bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diverse roles of SARS-CoV-2 Spike and Nucleocapsid proteins in EndMT stimulation through the TGF-β-MRTF axis inhibited by aspirin
Authors: Ciszewski Wojciech M. , Woźniak Lucyna A. , Sobierajska Katarzyna 
Published: May 2024

Abstract
Background
The SARS-CoV-2 virus causes severe COVID-19 in one-fifth of patients. In addition to high mortality, infection may induce respiratory failure and cardiovascular complications associated with inflammation. Acute or prolonged inflammation results in organ fibrosis, the cause of which might be endothelial disorders arising during the endothelial-mesenchymal transition (EndMT).

Methods
HUVECs and HMEC-1 cells were stimulated with SARS-CoV-2 S (Spike) and N (Nucleocapsid) proteins, and EndMT induction was evaluated by studying specific protein markers via Western blotting. Wound healing and tube formation assays were employed to assess the potential of SARS-CoV-2 to stimulate changes in cell behaviour. MRTF nuclear translocation, ROS generation, TLR4 inhibitors, TGF-β-neutralizing antibodies, and inhibitors of the TGF-β-dependent pathway were used to investigate the role of the TGF-β-MRTF signalling axis in SARS-CoV-2-dependent EndMT stimulation.

Results
Both viral proteins stimulate myofibroblast trans-differentiation. However, the N protein is more effective at EndMT induction. The TGF-β-MRTF pathway plays a critical role in this process. The N protein preferentially favours action through TGF-β2, whose secretion is induced through TLR4-ROS action. TGF-β2 stimulates MRTF-A and MRTF-B nuclear translocation and strongly regulates EndMT. In contrast, the Spike protein stimulates TGF-β1 secretion as a result of ACE2 downregulation. TGF-β1 induces only MRTF-B, which, in turn, weakly regulates EndMT. Furthermore, aspirin, a common nonsteroidal anti-inflammatory drug, might prevent and reverse SARS-CoV-2-dependent EndMT induction through TGF-β-MRTF pathway deregulation.

Conclusion
The reported study revealed that SARS-CoV-2 infection induces EndMT. Moreover, it was demonstrated for the first time at the molecular level that the intensity of the EndMT triggered by SARS-CoV-2 infection may vary and depend on the viral protein involved. The N protein acts through TLR4-ROS-TGF-β2-MRTF-A/B, whereas the S protein acts through ACE2-TGF-β1-MRTF-B. Furthermore, we identified aspirin as a potential anti-fibrotic drug for treating patients with SARS-CoV-2 infection.
Generalizable transcriptome-based tumor malignant level evaluation and molecular subtyping towards precision oncology
Authors: Hu Dingxue , Zhang Ziteng , Liu Xiaoyi , Wu Youchun , An Yunyun , Wang Wanqiu , Yang Mengqi , Pan Yuqi , Qiao Kun , Du Changzheng , Zhao Yu , Li Yan , Bao Jianqiang , Qin Tao , Pan Yue , Xia Zhaohua , Zhao Xin , Sun Kun 
Published: May 2024

AbstractIn cancer treatment, therapeutic strategies that integrate tumor-specific characteristics (i.e., precision oncology) are widely implemented to provide clinical benefits for cancer patients. Here, through in-depth integration of tumor transcriptome and patients’ prognoses across cancers, we investigated dysregulated and prognosis-associated genes and catalogued such important genes in a cancer type-dependent manner. Utilizing the expression matrices of these genes, we built models to quantitatively evaluate the malignant levels of tumors across cancers, which could add value to the clinical staging system for improved prediction of patients’ survival. Furthermore, we performed a transcriptome-based molecular subtyping on hepatocellular carcinoma, which revealed three subtypes with significantly diversified clinical outcomes, mutation landscapes, immune microenvironment, and dysregulated pathways. As tumor transcriptome was commonly profiled in clinical practice with low experimental complexity and cost, this work proposed easy-to-perform approaches for practical clinical promotion towards better healthcare and precision oncology of cancer patients.
Inhibition of mannan-binding lectin associated serine protease (MASP)-2 reduces the cognitive deficits in a mouse model of severe traumatic brain injury
Authors: Mercurio Domenico , Pischiutta Francesca , Seminara Serena , Tribuzio Francesca , Lisi Ilaria , Pasetto Laura , Bonetto Valentina , De Simoni Maria-Grazia , Schwaeble Wilhelm , Yaseen Sadam , Dudler Thomas , Zanier Elisa R. , Fumagalli Stefano 
Published: May 2024

