bluuebunny/crossref_metadata_2025 huggingface dataset:
Temporal trends in age- and stage-specific incidence of colorectal adenocarcinomas in Germany
Authors: Waldmann Annika , Borchers Pia , Katalinic Alexander
Published: December 2023

Background

A national colorectal cancer (CRC) screening programme was launched in 2002 in Germany. A comprehensive evaluation of the programme effectiveness using real-world data is still lacking. In addition, there are regional reports on increasing colorectal cancer incidence in younger populations. Therefore, we aimed to describe and compare the overall, age- and stage-specific incidence trends for colorectal, colon and rectal cancer.

Methods

We used data from seven population-based cancer registries in Germany. We report absolute and relative changes in incidence rates between the early screening phase (2003–2005) and the most recent time period available (2015–2017), as well as annual percent changes. We analysed incidences according to tumour site (colorectum, colon, and rectum) and to six age groups (young adults: 15–34, 35–39, 40–49, screening-entitled/older adults: 50–54, 55–69 and 70 + years old).

Results

In our sample of 271,011 colorectal adenocarcinomas, about two-thirds were located in the colon and 95% of them occurred in the age group 50+ (50–54: 5%, 55–69: 32.8%, 70+: 57.2%). For the time period 2003–2005 the age-specific incidence rates of individuals in the age group 55–69 were about 76/100,00 for colon and 54/100,000 for rectal cancer (age group 70 + colon: 179/100,000; rectum: 84/100,000). The incidence rates in young adults were less than 13% of that of individuals in the age group 55–69 (< 5% of individuals aged 70+; <33% of individuals aged 50–54).

Over time, incidence decreased in individuals at the age of 55+, for all subsites considered as well as for early and late stage cancers (with few exceptions), while incidence of young adult CRC (both early and late stage) increased steepest in the youngest age groups. For late stage rectal cancer, a shift was observed in all age groups from UICC stage IV to stage III being the most frequent stage.

Conclusions

Six years after the introduction of the national colonoscopy screening program, late stage CRC incidence began to decline substantially in the screening-eligible age groups (55-69, 70+). It is likely that this decline and the increase in early stage CRC observed in younger age groups can be attributed to the program. Long lasting public awareness campaigns for CRC screening might have led to opportunistic screening in younger adults. Whether these benefits outweigh the possible harm of screening in younger age groups remains unclear.
The validity and IRT psychometric analysis of Chinese version of Difficult Doctor-Patient Relationship Questionnaire (DDPRQ-10)
Authors: Du Jianhua , Wang Yufei , Wu Aoxue , Jiang Yinan , Duan Yanping , Geng Wenqi , Wan Lin , Li Jiarui , Hu Jiaojiao , Jiang Jing , Shi Lili , Wei Jing
Published: December 2023

Objective

The doctor-patient relationship (DPR) plays a crucial role in the Chinese healthcare system, functioning to improve medical quality and reduce medical costs. This study examined the psychometric properties of the Chinese version of the Difficult Doctor-Patient Relationship Questionnaire (DDPRQ-10) among general hospital inpatients in China.

Methods

The research recruited 38 resident doctors responsible for 120 participants, and factor analyses were used to assess the construct validity of the scale. Convergent validity was evaluated by examining the correlation between DDPRQ-10 and depressive symptoms, burnout, and self-efficacy, using the Patient Health Questionnaire Depression Scale-9 item (PHQ-9), and the Maslach Burnout Inventory (MBI). Both multidimensional item response theory (MIRT) and unidimensional item response theory (IRT) frameworks were used to estimate the parameters of each item.

Results

The Chinese version of DDPRQ-10 showed satisfactory internal consistency (Cronbach's alpha = 0.931), and fitted in a modified two-factor model of positive feelings and negative feelings (χ2/df = 1.494, GFI = 0.925, RMSEA = 0.071, SRMR = 0.008, CFI = 0.985, NFI = 0.958, NNFI = 0.980, TLI = 0.980, IFI = 0.986). Significant correlations with PHQ-9 with DDPRQ-10 and both subscales were revealed (r = 0.293 ~ 0.333, p < .001), while DDPRQ-10 score also significantly correlated with doctors’ MBI score (r = -0.467, p < .001). The MIRT model of full scale and IRT models of both subscales showed high discrimination of all items (a = 2.30 ~ 10.18), and the test information within the range of low-quality relationship was relatively high.

Conclusion

The Chinese version of DDPRQ-10 displayed satisfactory reliability and validity and thus was appropriate for measuring the DPR in Chinese medical settings.
Mean difference in timing of first antenatal checks across regions and associated factors among pregnant women attending health facilities in Ethiopia: evidence from Ethiopian demographic health survey, 2019
Authors: Feyisa Gemechu Chemeda , Dagne Alemayehu , Woyessa Delelegn , Ephrem Tenna , Ahmed Ausman , G/Senbet Habtamu , Chane Getachew , Wake Senahara Korsa
Published: December 2023

Introduction

Early initiation of antenatal care visits is an essential component of services to improve maternal health. Conducting a detailed study about the mean difference in timing at first antenatal checks across regions and factors associated with timing at first antenatal checks among women attending antenatal in Ethiopia is essential to ensure maternal and newborn health. Therefore, this study aimed to describe the mean difference in timing at first antenatal visits and associated factors among pregnant women attending different health facilities across regions in Ethiopia.

