bluuebunny/crossref_metadata_2025_split huggingface dataset:
YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner
Authors: Feng Mengdie , Xie Xueqin , Han Guoqiang , Zhang Tiantian , Li Yashu , Li Yicun , Yin Rong , Wang Qifan , Zhang Tong , Wang Peipei , Hu Jin , Cheng Ying , Gao Zhuying , Wang Jing , Chang Jiwei , Cui Manman , Gao Kexin , Chai Jihua , Liu Weidong , Guo Chengli , Li Shaoguang , Liu Lingbo , Zhou Fuling , Chen Jianjun , Zhang Haojian 
Published: March 2021

Abstract
RNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Although RBPs are increasingly recognized as being important for normal hematopoiesis and for hematologic malignancies as oncogenes or tumor suppressors, RBPs that are essential for the maintenance and survival of leukemia remain elusive. Here we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival in an N6-methyladenosine (m6A)-dependent manner. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 dramatically induces apoptosis and promotes differentiation coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia cells in vitro and in vivo. Loss of YBX1 has no obvious effect on normal hematopoiesis. Mechanistically, YBX1 interacts with insulin-like growth factor 2 messenger RNA (mRNA)-binding proteins (IGF2BPs) and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency dysregulates the expression of apoptosis-related genes and promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival that results from deletion of YBX1. Thus, our findings have uncovered a selective and critical role of YBX1 in maintaining myeloid leukemia survival, which might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.
Active case-finding of tuberculosis in general populations and at-risk groups: a systematic review and meta-analysis
Authors: Bohlbro Anders Solitander , Hvingelby Victor Schwartz , Rudolf Frauke , Wejse Christian , Patsche Cecilie Blenstrup 
Published: March 2021

BackgroundThe World Health Organization (WHO) recommends active case-finding (ACF) of tuberculosis (TB) in certain high-risk groups; however, more evidence is needed to elucidate the scope of ACF beyond the current recommendations. In this study we aimed to systematically review yields (the prevalence of active TB) of studies on ACF in general populations and at-risk groups.MethodsA literature search in PubMed, Embase and the Cochrane Central Library (CENTRAL) was performed for studies concluded after 31 December 1999 and published before 1 September 2020. Screening yields were estimated and yield/prevalence ratios (ratio between yield of study and WHO estimated prevalence of TB) were calculated to assess which groups might especially benefit from ACF. Finally, risk of bias was assessed and heterogeneity was investigated using meta-regression and sensitivity analyses.ResultsWe included 197 studies, with a total of 12 372 530 screened and 53 158 cases found. Yields were high among drug users, close contacts, the poor and marginalised, people living with HIV, and prison inmates across incidence strata, and estimated yield/prevalence ratios in screenings of general populations tended to be >1 with an overall ratio of 1.4 and ranging between 1.0 and 1.5. Sensitivity analyses suggested that inclusion of studies at high risk of bias contributed to underestimation of yields.ConclusionDespite many studies using insensitive screening methods, these results suggest that more at-risk groups should be considered for inclusion in future screening recommendations and that screening of general populations may outperform current case-finding practices, providing evidence for extending ACF beyond the current recommendations.
Multi-omics links IL-6 trans-signalling with neutrophil extracellular trap formation andHaemophilusinfection in COPD
Authors: Winslow Sofia , Odqvist Lina , Diver Sarah , Riise Rebecca , Abdillahi Suado , Wingren Cecilia , Lindmark Helena , Wellner Annika , Lundin Sofia , Yrlid Linda , Ax Elisabeth , Djukanovic Ratko , Sridhar Sriram , Higham Andrew , Singh Dave , Southworth Thomas , Brightling Christopher E. , Olsson Henric K. , Jevnikar Zala 
Published: March 2021