AbstractThe lectin pathway (LP) of complement mediates inflammatory processes linked to tissue damage and loss of function following traumatic brain injury (TBI). LP activation triggers a cascade of proteolytic events initiated by LP specific enzymes called MASPs (for Mannan-binding lectin Associated Serine Proteases). Elevated serum and brain levels of MASP-2, the effector enzyme of the LP, were previously reported to be associated with the severity of tissue injury and poor outcomes in patients with TBI. To evaluate the therapeutic potential of LP inhibition in TBI, we first conducted a pilot study testing the effect of an inhibitory MASP-2 antibody (α-MASP-2), administered systemically at 4 and 24 h post-TBI in a mouse model of controlled cortical impact (CCI). Treatment with α-MASP-2 reduced sensorimotor and cognitive deficits for up to 5 weeks post-TBI. As previous studies by others postulated a critical role of MASP-1 in LP activation, we conducted an additional study that also assessed treatment with an inhibitory MASP-1 antibody (α-MASP-1). A total of 78 mice were treated intraperitoneally with either α-MASP-2, or α-MASP-1, or an isotype control antibody 4 h and 24 h after TBI or sham injury. An amelioration of the cognitive deficits assessed by Barnes Maze, prespecified as the primary study endpoint, was exclusively observed in the α-MASP-2-treated group. The behavioral data were paralleled by a reduction of the lesion size when evaluated histologically and by reduced systemic LP activity. Our data suggest that inhibition of the LP effector enzyme MASP-2 is a promising treatment strategy to limit neurological deficits and tissue loss following TBI. Our work has translational value because a MASP-2 antibody has already completed multiple late-stage clinical trials in other indications and we used a clinically relevant treatment protocol testing the therapeutic mechanism of MASP-2 inhibition in TBI.
Improving physical movement during stroke rehabilitation: investigating associations between sleep measured by wearable actigraphy technology, fatigue, and key biomarkers
Authors: Smith Madeleine J. , Pellegrini Michael , Major Brendan , Graco Marnie , Porter Stephanie , Kramer Sharon , Sewell Katherine , Salberg Sabrina , Chen Zhibin , Mychasiuk Richelle , Lannin Natasha A. 
Published: May 2024

Abstract
Background
Sleep disturbance and fatigue are common in individuals undergoing inpatient rehabilitation following stroke. Understanding the relationships between sleep, fatigue, motor performance, and key biomarkers of inflammation and neuroplasticity could provide valuable insight into stroke recovery, possibly leading to personalized rehabilitation strategies. This study aimed to investigate the influence of sleep quality on motor function following stroke utilizing wearable technology to obtain objective sleep measurements. Additionally, we aimed to determine if there were relationships between sleep, fatigue, and motor function. Lastly, the study aimed to determine if salivary biomarkers of stress, inflammation, and neuroplasticity were associated with motor function or fatigue post-stroke.

Methods
Eighteen individuals who experienced a stroke and were undergoing inpatient rehabilitation participated in a cross-sectional observational study. Following consent, participants completed questionnaires to assess sleep patterns, fatigue, and quality of life. Objective sleep was measured throughout one night using the wearable Philips Actiwatch. Upper limb motor performance was assessed on the following day and saliva was collected for biomarker analysis. Correlation analyses were performed to assess the relationships between variables.

Results
Participants reported poor sleep quality, frequent awakenings, and difficulties falling asleep following stroke. We identified a significant negative relationship between fatigue severity and both sleep quality (r=-0.539, p = 0.021) and participants experience of awakening from sleep (r=-0.656, p = 0.003). A significant positive relationship was found between grip strength on the non-hemiplegic limb and salivary gene expression of Brain-derived Neurotrophic Factor (r = 0.606, p = 0.028), as well as a significant negative relationship between grip strength on the hemiplegic side and salivary gene expression of C-reactive Protein (r=-0.556, p = 0.048).