Method

The Ethiopian Demographic and Health Survey (EDHS) conducted a community-based cross-sectional study in 2019. In this study, data about the timing of the first antenatal check-ups were requested from the Demographic Health Survey in February 2023, and the required variables were downloaded in SAS and SPSS formats from the data set. A total of 2935 women from nine regional states and two city administrations with an age range of 15 to 49 years were included in the study. The mean difference in timing at first antenatal check-ups, its correlation and various factors were estimated using multiple linear regressions to identify factors.

Result

The majority of the 2034 (69.3%) of pregnant women who participated in the study were rural residents. The mean (± SD) age of the pregnant women was 29 (± 6.5) years. Approximately 32.5% of pregnant women visited their first antenatal check after 4 months of pregnancy. The results showed that counselling by health workers during a previous pregnancy (p < 0.01) significantly predicts timing at first antenatal checks in months holding previous delivery, previous antenatal care at both government and private facilities, ever attended school, and highest educational level. Timing at the first antenatal check-in months is expected to decrease by 0.99 months for every counselling session at each pregnancy. The results of the analysis suggested that the regression model significantly predicted timing at the first antenatal check (p = 0.001).

Conclusion

The mean difference in timing at the first antenatal check in months among Ethiopian pregnant women relatively significantly varies in two regions. Previous pregnancy counselling by health workers positively influences the timing of first antenatal check-ups for subsequent antenatal check follow-ups in Ethiopia.
Cordymin alleviates osteoporosis induced by hindlimb unloading via regulating the gut - microelements -bone axis --for non-clinical studies
Authors: Qi Wei , Ma Tiancheng , Ji Yufei , Jia Hong , Sun Qiang , Zhang Dawei
Published: December 2023

Introduction

The purpose of this study was to evaluate the protective effects of cordymin on osteoporosis induced by hindlimb unloading(HLU) in rats and whether cordymin can prevent bone loss from HLU.

Materials and methods

We employed the hindlimb suspension rats model to mimic physiological changes concomitant with space travel.The mechanical strength in the femoral neck,cancellous bone volume, gut microbiota structure,serum calcium and phosphorus contents, bone mineral content and bone mineral content can be changed after hindlimb unloading. Oral cordymin was administered for 4 weeks,cordymin treatment significantly increased the mechanical strength through elevated bone volume/tissue volume (BV/TV), trabecular number (Tb. N), trabecular thickness (Tb. Th) and decreased trabecular separation (Tb. Sp).

Results

Importantly, 16 S rRNA sequencing showed cordymin treatment regulated the various genera that were imbalanced in hindlimb unloading rats. At the same time,The plasma total calcium and inorganic phosphate concentrations in hindlimb unloading rats decreased and bone mineral content in the lumbar vertebrae and femur increased after treatment with cordymin.

Conclusion

These data indicate that the cordymin might exert bone protective effects indirectly via modulating the complex relationship between gut microbiota, microelements and bone loss.
Coexpression network analysis identified MT3 as a hub gene that promotes the chemoresistance of oral cancer by regulating the expression of YAP1
Authors: Luo Jingyi , Liu Xin , Zhang Yifei , Yin Miao , Xu Li , Cao Menglei , Cheng Bo , Yang Sisi
Published: December 2023

Background

Oral cancer is considered one of the most malignant types of tumors and is known for its high likelihood of recurrence and metastasis. During clinical treatment, patients with oral cancer often develop resistance to chemotherapy, making the treatment process challenging. The purpose of this study was to investigate the genes related to chemotherapy resistance and their mechanisms in oral cancer patients.

Methods

The “limma” package was used to identify the differentially expressed genes between tumor and normal tissues from TCGA dataset. Subsequently, the “WGCNA” package was utilized to discover genes associated with chemoresistance. Cisplatin-resistant oral cancer cell lines were obtained through exposure to gradually increasing doses of cisplatin. SiRNA was used to knock down the MT3 and YAP1 genes to validate their functions. Finally, the therapeutic efficacy of combining a YAP1 inhibitor with cisplatin was confirmed by inoculating an oral cancer cell line in mice.

Results

In our study, we analyzed 43 OSCC samples and identified 724 different genes using the weighted gene coexpression network analysis (WGCNA) method. Among these genes, MT3 stood out as strongly associated with chemotherapy resistance. Patients with high MT3 expression had worse prognoses, and MT3 levels were elevated in drug-resistant patients. Knocking down MT3 reversed tumor cell chemoresistance. We also observed that MT3 increased the expression of YAP1, potentially contributing to chemotherapy resistance by inducing tumor stemness through YAP1. In animal models, using YAP1 inhibitors improved the effectiveness of cisplatin in treating chemoresistant oral cancer.

Conclusions

MT3 is related to chemotherapy resistance, which may be caused by its promotion of YAP1 expression and induction of tumor cell stemness. Inhibiting the activity of MT3 and YAP1 is helpful for increasing chemotherapy sensitivity.
Identifying potential pathogenesis and immune infiltration in diabetic foot ulcers using bioinformatics and in vitro analyses
Authors: Xu Yuanyuan , Xu Jianchang , Chen Sirong , Zhou Anbang , Huang Guangjing , Huang Shidao , Yu Dianbo , Wu Biaoliang
Published: December 2023

Background

Diabetic foot ulcers (DFU) are among the fastest-growing diseases worldwide. Recent evidence has emphasized the critical role of microRNA (miRNA)-mRNA networks in various chronic wounds, including DFU. In this study, we aimed to clarify the miRNA-mRNA axes associated with the occurrence of DFU.