Background:Interleukin (IL)-6 trans-signalling (IL-6TS) is emerging as a pathogenic mechanism in chronic respiratory diseases; however, the drivers of IL-6TS in the airways and the phenotypic characteristic of patients with increased IL-6TS pathway activation remain poorly understood.Objective:Our aim was to identify and characterise COPD patients with increased airway IL-6TS and to elucidate the biological drivers of IL-6TS pathway activation.Methods:We used an IL-6TS-specific sputum biomarker profile (soluble IL-6 receptor (sIL-6R), IL-6, IL-1β, IL-8, macrophage inflammatory protein-1β) to stratify sputum data from patients with COPD (n=74; Biomarkers to Target Antibiotic and Systemic Corticosteroid Therapy in COPD Exacerbation (BEAT-COPD)) by hierarchical clustering. The IL-6TS signature was related to clinical characteristics and sputum microbiome profiles. The induction of neutrophil extracellular trap formation (NETosis) and IL-6TS byHaemophilus influenzaewere studied in human neutrophils.Results:Hierarchical clustering revealed an IL-6TS-high subset (n=24) of COPD patients, who shared phenotypic traits with an IL-6TS-high subset previously identified in asthma. The subset was characterised by increased sputum cell counts (p=0.0001), persistent sputum neutrophilia (p=0.0004), reduced quality of life (Chronic Respiratory Questionnaire total score; p=0.008), and increased levels of pro-inflammatory mediators and matrix metalloproteinases in sputum. IL-6TS-high COPD patients showed an increase in Proteobacteria, withHaemophilusas the dominating genus. NETosis induced byH. influenzaewas identified as a potential mechanism for increased sIL-6R levels. This was supported by a significant positive correlation between sIL-6R and NETosis markers in bronchoalveolar lavage fluid from COPD patients.Conclusion:IL-6TS pathway activation due to chronic colonisation withHaemophilusmay be an important disease driver in a subset of COPD patients.
Clustering based approach for population level identification of condition-associated T-cell receptor β-chain CDR3 sequences
Authors: Yohannes Dawit A. , Kaukinen Katri , Kurppa Kalle , Saavalainen Päivi , Greco Dario 
Published: March 2021

Abstract
Background
Deep immune receptor sequencing, RepSeq, provides unprecedented opportunities for identifying and studying condition-associated T-cell clonotypes, represented by T-cell receptor (TCR) CDR3 sequences. However, due to the immense diversity of the immune repertoire, identification of condition relevant TCR CDR3s from total repertoires has mostly been limited to either “public” CDR3 sequences or to comparisons of CDR3 frequencies observed in a single individual. A methodology for the identification of condition-associated TCR CDR3s by direct population level comparison of RepSeq samples is currently lacking.

Results
We present a method for direct population level comparison of RepSeq samples using immune repertoire sub-units (or sub-repertoires) that are shared across individuals. The method first performs unsupervised clustering of CDR3s within each sample. It then finds matching clusters across samples, called immune sub-repertoires, and performs statistical differential abundance testing at the level of the identified sub-repertoires. It finally ranks CDR3s in differentially abundant sub-repertoires for relevance to the condition. We applied the method on total TCR CDR3β RepSeq datasets of celiac disease patients, as well as on public datasets of yellow fever vaccination. The method successfully identified celiac disease associated CDR3β sequences, as evidenced by considerable agreement of TRBV-gene and positional amino acid usage patterns in the detected CDR3β sequences with previously known CDR3βs specific to gluten in celiac disease. It also successfully recovered significantly high numbers of previously known CDR3β sequences relevant to each condition than would be expected by chance.

Conclusion
We conclude that immune sub-repertoires of similar immuno-genomic features shared across unrelated individuals can serve as viable units of immune repertoire comparison, serving as proxy for identification of condition-associated CDR3s.
Lipopolysaccharide- TLR-4 Axis regulates Osteoclastogenesis independent of RANKL/RANK signaling
Authors: AlQranei Mohammed S. , Senbanjo Linda T. , Aljohani Hanan , Hamza Therwa , Chellaiah Meenakshi A. 
Published: March 2021

Abstract
Background
Lipopolysaccharide (LPS) is an endotoxin and a vital component of gram-negative bacteria’s outer membrane. During gram-negative bacterial sepsis, LPS regulates osteoclast differentiation and activity, in addition to increasing inflammation. This study aimed to investigate how LPS regulates osteoclast differentiation of RAW 264.7 cells in vitro.