Conclusion
The findings of this study emphasize the importance of considering sleep quality, fatigue, and biomarkers in stroke rehabilitation to optimize recovery and that interventions may need to be tailored to the individual. Future longitudinal studies are required to explore these relationships over time. Integrating wearable technology for sleep and biomarker analysis can enhance monitoring and prediction of outcomes following stroke, ultimately improving rehabilitation strategies and patient outcomes.
Quantifying the effects of sleep on sensor-derived variables from upper limb accelerometry in people with and without upper limb impairment
Authors: Miller Allison E. , Lang Catherine E. , Bland Marghuretta D. , Lohse Keith R. 
Published: May 2024

Abstract
Background
Despite the promise of wearable sensors for both rehabilitation research and clinical care, these technologies pose significant burden on data collectors and analysts. Investigations of factors that may influence the wearable sensor data processing pipeline are needed to support continued use of these technologies in rehabilitation research and integration into clinical care settings. The purpose of this study was to investigate the effect of one such factor, sleep, on sensor-derived variables from upper limb accelerometry in people with and without upper limb impairment and across a two-day wearing period.

Methods
This was a secondary analysis of data collected during a prospective, longitudinal cohort study (n = 127 individuals, 62 with upper limb impairment and 65 without). Participants wore a wearable sensor on each wrist for 48 h. Five upper limb sensor variables were calculated over the full wear period (sleep included) and with sleep time removed (sleep excluded): preferred time, non-preferred time, use ratio, non-preferred magnitude and its standard deviation. Linear mixed effects regression was used to quantify the effect of sleep on each sensor variable and determine if the effect differed between people with and without upper limb impairment and across a two-day wearing period.

Results
There were significant differences between sleep included and excluded for the variables preferred time (p < 0.001), non-preferred time (p < 0.001), and non-preferred magnitude standard deviation (p = 0.001). The effect of sleep was significantly different between people with and without upper limb impairment for one variable, non-preferred magnitude (p = 0.02). The effect of sleep was not substantially different across wearing days for any of the variables.

Conclusions
Overall, the effects of sleep on sensor-derived variables of upper limb accelerometry are small, similar between people with and without upper limb impairment and across a two-day wearing period, and can likely be ignored in most contexts. Ignoring the effect of sleep would simplify the data processing pipeline, facilitating the use of wearable sensors in both research and clinical practice.
Fistula of the mitral-aortic intervalvular fibrosa in a patient with bacterial endocarditis: a case report and systematic literature review
Authors: Figueroa-Casanova Rafael , Saavedra-Henao Juan D. , Figueroa-Laverde Juan S. , Beltrán-Gonzales Diego A. , Labrador-Rosales José G. , Eslait-Olaciregui Sara , Pérez Rivera Carlos J. 
Published: May 2024

Summary
Background
A fistulous tract in the mitro-aortic intervalvular fibrosa (MAIVF) is a rare entity, which presents as a complication of endocarditis or surgical trauma. Generally, it is associated to a pseudoaneurysm of the MAIVF (p-MAIVF) or aortic abscesses. MAIVF fistulas could potentially lead to devastating complications and a high mortality rate. This condition is managed surgically, either by a percutaneous closure or an open surgical approach. Herein we report the complex case of a patient with a MAIVF fistula secondary to bacterial endocarditis. Further clinical deterioration was caused by severe aortic valve insufficiency and hemodynamic compromise, requiring surgical intervention.

Case presentation
A 74-year-old male patient was admitted to a primary care center with complaints of malaise, asthenia, adynamia, hyporexia, and lower limb edema over the past eight days. His past medical history is positive for arterial hypertension and being monorenal. A transesophageal echocardiogram (TEE) was performed, exhibiting a 56% left ventricle ejection fraction (LVEF) and complicated aortic valve endocarditis. Surgical management through an open approach included vegetation resection, valve replacement, and closure of the MAIVF fistula. After completing antibiotic therapy, the patient was discharged without complications. During postoperative follow-up, the patient remained asymptomatic, and the control echocardiogram showed no signs of MAIVF fistula.4.

Conclusions
The clinical case of a patient with a MAIVF fistula secondary to endocarditis by Streptococcus Anginous was presented. The fistulous tract was not associated to p-MAIVF or aortic abscess, findings which further deteriorate the patient’s condition and increase the likelihood of fatality. This case reinforces the importance of a prompt diagnosis through cardiac imaging and timely surgical closure of the defect.
Mortality after paediatric emergency calls for patients with or without pre-existing comorbidity: a nationwide population based cohort study
Authors: Nielsen Vibe Maria Laden , Søvsø Morten Breinholt , Skals Regitze Gyldenholm , Bender Lars , Corfield Alasdair Ross , Lossius Hans Morten , Mikkelsen Søren , Christensen Erika Frischknecht 
Published: May 2024

Abstract
Background
Life-threatening conditions are infrequent in children. Current literature in paediatric prehospital research is centred around trauma and paediatric out-of-hospital cardiac arrests (POHCA). The aims of this study were to (1) outline the distribution of trauma, POHCA or other medical symptoms among survivors and non-survivors after paediatric emergency calls, and (2) to investigate these clinical presentations’ association with mortality in children with and without pre-existing comorbidity, respectively.