Methods

Expression profiles of miRNAs and mRNAs were extracted from the Gene Expression Omnibus. Differentially expressed genes and differentially expressed miRNAs were identified, and miRNA-mRNA regulatory axes were constructed through integrated bioinformatics analyses. We validated the miRNA-mRNA axes using quantitative real-time PCR (qPCR) and dual-luciferase reporter assays. We conducted an immune infiltration analysis and confirmed the bioinformatics results using immunofluorescence staining. Single-sample gene set enrichment analysis (ssGSEA) was used to analyze the metabolic mechanisms.

Results

miR-182-5p-CHL1/MITF and miR-338-3p-NOVA1 interactions were identified using in silico analysis. The qPCR results showed apparent dysregulation of these miRNA-mRNA axes in DFU. The dual-luciferase reporter assay confirmed that miR-182-5p targeted CHL1 and MITF, and miR-338-3p targeted NOVA1. We conducted an immune infiltration analysis and observed that key genes correlated with decreased infiltration of M1 macrophages and resting mast cells in DFU. Immunofluorescence staining verified the co-localization of CHL1 and tryptase, while MITF and CD68 showed weak positive correlations. Metabolic pathways related to these three genes were identified using ssGSEA.

Conclusions

In summary, the miR-182-5p-CHL1/MITF and miR-338-3p-NOVA1 pathway interactions and decreased infiltration of M1 macrophages and resting mast cells may provide novel clues to the pathogenesis of DFU.

Trial registration

The clinical trial included in this study was registered in the Chinese Clinical Trial Registry (ChiCTR2200066660) on December 13, 2022.
CSE triggers ferroptosis via SIRT4-mediated GNPAT deacetylation in the pathogenesis of COPD
Authors: Li Congping , Chen Fei , Lin Liangfen , Li Jiwei , Zheng Yamei , Chen Qingyun
Published: December 2023

Background

It is now understood that ferroptosis plays a significant role in the progression of chronic obstructive pulmonary disease (COPD) induced by cigarette smoke extract (CSE). However, the mechanisms underlying this relationship remain largely unclear.

Methods

In this study, we established a COPD mouse model through exposure to cigarette smoke particulates, followed by H&E staining, analysis of bronchoalveolar lavage fluid, and immunohistochemistry assay. A549 cells were exposed to increasing concentrations of CSE, with the addition of the ferroptosis activator erastin or the inhibitor Fer-1. Cell viability, LDH (lactate dehydrogenase) release, inflammatory cytokines, total ROS (reactive oxygen species), and lipid ROS were measured using the corresponding assay kits. The acetylation level of GNPAT was determined through immunoprecipitation. We assessed the expression levels of molecules involved in plasmalogen biosynthesis (FAR1, AGPS, and GNPAT), GPX4, and SIRT4 using quantitative real-time PCR, western blot analysis, and immunofluorescence staining.

Results

CSE-induced lung tissue damage was initially observed, accompanied by oxidative stress, ferroptosis, and increased plasmalogen biosynthesis molecules (FAR1, AGPS, and GNPAT). CSE also induced ferroptosis in A549 cells, resulting in reduced cell viability, GSH, and GPX4 levels, along with increased LDH, ROS, MDA (malondialdehyde) levels, oxidized lipids, and elevated FAR1, AGPS, and GNPAT expression. Knockdown of GNPAT mitigated CSE-induced ferroptosis. Furthermore, we found that CSE regulated the acetylation and protein levels of GNPAT by modulating SIRT4 expression. Importantly, the overexpression of GNPAT countered the inhibitory effects of SIRT4 on ferroptosis.

Conclusions

Our study revealed GNPAT could be deacetylated by SIRT4, providing novel insights into the mechanisms underlying the relationship between CSE-induced ferroptosis and COPD.
Automated design of dynamic programming schemes for RNA folding with pseudoknots
Authors: Marchand Bertrand , Will Sebastian , Berkemer Sarah J. , Ponty Yann , Bulteau Laurent
Published: December 2023

Although RNA secondary structure prediction is a textbook application of dynamic programming (DP) and routine task in RNA structure analysis, it remains challenging whenever pseudoknots come into play. Since the prediction of pseudoknotted structures by minimizing (realistically modelled) energy is NP-hard, specialized algorithms have been proposed for restricted conformation classes that capture the most frequently observed configurations. To achieve good performance, these methods rely on specific and carefully hand-crafted DP schemes. In contrast, we generalize and fully automatize the design of DP pseudoknot prediction algorithms. For this purpose, we formalize the problem of designing DP algorithms for an (infinite) class of conformations, modeled by (a finite number of) fatgraphs, and automatically build DP schemes minimizing their algorithmic complexity. We propose an algorithm for the problem, based on the tree-decomposition of a well-chosen representative structure, which we simplify and reinterpret as a DP scheme. The algorithm is fixed-parameter tractable for the treewidth tw of the fatgraph, and its output represents a $${\mathcal {O}}(n^{tw+1})$$

