support to the sleep-inducing effect of RHY, expose the relevance to shape wake/sleep oscillations, and highlight its effects on the transcriptome with a high spatial resolution. The exposed molecular mechanisms underlying the effect of a natural compound should benefit sleep- and brain-related medicine.

Graphical Abstract
Cartilage diversification and modularity drove the evolution of the ancestral vertebrate head skeleton
Authors: Root Zachary D. , Jandzik David , Gould Claire , Allen Cara , Brewer Margaux , Medeiros Daniel M. 
Published: May 2023

AbstractThe vertebrate head skeleton has evolved a myriad of forms since their divergence from invertebrate chordates. The connection between novel gene expression and cell types is therefore of importance in this process. The transformation of the jawed vertebrate (gnathostome) head skeleton from oral cirri to jointed jaw elements required a diversity of cartilages as well as changes in the patterning of these tissues. Although lampreys are a sister clade to gnathostomes, they display skeletal diversity with distinct gene expression and histologies, a useful model for addressing joint evolution. Specifically, the lamprey tissue known as mucocartilage has noted similarities with the jointed elements of the mandibular arch in jawed vertebrates. We thus asked whether the cells in lamprey mucocartilage and gnathostome joint tissue could be considered homologous. To do this, we characterized new genes that are involved in gnathostome joint formation and characterized the histochemical properties of lamprey skeletal types. We find that most of these genes are minimally found in mucocartilage and are likely later innovations, but we do identify new activity for gdf5/6/7b in both hyaline and mucocartilage, supporting its role as a chondrogenic regulator. Contrary to previous works, our histological assays do not find any perichondrial fibroblasts surrounding mucocartilage, suggesting that mucocartilage is non-skeletogenic tissue that is partially chondrified. Interestingly, we also identify new histochemical features of the lamprey otic capsule that diverge from normal hyaline. Paired with our new insights into lamprey mucocartilage, we propose a broader framework for skeletal evolution in which an ancestral soxD/E and gdf5/6/7 network directs mesenchyme along a spectrum of cartilage-like features.
Utilization of non-coherent accumulation for LTE TOA estimation in weak LOS signal environments
Authors: Tian Jin , Fangchi Li , Yafei Tian , Dongmei Liu 
Published: May 2023

AbstractGround localization systems based on cellular signals are vulnerable to the hazards of signal power attenuation and multipath propagation in urban environments. Non-coherent accumulation is an effective solution to this problem, but its application to cellular localization systems has not been properly discussed. In this paper, we propose two cellular time-of-arrival (TOA) estimation methods based on non-coherent accumulation: the “TOA estimation algorithm based on non-coherent accumulation of the channel impulse response” (nch-CIR) in the time domain and the “Super Resolution TOA Estimation Algorithm based on non-coherent accumulation of the covariance matrix” (nch-SRA) in the frequency domain. Among these two methods, the nch-CIR algorithm has a lower computational cost and better anti-noise performance, and the nch-SRA algorithm has better performance in terms of multipath delay estimation. Through theoretical analysis and extensive simulations, we also discuss the influence of mobility on these two methods. In addition, experiments are conducted to evaluate the performance of the proposed method using real collected cellular signals. The results show that both nch-CIR and nch-SRA can achieve a better performance compared with the conventional methods.
Efficacy and safety of different regimens in the treatment of patients with latent tuberculosis infection: a systematic review and network meta-analysis of randomized controlled trials
Authors: Assefa Dawit Getachew , Bedru Ahmed , Zeleke Eden Dagnachew , Negash Solomon Emiru , Debela Dejene Tolossa , Molla Wondowsen , Mengistu Nebiyu , Woldesenbet Tigist Tekle , Bedane Neway Fekede , Kajogoo Violet Dismas , Atim Mary Gorret , Manyazewal Tsegahun 
Published: May 2023