Methods
Nationwide population-based cohort study including ground and helicopter emergency medical services in Denmark for six consecutive years (2016–2021). The study included all calls to the emergency number 1-1-2 regarding children ≤ 15 years (N = 121,230). Interhospital transfers were excluded, and 1,143 patients were lost to follow-up. Cox regressions were performed with trauma or medical symptoms as exposure and 7-day mortality as the outcome, stratified by ‘Comorbidity’, ‘Severe chronic comorbidity’ and ’None’ based on previous healthcare visits.

Results
Mortality analysis included 76,956 unique patients (median age 5 (1–12) years). Annual all-cause mortality rate was 7 per 100,000 children ≤ 15 years. For non-survivors without any pre-existing comorbidity (n = 121), reasons for emergency calls were trauma 18.2%, POHCA 46.3% or other medical symptoms 28.9%, whereas the distribution among the 134 non-survivors with any comorbidity was 7.5%, 27.6% and 55.2%, respectively. Compared to trauma patients, age- and sex-adjusted hazard ratio for patients with calls regarding medical symptoms besides POHCA was 0.8 [0.4;1.3] for patients without comorbidity, 1.1 [0.5;2.2] for patients with comorbidity and 6.1 [0.8;44.7] for patients with severe chronic comorbidity.

Conclusion
In both non-survivors with and without comorbidity, a considerable proportion of emergency calls had been made because of various medical symptoms, not because of trauma or POHCA. This outline of diagnoses and mortality following paediatric emergency calls can be used for directing paediatric in-service training in emergency medical services.
Composite outcome measures in high-impact critical care randomised controlled trials: a systematic review
Authors: Walker Humphrey G. M. , Brown Alastair J. , Vaz Ines P. , Reed Rebecca , Schofield Max A. , Shao Jeffrey , Nanjayya Vinodh B. , Udy Andrew A. , Jeffcote Toby 
Published: May 2024

Abstract
Background
The use of composite outcome measures (COM) in clinical trials is increasing. Whilst their use is associated with benefits, several limitations have been highlighted and there is limited literature exploring their use within critical care. The primary aim of this study was to evaluate the use of COM in high-impact critical care trials, and compare study parameters (including sample size, statistical significance, and consistency of effect estimates) in trials using composite versus non-composite outcomes.

Methods
A systematic review of 16 high-impact journals was conducted. Randomised controlled trials published between 2012 and 2022 reporting a patient important outcome and involving critical care patients, were included.

Results
8271 trials were screened, and 194 included. 39.1% of all trials used a COM and this increased over time. Of those using a COM, only 52.6% explicitly described the outcome as composite. The median number of components was 2 (IQR 2–3). Trials using a COM recruited fewer participants (409 (198.8–851.5) vs 584 (300–1566, p = 0.004), and their use was not associated with increased rates of statistical significance (19.7% vs 17.8%, p = 0.380). Predicted effect sizes were overestimated in all but 6 trials. For studies using a COM the effect estimates were consistent across all components in 43.4% of trials. 93% of COM included components that were not patient important.

Conclusions
COM are increasingly used in critical care trials; however effect estimates are frequently inconsistent across COM components confounding outcome interpretations. The use of COM was associated with smaller sample sizes, and no increased likelihood of statistically significant results. Many of the limitations inherent to the use of COM are relevant to critical care research.
Elevated expression of wildtype RhoC promotes ErbB2- and Pik3ca-induced mammary tumor formation
Authors: Raghuram Nandini , Temel E. Idil , Kawamata Toshihiro , Kozma Katelyn J. , Loch Amanda J. , Wang Wei , Adams Jessica R. , Muller William J. , Egan Sean E. 
Published: May 2024