O
(

n

t
w
+
1

)

algorithm (and even possibly $${\mathcal {O}}(n^{tw})$$

O
(

n

tw

)

in simple energy models) for predicting the MFE folding of an RNA of length n. We demonstrate, for the most common pseudoknot classes, that our automatically generated algorithms achieve the same complexities as reported in the literature for hand-crafted schemes. Our framework supports general energy models, partition function computations, recursive substructures and partial folding, and could pave the way for algebraic dynamic programming beyond the context-free case.
Cell and rat serum, urine and tissue metabolomics analysis elucidates the key pathway changes associated with chronic nephropathy and reveals the mechanism of action of rhein
Authors: Wang Li , Yu Xixi , Li Hongju , He Dahong , Zeng Su , Xiang Zheng
Published: December 2023

Background

Rhein can significantly delay the progression of chronic nephropathy. However, its mechanism of action has not been adequately elaborated, which hinders its extensive clinical application. In this work, the effects of rhein on models of TGF-β-induced NRK-49F cellular fibrosis and rat renal ischemia–reperfusion fibrosis were evaluated using metabolomics and western blotting.

Methods

The metabolic profiles of NRK-49F cells and rat urine, serum, and kidney tissues in the control, model, and rhein groups were investigated using UPLC-QTOF-MS. The levels of p-P65, p-IKK, p-AKT, p-P38, p-JNK and AP-1 in NRK-49F cells were measured using western blotting and immunofluorescence methods. Molecular docking and network pharmacology methods were employed to explore the relationship between the potential targets of rhein and key proteins in the NF-κB and MAPK signaling pathways.

Results

Various potential metabolites, including sphingolipids, ceramides, phosphatidylcholine, and lysophosphatidylcholine,14-hydroxy-E4-neuroprostane E, and 5-HPETE, were present in the cell, tissue, urine, and serum samples; however, few metabolites matches exactly among the four type of biological samples. These differential metabolites can effectively differentiated between the control, model, and rhein groups. Pathway enrichment analysis of differential metabolites unveiled that sphingolipid metabolism, arachidonic acid metabolism, and glycerophospholipid metabolism were closely related to nephropathy. Phosphorylation levels of AKT, IKK, P65 and AP-1 in NRK-49F cells was reduced by rhein treatment. Network pharmacology and molecular docking showed that the potential targets of rhein might regulated the expression of MAPK and AKT in the NF-κB and MAPK signaling pathways.

Conclusion

In brief, rhein might delays the progression of chronic nephropathy via the metabolic pathways, NF-κB and MAPKs signaling pathways, which provides the foundation for its development and clinical application.
The improvement of motor symptoms in Huntington’s disease during cariprazine treatment
Authors: Csehi Reka , Molnar Viktor , Fedor Mariann , Zsumbera Vivien , Palasti Agnes , Acsai Karoly , Grosz Zoltan , Nemeth Gyorgy , Molnar Maria Judit
Published: December 2023

Background

Huntington’s disease (HD) is a progressive neurodegenerative disease, characterised by motor disturbances and non-motor (i.e., psychiatric) symptoms. Motor symptoms are the hallmark features of HD and take many forms. Their emergence is related to alterations in striatal dopaminergic neurotransmission: dopamine levels increase in the early stages of the disease, while more advanced stages are characterised by reduced dopamine levels. Such a biphasic change potentially explains the alterations in motor symptoms: increased dopamine-production induces hyperkinetic movements early in the disease course, while depleted dopamine storage leads to hypokinetic symptoms in the advanced phase. Dopamine D2-D3 partial agonists could be a promising treatment option in HD, as they have the potential to either elevate or lower the surrounding dopamine levels if the levels are too low or too high, respectively, potentially offering symptom-relief across the illness-course. Therefore, the present study aimed at exploring the effects of cariprazine, a dopamine D2-D3 partial agonist with high affinity to D3 receptors, on motor symptoms associated with HD.

Methods

This was a single-centre, retrospective study where sixteen patients received off-label cariprazine treatment for 12 weeks (1.5-3 mg/day). Motor symptoms were evaluated using the Motor Assessment of the Unified Huntington’s Disease Rating Scale. Least Square (LS) Mean Changes from Baseline (BL) to Week 8 and Week 12 in the Total Motor Score (TMS) were analysed using the Mixed Model for Repeated Measures method. In addition, improvement from BL to Week 8 and 12 was calculated for all motor items.

Results

Data of 16 patients were collected, but data of only 15 patients were analysed as one patient dropped out due to non-compliance. Significant changes were observed from BL to Week 8 (LS Mean Change: -9.4, p < 0.0001) and to Week 12 (LS Mean Change: -12.8, p < 0.0001) in the TMS. The improvement was captured in the majority of motor functions, excluding bradykinesia and gait. Mild akathisia was the most commonly reported side-effect, affecting 3 patients.

Conclusion

This is the first study investigating the effectiveness of a D2-D3 partial agonist, cariprazine, in the treatment of HD. The findings of this study revealed that cariprazine was effective in the treatment of a wide range of motor symptoms associated with HD.
Using theory of change to co-create a programme theory for a telerehabilitation intervention for pain management in people with haemophilia
Authors: McLaughlin Paul , Hurley Michael , Chowdary Pratima , Khair Kate , Smith Clive , Stephensen David
Published: December 2023

Background

Improved approaches for chronic pain management are a clinical and research priority for people with haemophilia (PWH). Involving people with lived experience in the design of a complex rehabilitation intervention strengthens the credibility and plausibility of the intervention, particularly in relation to rare disorders. Here we describe using a ‘Theory of Change’ (ToC) dialogue-based stakeholder process to create a programme theory for a telerehabilitation intervention.