Results
Herein, we revealed that RAW cells failed to differentiate into mature osteoclasts in vitro in the presence of LPS. However, differentiation occurred in cells primed with receptor activator of nuclear factor-kappa-Β ligand (RANKL) for 24 h and then treated with LPS for 48 h (henceforth, denoted as LPS-treated cells). In cells treated with either RANKL or LPS, an increase in membrane levels of toll-like receptor 4 (TLR4) receptor was observed. Mechanistically, an inhibitor of TLR4 (TAK-242) reduced the number of osteoclasts as well as the secretion of tumor necrosis factor (TNF)-α in LPS-treated cells. RANKL-induced RAW cells secreted a very basal level TNF-α. TAK-242 did not affect RANKL-induced osteoclastogenesis. Increased osteoclast differentiation in LPS-treated osteoclasts was not associated with the RANKL/RANK/OPG axis but connected with the LPS/TLR4/TNF-α tumor necrosis factor receptor (TNFR)-2 axis. We postulate that this is because TAK-242 and a TNF-α antibody suppress osteoclast differentiation. Furthermore, an antibody against TNF-α reduced membrane levels of TNFR-2. Secreted TNF-α appears to function as an autocrine/ paracrine factor in the induction of osteoclastogenesis independent of RANKL.

Conclusion
TNF-α secreted via LPS/TLR4 signaling regulates osteoclastogenesis in macrophages primed with RANKL and then treated with LPS. Our findings suggest that TLR4/TNF-α might be a potential target to suppress bone loss associated with inflammatory bone diseases, including periodontitis, rheumatoid arthritis, and osteoporosis.
Vaccinomic approach for novel multi epitopes vaccine against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)
Authors: Almofti Yassir A. , Abd-elrahman Khoubieb Ali , Eltilib Elsideeq E. M. 
Published: March 2021

Abstract
Background
The spread of a novel coronavirus termed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in China and other countries is of great concern worldwide with no effective vaccine. This study aimed to design a novel vaccine construct against SARS-CoV-2 from the spike S protein and orf1ab polyprotein using immunoinformatics tools. The vaccine was designed from conserved epitopes interacted against B and T lymphocytes by the combination of highly immunogenic epitopes with suitable adjuvant and linkers.

Results
The proposed vaccine composed of 526 amino acids and was shown to be antigenic in Vaxigen server (0.6194) and nonallergenic in Allertop server. The physiochemical properties of the vaccine showed isoelectric point of 10.19. The instability index (II) was 31.25 classifying the vaccine as stable. Aliphatic index was 84.39 and the grand average of hydropathicity (GRAVY) was − 0.049 classifying the vaccine as hydrophilic. Vaccine tertiary structure was predicted, refined and validated to assess the stability of the vaccine via Ramachandran plot and ProSA-web servers. Moreover, solubility of the vaccine construct was greater than the average solubility provided by protein sol and SOLpro servers indicating the solubility of the vaccine construct. Disulfide engineering was performed to reduce the high mobile regions in the vaccine to enhance stability. Docking of the vaccine construct with TLR4 demonstrated efficient binding energy with attractive binding energy of − 338.68 kcal/mol and − 346.89 kcal/mol for TLR4 chain A and chain B respectively. Immune simulation significantly provided high levels of immunoglobulins, T-helper cells, T-cytotoxic cells and INF-γ. Upon cloning, the vaccine protein was reverse transcribed into DNA sequence and cloned into pET28a(+) vector to ensure translational potency and microbial expression.

Conclusion
A unique vaccine construct from spike S protein and orf1ab polyprotein against B and T lymphocytes was generated with potential protection against the pandemic. The present study might assist in developing a suitable therapeutics protocol to combat SARSCoV-2 infection.
Association between the vertebrobasilar artery geometry and basilar artery plaques determined by high-resolution magnetic resonance imaging
Authors: Zheng Jinmei , Sun Bin , Lin Ruolan , Teng Yongqi , Zhao Xihai , Xue Yunjing 
Published: March 2021

Abstract
Background
Atherosclerotic plaques are often present in regions of arteries with complicated flow patterns. Vascular morphology plays important role in hemodynamics. In this study, we investigated the relationship between the geometry of the vertebrobasilar artery system and presence of basilar artery (BA) plaque.

Methods
We enrolled 290 patients with posterior circulation ischemic stroke. We distinguished four configurations of the vertebrobasilar artery: Walking, Tuning Fork, Lambda, and No Confluence. Patients were divided into multi-bending (≥ 3 bends) and oligo-bending (< 3 bends) VA groups. The diameter of the vertebral artery (VA) and the number of bends in the intracranial VA segment were assessed using three-dimensional time-of-flight magnetic resonance angiography. High-resolution magnetic resonance imaging was used to evaluate BA plaques. Logistic regression models were used to determine the relationship between the geometry type and BA plaque prevalence.