AbstractBackgroundTreatment of latent tuberculosis infection (LTBI) is effective in preventing progression to TB disease. This study aimed to synthesize available evidence on the efficacy, adherence, and safety of LTBI treatment in order to assist policymakers to design appropriate national treatment policies and treatment protocols.MethodThe PRISMA-NMA was used to review and report this research. Randomized controlled trials which compared the efficacy and safety of LTBI treatments were included. A systematic literature search was done to identify relevant articles from online databases PubMed/ MEDLINE, Embase, and Cochrane Center for Clinical Trial database (CENTRAL). The network meta-analysis was done using R- studio Version 1.4.1103.ResultIn this review, 42 studies were included, which enrolled 46,022 people who had recent contact with patients with active tuberculosis, evidence radiological of previous tuberculosis, tuberculin test equal or greater than 5 mm, radiographs that indicated inactive fibrotic or calcified parenchymal and/or lymph node lesions, had conversion to positive results on a tuberculin skin test, participants living with HIV, chronic Silicosis, immigrants, prisoners, old people, and pregnant women who were at risk for latent TB were included.The incidence of TB among people living with HIV who have taken 3RH as TPT was lower, followed by 48%,followed by 6H (41%). However, 3HP has also the potential to reduce the incidence of TB by 36% among HIV negative patients who had TB contact history. Patients’ adherence to TPT was higher among patients who have taken 4R (RR 1.38 95% CI 1.0,1.89) followed by 3RH (34%). The proportion of subjects who permanently discontinued a study drug because of an adverse event were three times higher in the 3RH treatment group. Furthermore, the risk of grade 3 and 4 liver toxicity was significantly higher in 9H followed by 1HP, and 6H.ConclusionFrom this review, it can be concluded 3RH and 6H has a significant impact on the reduction of TB incidence among PLWH and 3HP among HIV negative people who had TB contact history. However, combinations of rifampicin either with isoniazid were significantly associated with adverse events which resulted in permanent discontinuation among adult patients. Furthermore, grade 3 and 4 liver toxicity was more common in patents who have taken 9H, 1HP, and 6H. This may support the current recommended TPT regimen of 3HP, 3RH, and 6H.
Dietary fiber during gestation improves lactational feed intake of sows by modulating gut microbiota
Authors: Li Shuang , Zheng Jie , He Jiaqi , Liu Hao , Huang Yingyan , Huang Liansu , Wang Ke , Zhao Xilun , Feng Bin , Che Lianqiang , Fang Zhengfeng , Li Jian , Xu Shengyu , Lin Yan , Jiang Xuemei , Hua Lun , Zhuo Yong , Wu De 
Published: May 2023

Abstract
Background
The feed intake of sows during lactation is often lower than their needs. High-fiber feed is usually used during gestation to increase the voluntary feed intake of sows during lactation. However, the mechanism underlying the effect of bulky diets on the appetites of sows during lactation have not been fully clarified. The current study was conducted to determine whether a high-fiber diet during gestation improves lactational feed intake (LFI) of sows by modulating gut microbiota.

Methods
We selected an appropriate high-fiber diet during gestation and utilized the fecal microbial transplantation (FMT) method to conduct research on the role of the gut microbiota in feed intake regulation of sows during lactation, as follows: high-fiber (HF) diet during gestation (n = 23), low-fiber (LF) diet during gestation (n = 23), and low-fiber diet + HF-FMT (LFM) during gestation (n = 23).

Results
Compared with the LF, sows in the HF and LFM groups had a higher LFI, while the sows also had higher peptide tyrosine tyrosine and glucagon-like peptide 1 on d 110 of gestation (G110 d). The litter weight gain of piglets during lactation and weaning weight of piglets from LFM group were higher than LF group. Sows given a HF diet had lower Proteobacteria, especially Escherichia-Shigella, on G110 d and higher Lactobacillus, especially Lactobacillus_mucosae_LM1 and Lactobacillus_amylovorus, on d 7 of lactation (L7 d). The abundance of Escherichia-Shigella was reduced by HF-FMT in numerically compared with the LF. In addition, HF and HF-FMT both decreased the perinatal concentrations of proinflammatory factors, such as endotoxin (ET), lipocalin-2 (LCN-2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). The concentration of ET and LCN-2 and the abundance of Proteobacteria and Escherichia-Shigella were negatively correlated with the LFI of sows.

Conclusion
The high abundance of Proteobacteria, especially Escherichia-Shigella of LF sows in late gestation, led to increased endotoxin levels, which result in inflammatory responses and adverse effects on the LFI of sows. Adding HF during gestation reverses this process by increasing the abundance of Lactobacillus, especially Lactobacillus_mucosae_LM1 and Lactobacillus_amylovorus.