Methods

An online workshop was convened and stakeholders received a briefing document in advance. Five stakeholders took part (3 PWH and 2 physiotherapists). At the workshop the group first agreed the overall aim of the intervention. Discussions then identified the resources, activities, barriers and enablers needed to achieve this outcome. All discussions were recorded and annotated by the workshop moderator. Behaviour change techniques were mapped for inclusion in the theory.

Results

A programme theory and narrative report were produced. All stakeholders reviewed these for clarity and to ensure a true reflection of the workshop discussions. Agreement was based on how meaningful, well-defined, do-able, plausible, credible, and testable each component was. Stakeholders highlighted the importance of issues unique to PWH. Key components included the need for physiotherapists to be knowledgeable of the condition, a range of exercises that were inclusive of all abilities, and the need for people to feel safe and supported whilst taking part.

Conclusions

Co-developed theory based approaches to intervention design offer an inclusive and transparent way to develop novel and meaningful interventions for people with complex health conditions. The ToC is wholly transparent in its design and content. Together with the identified behaviour change techniques, the theory informs the protocol for a feasibility study evaluating a telerehabilitation intervention. Importantly, it allows the opportunity to revise, adapt and improve the programme theory for further implementation and evaluation.
Sleep restoration by optogenetic targeting of GABAergic neurons reprograms microglia and ameliorates pathological phenotypes in an Alzheimer’s disease model
Authors: Zhao Qiuchen , Maci Megi , Miller Morgan R. , Zhou Heng , Zhang Fang , Algamal Moustafa , Lee Yee Fun , Hou Steven S. , Perle Stephen J. , Le Hoang , Russ Alyssa N. , Lo Eng H. , Gerashchenko Dmitry , Gomperts Stephen N. , Bacskai Brian J. , Kastanenka Ksenia V.
Published: December 2023

Background

Alzheimer’s disease (AD) patients exhibit memory disruptions and profound sleep disturbances, including disruption of deep non-rapid eye movement (NREM) sleep. Slow-wave activity (SWA) is a major restorative feature of NREM sleep and is important for memory consolidation.

Methods

We generated a mouse model where GABAergic interneurons could be targeted in the presence of APPswe/PS1dE9 (APP) amyloidosis, APP-GAD-Cre mice. An electroencephalography (EEG) / electromyography (EMG) telemetry system was used to monitor sleep disruptions in these animals. Optogenetic stimulation of GABAergic interneurons in the anterior cortex targeted with channelrhodopsin-2 (ChR2) allowed us to examine the role GABAergic interneurons play in sleep deficits. We also examined the effect of optogenetic stimulation on amyloid plaques, neuronal calcium as well as sleep-dependent memory consolidation. In addition, microglial morphological features and functions were assessed using confocal microscopy and flow cytometry. Finally, we performed sleep deprivation during optogenetic stimulation to investigate whether sleep restoration was necessary to slow AD progression.

Results

APP-GAD-Cre mice exhibited impairments in sleep architecture including decreased time spent in NREM sleep, decreased delta power, and increased sleep fragmentation compared to nontransgenic (NTG) NTG-GAD-Cre mice. Optogenetic stimulation of cortical GABAergic interneurons increased SWA and rescued sleep impairments in APP-GAD-Cre animals. Furthermore, it slowed AD progression by reducing amyloid deposition, normalizing neuronal calcium homeostasis, and improving memory function. These changes were accompanied by increased numbers and a morphological transformation of microglia, elevated phagocytic marker expression, and enhanced amyloid β (Aβ) phagocytic activity of microglia. Sleep was necessary for amelioration of pathophysiological phenotypes in APP-GAD-Cre mice.

Conclusions

In summary, our study shows that optogenetic targeting of GABAergic interneurons rescues sleep, which then ameliorates neuropathological as well as behavioral deficits by increasing clearance of Aβ by microglia in an AD mouse model.
MLKL deficiency alleviates neuroinflammation and motor deficits in the α-synuclein transgenic mouse model of Parkinson’s disease
Authors: Geng Lu , Gao Wenqing , Saiyin Hexige , Li Yuanyuan , Zeng Yu , Zhang Zhifei , Li Xue , Liu Zuolong , Gao Qiang , An Ping , Jiang Ning , Yu Xiaofei , Chen Xiangjun , Li Suhua , Chen Lei , Lu Boxun , Li Aiqun , Chen Guoyuan , Shen Yidong , Zhang Haibing , Tian Mei , Zhang Zhuohua , Li Jixi
Published: December 2023