Results
After adjusting for sex, age, body mass index ≥ 28, hypertension, and diabetes mellitus, the Walking, Lambda, and No Confluence geometries were associated with the presence of BA plaque (all p < 0.05). Patients with multi-bending VAs in both the Walking (20/28, 71.43% vs. 6/21, 28.57%, p = 0.003) and Lambda group (19/47, 40.43% vs. 21/97, 21.65%, p = 0.018) had more plaques compared to patients with oligo-bending VAs in these groups. In the Lambda group, the difference in diameter of bilateral VAs was larger in patients with BA plaques than that in patients without BA plaques (1.4 mm [IQR: 0.9–1.6 mm] vs. 0.9 mm [IQR: 0.6–1.3 mm], p < 0.001).

Conclusions
The Walking, Lambda, and No Confluence geometry, ≥ 3 bends in the VAs, and a large diameter difference between bilateral VAs are associated with the presence of BA plaque.
Distinguishing cardiac myxomas from cardiac thrombi by a radiomics signature based on cardiovascular contrast-enhanced computed tomography images
Authors: Qian Wen-lei , Jiang Yu , Liu Xi , Guo Ying-kun , Li Yuan , Tang Xin , Yang Zhi-gang 
Published: March 2021

Abstract
Background
Cardiac myxomas (CMs) and thrombi are associated with high morbidity and mortality. These two conditions need totally different treatments. However, they are difficult to distinguish using naked eye. In clinical, misdiagnoses occur now and then. This study aimed to compare the characteristics of CMs and cardiac thrombi and investigate the value of a radiomics signature in distinguishing CMs from cardiac thrombi, based on cardiovascular contrast-enhanced computed tomography (CECT) images.

Methods
A total of 109 patients who had CMs (n = 59) and cardiac thrombi (n = 50) were enrolled in this retrospective study from 2009 to 2019. First, the lesion characteristics of cardiovascular CECT images were documented and compared by two radiologists. Then all patients were randomly allotted to either a primary group or a validation group according to a 7:3 ratio. Univariate analysis and the least absolute shrinkage and selection operator were used to select robust features. The best radiomics signature was constructed and validated using multivariate logistic regression. An independent clinical model was created for comparison.

Results
The best radiomics signature was developed using eight selected radiomics. The classification accuracies of the radiomics signature were 90.8% and 90.9%, and the area under the receiver operating characteristic curves were 0.969 and 0.926 in the training and testing cohorts, respectively. Cardiovascular CECT images showed that the two diseases had significant differences in location, surface, Hydrothorax, pericardial effusion and heart enlargement. The naked eye findings were used to create the clinical model. All metrics of the radiomics signature were higher than those of clinical model.

Conclusions
Compared with clinical model, the radiomics signature based on cardiovascular CECT performed better in differentiating CMs and thrombi, suggesting that it could help improving the diagnostic efficiency.
Economic burden of non-alcoholic steatohepatitis with significant fibrosis in Thailand
Authors: Phisalprapa Pochamana , Prasitwarachot Ratthanon , Kositamongkol Chayanis , Hengswat Pranaidej , Srivanichakorn Weerachai , Washirasaksiri Chaiwat , Treeprasertsuk Sombat , Charatcharoenwitthaya Phunchai , Chaiyakunapruk Nathorn 
Published: March 2021

Abstract
Background
Non-alcoholic steatohepatitis (NASH) has been recognised as a significant form of chronic liver disease and a common cause of cirrhosis and hepatocellular carcinoma, resulting in a considerable financial burden on healthcare resources. Currently, there is no information regarding the economic burden of NASH in low- and middle-income countries (LMICs). The aim of this study was to estimate the economic burden of NASH in Thailand as a lesson learned for LMICs.

Methods
To estimate the healthcare costs and prevalence of NASH with significant fibrosis (fibrosis stage ≥ 2) in the general Thai population, an eleven-state lifetime horizon Markov model with 1-year cycle length was performed. The model comprised Thai population aged 18 years and older. The cohort size was based on Thailand Official Statistic Registration Systems. The incidence of NASH, transitional probabilities, and costs-of-illness were based on previously published literature, including systematic reviews and meta-analyses. The age-specific prevalence of NASH was based on Thai NASH registry data. Costs were expressed in 2019 US Dollars ($). As we undertook analysis from the payer perspective, only direct medical costs were included. All future costs were discounted at an annual rate of 3%. A series of sensitivity analyses were performed.