AbstractCopy number gains in genes coding for Rho activating exchange factors as well as losses affecting genes coding for RhoGAP proteins are common in breast cancer (BC), suggesting that elevated Rho signaling may play an important role. Extra copies and overexpression of RHOC also occur, although a role for RhoC overexpression in driving tumor formation has not been assessed in vivo. To this end, we report on the development of a Rosa26 (R26)-targeted Cre-conditional RhoC overexpression mouse (R26RhoC). This mouse was crossed to two models for ERBB2/NEU+ breast cancer: one based on expression of an oncogenic ErbB2/Neu cDNA downstream of the endogenous ErbB2 promoter (FloxNeoNeuNT), the other, a metastatic model that is based on high-level expression from MMTV regulatory elements (NIC). RhoC overexpression dramatically enhanced mammary tumor formation in FloxNeoNeuNT mice but showed a more subtle effect in the NIC line, which forms multiple mammary tumors after a very short latency. RhoC overexpression also enhanced mammary tumor formation in an activated Pik3ca model for breast cancer (Pik3caH1047R). The transforming effect of RhoC was associated with epithelial/mesenchymal transition (EMT) in ErbB2/NeuNT and Pik3caH1047R systems. Thus, our study reveals the importance of elevated wildtype Rho protein expression as a driver of breast tumor formation and highlights the significance of Copy Number Abberations that affect Rho signalling.
Efficacy of endometrial receptivity testing for recurrent implantation failure in patients with euploid embryo transfers: study protocol for a randomized controlled trial
Authors: Lu Yao , Mao Xinyi , He Yaqiong , Wang Yuan , Sun Yun 
Published: May 2024

Abstract
Background
Embryo implantation remains a critical barrier in assisted reproductive technologies. One of the main causes of unsuccessful embryo implantation is window of implantation (WOI) displacement, particularly in patients with recurrent implantation failure (RIF). Therefore, a reliable diagnostic tool for identifying the optimal WOI is essential. Previous data has suggested that a novel RNA-Seq-based endometrial receptivity testing (ERT) can diagnose WOI, guide personalized embryo transfer (pET), and improve pregnancy outcomes in patients with RIF compared to standard embryo transfer (sET). However, there is still a lack of evidence from randomized controlled trials (RCT) with sufficient power to determine whether pET based on ERT can increase the rate of live births as the primary outcome.

Methods
This trial is a prospective, single-blind, parallel-group RCT (1:1 ratio of pET versus sET). Infertile women with RIF who intend to undergo frozen-thawed embryo transfer (FET) after preimplantation genetic testing for aneuploidy (PGT-A) with the availability of at least one euploid blastocyst for transfer will be enrolled and assigned into two parallel groups randomly. Participants in the intervention group will undergo ERT and then pET based on the results of ERT, while those in the control group will undergo sET. The primary outcome is live birth rate.

Discussion
The findings of this study will provide evidence for the effect of pET guided by ERT on pregnancy outcomes in patients with RIF.

Trial registration
Chinese Clinical Trial Registry ChiCTR2100049041. Registered on 20 July 2021.
Metabolome-wide Mendelian randomization for age at menarche and age at natural menopause
Authors: Yazdanpanah Mojgan , Yazdanpanah Nahid , Gamache Isabel , Ong Ken , Perry John R. B. , Manousaki Despoina 
Published: May 2024

Abstract
Background
The role of metabolism in the variation of age at menarche (AAM) and age at natural menopause (ANM) in the female population is not entirely known. We aimed to investigate the causal role of circulating metabolites in AAM and ANM using Mendelian randomization (MR).

Methods
We combined MR with genetic colocalization to investigate potential causal associations between 658 metabolites and AAM and between 684 metabolites and ANM. We extracted genetic instruments for our exposures from four genome-wide association studies (GWAS) on circulating metabolites and queried the effects of these variants on the outcomes in two large GWAS from the ReproGen consortium. Additionally, we assessed the mediating role of the body mass index (BMI) in these associations, identified metabolic pathways implicated in AAM and ANM, and sought validation for selected metabolites in the Avon Longitudinal Study of Parents and Children (ALSPAC).

Results
Our analysis identified 10 candidate metabolites for AAM, but none of them colocalized with AAM. For ANM, 76 metabolites were prioritized (FDR-adjusted MR P-value ≤ 0.05), with 17 colocalizing, primarily in the glycerophosphocholines class, including the omega-3 fatty acid and phosphatidylcholine (PC) categories. Pathway analyses and validation in ALSPAC mothers also highlighted the role of omega and polyunsaturated fatty acids levels in delaying age at menopause.

Conclusions
Our study suggests that metabolites from the glycerophosphocholine and fatty acid families play a causal role in the timing of both menarche and menopause. This underscores the significance of specific metabolic pathways in the biology of female reproductive longevity.