Parkinson’s disease (PD), one of the most devastating neurodegenerative brain disorders, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and deposits of α-synuclein aggregates. Currently, pharmacological interventions for PD remain inadequate. The cell necroptosis executor protein MLKL (Mixed-lineage kinase domain-like) is involved in various diseases, including inflammatory bowel disease and neurodegenerative diseases; however, its precise role in PD remains unclear. Here, we investigated the neuroprotective role of MLKL inhibition or ablation against primary neuronal cells and human iPSC-derived midbrain organoids induced by toxic α-Synuclein preformed fibrils (PFFs). Using a mouse model (Tg-Mlkl−/−) generated by crossbreeding the SNCA A53T synuclein transgenic mice with MLKL knockout (KO)mice, we assessed the impact of MLKL deficiency on the progression of Parkinsonian traits. Our findings demonstrate that Tg-Mlkl−/− mice exhibited a significant improvement in motor symptoms and reduced phosphorylated α-synuclein expression compared to the classic A53T transgenic mice. Furthermore, MLKL deficiency alleviated tyrosine hydroxylase (TH)-positive neuron loss and attenuated neuroinflammation by inhibiting the activation of microglia and astrocytes. Single-cell RNA-seq (scRNA-seq) analysis of the SN of Tg-Mlkl−/− mice revealed a unique cell type-specific transcriptome profile, including downregulated prostaglandin D synthase (PTGDS) expression, indicating reduced microglial cells and dampened neuron death. Thus, MLKL represents a critical therapeutic target for reducing neuroinflammation and preventing motor deficits in PD.
Novel insect-based child nutrition: the position of the nutritional committee of the Italian society of pediatric gastroenterology, hepatology and nutrition (SIGENP)
Authors: Norsa Lorenzo , Agostoni Carlo , Capriati Teresa , Campanozzi Angelo , Diamanti Antonella , Lezo Antonella , Gandullia Paolo , Spagnuolo Maria Immacolata , Romano Claudio
Published: December 2023

Background

The European Union (EU) approved the placement on European market of insect-based novel foods. Those foods were defined safe for the consumption for all European population, including children.

Main body

The nutrition committee of the Italian society of Paediatric Hepatology and Nutrition (SIGENP) performed literature research to understand benefits and risk of those use of those NF for Italian children. A special attention was reserved to the European Food Safety Agency (EFSA) reports upon which those novel insect-based were approved.

Conclusions

Based on the current knowledge, despite a possible ecological advantage, the group of expert suggests additional researches before pronouncing on a possible use for children diet, because of insufficient evidence on nutritional benefits and possible food allergies.
Involvement of transcribed lncRNA uc.291 in hyperproliferative skin disorders
Authors: Mancini Mara , Sergio Simone , Cappello Angela , Farkas Timea , Bernassola Francesca , Scarponi Claudia , Albanesi Cristina , Melino Gerry , Candi Eleonora
Published: December 2023

The uc.291 transcript controls keratinocytes differentiation by physical interaction with ACTL6A and subsequent induction of transcription of the genes belonging to the epidermal differentiation complex (EDC). Uc.291 is also implicated in the dedifferentiation phenotype seen in poorly differentiated cutaneous squamous cell carcinomas. Here, we would like to investigate the contribution of uc.291 to the unbalanced differentiation state of keratinocytes observed in hyperproliferative skin disorders, e. g., psoriasis. Psoriasis is a multifactorial inflammatory disease, caused by alteration of keratinocytes homeostasis. The imbalanced differentiation state, triggered by the infiltration of immune cells, represents one of the events responsible for this pathology. In the present work, we explore the role of uc.291 and its interactor ACTL6A in psoriasis skin, using quantitative real-time PCR (RT-qPCR), immunohistochemistry and bioinformatic analysis of publicly available datasets. Our data suggest that the expression of the uc.291 and of EDC genes loricrin and filaggrin (LOR, FLG) is reduced in lesional skin compared to nonlesional skin of psoriatic patients; conversely, the mRNA and protein level of ACTL6A are up-regulated. Furthermore, we provide evidence that the expression of uc.291, FLG and LOR is reduced, while ACTL6A mRNA is up-regulated, in an in vitro psoriasis-like model obtained by treating differentiated keratinocytes with interleukin 22 (IL-22). Furthermore, analysis of a publicly available dataset of human epidermal keratinocytes treated with IL-22 (GSE7216) confirmed our in vitro results. Taken together, our data reveal a novel role of uc.291 and its functional axis with ACTL6A in psoriasis disorder and a proof of concept that biological inhibition of this molecular axis could have a potential pharmacological effect against psoriasis and, in general, in skin diseases with a suppressed differentiation programme.
Different dosages of vonoprazan for gastroesophageal reflux disease: study protocol for a pragmatic, crossover-cluster, randomized controlled trial with patient preference arms
Authors: Wang Dongke , Zhou Dan , Liu Xinghuang , Xu Zhiyue , Bai Tao , Hou Xiaohua
Published: December 2023

Background

Vonoprazan results in more potent acid suppression for gastroesophageal reflux disease (GERD) than proton pump inhibitors. It has only been approved for treating erosive esophagitis in China, but 30–40% of GERD patients cannot achieve the goal of treatment with vonoprazan 20 mg daily. This study aims to investigate whether vonoprazan could relieve the symptoms of Chinese patients with non-erosive reflux disease (NERD) and whether increased dosage or different times of dosing could increase the response rate of GERD.

Methods

This study is a pragmatic, open-label, crossover-cluster, randomized controlled trial with patient preference arms. Two thousand eight hundred eighty patients with GERD from 48 hospitals in China will be enrolled. These hospitals will be divided into a compulsory randomization cluster (24 hospitals) and a patient preference cluster (24 hospitals). Patients in the compulsory randomization cluster will be randomized to three regimens according to the crossover-cluster randomization. Patients in the patient preference cluster may choose to receive any regimen if they have a preference; otherwise, patients will be randomly assigned. The three treatment regimens will last 4 weeks, including (1) vonoprazan 20 mg p.o. after breakfast, (2) vonoprazan 20 mg p.o. after dinner, and (3) vonoprazan 20 mg p.o. after breakfast and after dinner. Patients will attend a baseline visit, a 4-week e-diary, a fourth-week visit, and a sixth-month visit online. The primary outcome is the symptom relief rate of all patients after 4-week therapy. Secondary outcomes include the healing rate of EE patients, the severity of symptoms, compliance with the therapy at the fourth-week follow-up visit, recurrent symptoms, and the frequency of self-conscious doctor visits at the sixth-month follow-up visit.