Results
The estimated total number of patients with significant NASH was 2.9 million cases in 2019, based on a NASH prevalence of 5.74%. The total lifetime cost of significant NASH was $15.2 billion ($5,147 per case), representing approximately 3% of the 2019 GDP of Thailand. The probabilistic sensitivity analysis showed that the lifetime costs of significant NASH varied from $11.4 billion to $18.2 billion.

Conclusions
The economic burden associated with NASH is substantial in Thailand. This prompts clinicians and policy makers to consider strategies for NASH prevention and management.
Willingness and preparedness to provide care: interviews with individuals of different ages and with different caregiving experiences
Authors: de Jong Lea , Stahmeyer Jona Theodor , Eberhard Sveja , Zeidler Jan , Damm Kathrin 
Published: March 2021

Abstract
Background
At present, the provision of informal care to older relatives is an essential pillar of the long-term care system in Germany. However, the impact of demographic and social changes on informal caregiving remains unclear.

Methods
Thirty-three semi-structured interviews were conducted with care consultants, informal caregivers and people without any caregiving experience to explore if people are willing to provide older adult care and how prepared these are with regard to the possibility of becoming care dependent themselves.

Results
In total, three main categories (willingness to provide care, willingness to receive care and information as preparation) with several sub-categories were identified during the content analysis. While almost all interviewees were willing to provide care for close family members, most were hesitant to receive informal care. Other factors such as the available housing space, flexible working hours and the proximity of relatives were essential indicators of a person’s preparedness to provide informal care. It is, however, unclear if care preferences change over time and generations. Six out of 12 informal caregivers and nine out of 14 care consultants also reported an information gap. Because they do not possess adequate information, informal caregivers do not seek help until it is too late and they experience high physical and mental strain. Despite the increased efforts of care consultants in recent years, trying to inform caregivers earlier was seen as almost impossible.

Conclusions
The very negative perception of caregiving as a burden was a reoccurring theme throughout all interviews and influenced people’s willingness to receive care as well as seeking timely information. Despite recent political efforts to strengthen home-based care in Germany, it remains unclear whether political efforts will be effective in changing individuals’ perceptions of informal caregiving and their willingness to be better prepared for the highly likely scenario of having to care for a close relative or becoming care dependent at a later stage in life.
‘Long COVID’: persistent COVID-19 symptoms in survivors managed in Lagos State, Nigeria
Authors: Osikomaiya Bodunrin , Erinoso Olufemi , Wright Kikelomo Ololade , Odusola Aina Olufemi , Thomas Babafemi , Adeyemi Oluwatosin , Bowale Abimbola , Adejumo Olusola , Falana Ayodeji , Abdus-salam Ismail , Ogboye Olusegun , Osibogun Akin , Abayomi Akin 
Published: March 2021

Abstract
Background
Coronavirus disease once thought to be a respiratory infection is now recognised as a multi-system disease affecting the respiratory, cardiovascular, gastrointestinal, neurological, immune, and hematopoietic systems. An emerging body of evidence suggests the persistence of COVID-19 symptoms of varying patterns among some survivors. This study aimed to describe persistent symptoms in COVID-19 survivors and investigate possible risk factors for these persistent symptoms.

Methods
The study used a retrospective study design. The study population comprised of discharged COVID-19 patients. Demographic information, days since discharge, comorbidities, and persistent COVID-19 like symptoms were assessed in patients attending the COVID-19 outpatient clinic in Lagos State. Statistical analysis was done using STATA 15.0 software (StataCorp Texas) with significance placed at p-value < 0.05.

Results
A total of 274 patients were enrolled in the study. A majority were within the age group > 35 to ≤49 years (38.3%), and male (66.1%). More than one-third (40.9%) had persistent COVID-19 symptoms after discharge, and 19.7% had more than three persistent COVID-like symptoms. The most persistent COVID-like symptoms experienced were easy fatigability (12.8%), headaches (12.8%), and chest pain (9.8%). Symptomatic COVID-19 disease with moderate severity compared to mild severity was a predictor of persistent COVID-like symptoms after discharge (p < 0.05).

Conclusion
Findings from this study suggests that patients who recovered from COVID-19 disease may still experience COVID-19 like symptoms, particularly fatigue and headaches. Therefore, careful monitoring should be in place after discharge to help mitigate the effects of these symptoms and improve the quality of life of COVID-19 survivors.