Discussion

This trial will explore the effectiveness of different regimens of vonoprazan that will be implemented with GERD patients in China. The randomization with patient preferences considered and the crossover-cluster component may improve the robustness and extrapolation of study conclusions.

Trial registration

https://www.chictr.org.cn ChiCTR2300069857. Registered on 28 March 2023. Protocol version: February 18, 2023, Version 2.
Personalized tumor combination therapy optimization using the single-cell transcriptome
Authors: Tang Chen , Fu Shaliu , Jin Xuan , Li Wannian , Xing Feiyang , Duan Bin , Cheng Xiaojie , Chen Xiaohan , Wang Shuguang , Zhu Chenyu , Li Gaoyang , Chuai Guohui , He Yayi , Wang Ping , Liu Qi
Published: December 2023

Background

The precise characterization of individual tumors and immune microenvironments using transcriptome sequencing has provided a great opportunity for successful personalized cancer treatment. However, the cancer treatment response is often characterized by in vitro assays or bulk transcriptomes that neglect the heterogeneity of malignant tumors in vivo and the immune microenvironment, motivating the need to use single-cell transcriptomes for personalized cancer treatment.

Methods

Here, we present comboSC, a computational proof-of-concept study to explore the feasibility of personalized cancer combination therapy optimization using single-cell transcriptomes. ComboSC provides a workable solution to stratify individual patient samples based on quantitative evaluation of their personalized immune microenvironment with single-cell RNA sequencing and maximize the translational potential of in vitro cellular response to unify the identification of synergistic drug/small molecule combinations or small molecules that can be paired with immune checkpoint inhibitors to boost immunotherapy from a large collection of small molecules and drugs, and finally prioritize them for personalized clinical use based on bipartition graph optimization.

Results

We apply comboSC to publicly available 119 single-cell transcriptome data from a comprehensive set of 119 tumor samples from 15 cancer types and validate the predicted drug combination with literature evidence, mining clinical trial data, perturbation of patient-derived cell line data, and finally in-vivo samples.

Conclusions

Overall, comboSC provides a feasible and one-stop computational prototype and a proof-of-concept study to predict potential drug combinations for further experimental validation and clinical usage using the single-cell transcriptome, which will facilitate and accelerate personalized tumor treatment by reducing screening time from a large drug combination space and saving valuable treatment time for individual patients. A user-friendly web server of comboSC for both clinical and research users is available at www.combosc.top. The source code is also available on GitHub at https://github.com/bm2-lab/comboSC.
Machine learning and molecular subtype analyses provide insights into PANoptosis-associated genes in rheumatoid arthritis
Authors: Li Jing , Cui Jun , Wu Li , Liu Ya-bing , Wang Qi
Published: December 2023

Background

PANoptosis represents a newly identified form of programmed cell death that plays a significant role in the autoimmune diseases. Rheumatoid arthritis (RA) is characterized by the presence of autoantibodies. Nevertheless, the specific biomarkers and molecular mechanisms responsible for the apoptotic characteristics of RA remain largely uninvestigated.

Methods

We utilized 8 synovial tissue RA datasets. We selected genes associated with PANoptosis from the GeneCard database. By employing the limma, WGCNA, and machine learning algorithms we identified core genes. We utilized consensus clustering analysis to identify distinct PANoptosis subtypes of RA. Boruta algorithm was employed to construct a PANoptosis signature score. The sensitivity of distinct subtypes to drug treatment was verified using an independent dataset.

Results

The SPP1 emerged as the significant gene, with its elevated expression in RA patients. We identified two PANoptosis RA subtypes. Cluster 1 showed high expression of Tregs, resting dendritic cells, and resting mast cells. Cluster 2 exhibited high expression of CD4 memory T cells and follicular helper T cells. Cluster 2 exhibited a higher degree of sensitivity towards immune checkpoint therapy. Employing the Boruta algorithm, a subtype score was devised for 37 PANoptosis genes, successfully discerning the subtypes (AUC = 0.794), wherein patients with elevated scores demonstrated enhanced responsiveness to Rituximab treatment.

Conclusion

Our analysis revealed that SPP1 holds potential biomarker for the diagnosis of RA. Cluster 2 exhibited enhanced sensitivity to immune checkpoint therapy, higher PANoptosis scores, and improved responsiveness to drug treatment. This study offers potential implications in the realm of diagnosis and treatment.
Host cell factors involved in classical swine fever virus entry
Authors: Lamothe-Reyes Yaneysis , Figueroa Maximiliano , Sánchez Oliberto
Published: December 2023

Classical swine fever virus (CSFV) is an ancient pathogen that continues to pose a threat to animal agriculture worldwide. The virus belongs to the genus Pestivirus and the family Flaviviridae. It causes a multisystemic disease that affects only pigs and is responsible for significant economic losses. CSFV infection is probably a multistep process that involves the proteins in the virus envelope and more than one receptor in the membrane of permissive cells. To date, the cellular receptors essential for CSFV entry and their detailed functions during this process remains unknown. All the viral envelope proteins Erns, E1 and E2 are involved in the entry process to some extent and the experimental approaches conducted until now have helped to unveil their contributions. This review aims to provide an overview of current knowledge on cellular molecules described to be involved in CSFV entry, including complement regulatory protein 46 (CD46), heparan sulphate (HS), Laminin receptor, Integrin ß3, Annexin II, MERKT and ADAM17. This knowledge would not only help to understand the molecular mechanisms involved in pestivirus infection, but also provide a rational basis for the development of nonvaccinal alternatives for CSFV control.
High-precision reconstruction method based on MTS-GAN for electromagnetic environment data in SAGIoT
Authors: Guo Lantu , Liu Yuchao , Li Yuqian , Yang Kai
Published: December 2023

Equipment failures and communication interruptions of satellites, aircraft and ground devices lead to data loss in Space-Air-Ground Integrated Internet of Things (SAGIoT). The incomplete data affect the accuracy of data modeling, decision-making and spectrum prediction. Reconstructing the incomplete data of electromagnetic environment is a significant task in the SAGIoT. Most spectral data completion algorithms have the problem of limited accuracy and slow iterative optimization. In light of these challenges, a novel high-precision reconstruction method for electromagnetic environment data based on multi-component time series generation adversarial network (MTS-GAN) is proposed in this paper. MTS-GAN transforms the reconstruction method of electromagnetic environment data into the data generation problem of multiple time series. It extracts the time–frequency joint features and the overall distribution of electromagnetic environment data. To improve the reconstruction precision, MTS-GAN simulates the time irregularity of incomplete time series by applying a gate recursive element to adapt to the attenuation effect of discontinuous time series observations. Experimental results show that the proposed MTS-GAN provides high completion accuracy and achieves better results than competitive data completion algorithms.
Evaluation of antibody drug delivery efficiency via nebulizer in various airway models and breathing patterns
Authors: Hong Soon Woo , Chang Kyung Hwa , Woo Chang Jae , Kim Ho Chul , Kwak Bong Seop , Park Bong Joo , Nam Ki Chang
Published: December 2023

Background

Nebulizers are commonly used to treat respiratory diseases, which are a major cause of morbidity and mortality. While inhalation therapy with antibodies has been evaluated in preclinical studies and clinical trials for respiratory diseases, it has not yet been approved for treatment. Moreover, there is limited information regarding the delivery efficiency of therapeutic antibodies via nebulizer.

Methods

In this study, the nebulization characteristics and drug delivery efficiencies were compared when immunoglobulin G (IgG) was delivered by five nebulizers using two airway models and five breathing patterns. The study confirmed that the delivered dose and drug delivery efficiency were reduced in the child model compared to those in the adult model and in the asthma pattern compared to those in the normal breathing pattern.

Results

The NE-SM1 NEPLUS vibrating mesh nebulizer demonstrated the highest delivery efficiency when calculated as a percentage of the loading dose, whereas the PARI BOY SX + LC SPRINT (breath-enhanced) jet nebulizer had the highest delivery efficiency when calculated as a percentage of the emitted dose.

Conclusion

The results suggest that the total inspiration volume, output rate, and particle size should be considered when IgG nebulization is used. We, therefore, propose a method for evaluating the efficiency of nebulizer for predicting antibody drug delivery.
Temperature and microclimate refugia use influence migratory timings of a threatened grassland bird
Authors: Ramos Rita F. , Franco Aldina M.A. , Gilroy James J. , Silva João P.
Published: December 2023

Background

Seasonal changes in resource availability are known to influence the migratory behaviour of animals, including both timing and distance. While the influence of environmental cues on migratory behaviour has been widely studied at the population level, it has rarely been examined at the spatial scale at which individuals experience their environment. Here, we test the hypothesis that individuals exposed to similar large-scale environmental cues may vary in migratory behaviour in response to the different microclimate conditions they experience at fine scales.

Methods

We combine high-spatial and temporal resolution microclimate and habitat information with GPS tracking data for a partially migratory threatened grassland bird. Data from 47 little bustards (Tetrax tetrax; 67 breeding events) tracked between 2009 and 2019 was used to (i) evaluate individual consistency in migratory behaviour (timing and distance) and (ii) assess whether the local environmental characteristics experienced by individuals – and in particular their use of microclimate refugia - influence distance and timing of migration, from and to the breeding sites.

Results

Migratory distance was consistent for birds tracked over multiple years, while the timing of migration showed high variability among individuals. Departures from breeding areas spanned from May to August, with a few birds remaining in their breeding areas. Vegetation greenness (a proxy for food availability) was positively associated with the time birds spent in the breeding area. The best model also included a positive effect of microclimate refugia availability on breeding season length, although an interaction with temperature suggested that this effect did not occur at the highest relative temperatures. The return date to breeding grounds, although spanning from September to April, was not influenced by the environmental conditions or food availability.

Conclusions

Food availability, measured by a vegetation greenness proxy, was associated with later migration at the end of the breeding season. Availability of cooler microclimate refugia may also allow for later departures from the breeding sites in all but the hottest conditions. Management measures that increase microclimate refugia availability and provide foraging resources can thus potentially increase the length of the breeding season for this species.