bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical phenotyping in sarcoidosis using cluster analysis
Authors: Lin Nancy W. , Arbet Jaron , Mroz Margaret M. , Liao Shu-Yi , Restrepo Clara I. , Mayer Annyce S. , Li Li , Barkes Briana Q. , Schrock Sarah , Hamzeh Nabeel , Fingerlin Tasha E. , Carlson Nichole E. , Maier Lisa A. 
Published: April 2022

AbstractBackgroundMost phenotyping paradigms in sarcoidosis are based on expert opinion; however, no paradigm has been widely adopted because of the subjectivity in classification. We hypothesized that cluster analysis could be performed on common clinical variables to define more objective sarcoidosis phenotypes.MethodsWe performed a retrospective cohort study of 554 sarcoidosis cases to identify distinct phenotypes of sarcoidosis based on 29 clinical features. Model-based clustering was performed using the VarSelLCM R package and the Integrated Completed Likelihood (ICL) criteria were used to estimate number of clusters. To identify features associated with cluster membership, features were ranked based on variable importance scores from the VarSelLCM model, and additional univariate tests (Fisher’s exact test and one-way ANOVA) were performed using q-values correcting for multiple testing. The Wasfi severity score was also compared between clusters.ResultsCluster analysis resulted in 6 sarcoidosis phenotypes. Salient characteristics for each cluster are as follows: Phenotype (1) supranormal lung function and majority Scadding stage 2/3; phenotype (2) supranormal lung function and majority Scadding stage 0/1; phenotype (3) normal lung function and split Scadding stages between 0/1 and 2/3; phenotype (4) obstructive lung function and majority Scadding stage 2/3; phenotype (5) restrictive lung function and majority Scadding stage 2/3; phenotype (6) mixed obstructive and restrictive lung function and mostly Scadding stage 4. Although there were differences in the percentages, all Scadding stages were encompassed by all of the phenotypes, except for phenotype 1, in which none were Scadding stage 4. Clusters 4, 5, 6 were significantly more likely to have ever been on immunosuppressive treatment and had higher Wasfi disease severity scores.ConclusionsCluster analysis produced 6 sarcoidosis phenotypes that demonstrated less severe and severe phenotypes. Phenotypes 1, 2, 3 have less lung function abnormalities, a lower percentage on immunosuppressive treatment and lower Wasfi severity scores. Phenotypes 4, 5, 6 were characterized by lung function abnormalities, more parenchymal abnormalities, an increased percentage on immunosuppressive treatment and higher Wasfi severity scores. These data support using cluster analysis as an objective and clinically useful way to phenotype sarcoidosis subjects and to empower clinicians to identify those with more severe disease versus those who have less severe disease, independent of Scadding stage.
Engineering cascade biocatalysis in whole cells for bottom-up synthesis of cello-oligosaccharides: flux control over three enzymatic steps enables soluble production
Authors: Schwaiger Katharina N. , Voit Alena , Wiltschi Birgit , Nidetzky Bernd 
Published: April 2022

Abstract
Background
Soluble cello-oligosaccharides (COS, β‐1,4‐D‐gluco‐oligosaccharides with degree of polymerization DP 2–6) have been receiving increased attention in different industrial sectors, from food and feed to cosmetics. Development of large-scale COS applications requires cost-effective technologies for their production. Cascade biocatalysis by the three enzymes sucrose-, cellobiose- and cellodextrin phosphorylase is promising because it enables bottom-up synthesis of COS from expedient substrates such as sucrose and glucose. A whole-cell-derived catalyst that incorporates the required enzyme activities from suitable co-expression would represent an important step towards making the cascade reaction fit for production. Multi-enzyme co-expression to reach distinct activity ratios is challenging in general, but it requires special emphasis for the synthesis of COS. Only a finely tuned balance between formation and elongation of the oligosaccharide precursor cellobiose results in the desired COS.

Results
Here, we show the integration of cellodextrin phosphorylase into a cellobiose-producing whole-cell catalyst. We arranged the co-expression cassettes such that their expression levels were upregulated. The most effective strategy involved a custom vector design that placed the coding sequences for cellobiose phosphorylase (CbP), cellodextrin phosphorylase (CdP) and sucrose phosphorylase (ScP) in a tricistron in the given order. The expression of the tricistron was controlled by the strong T7lacO promoter and strong ribosome binding sites (RBS) for each open reading frame. The resulting whole-cell catalyst achieved a recombinant protein yield of 46% of total intracellular protein in an optimal ScP:CbP:CdP activity ratio of 10:2.9:0.6, yielding an overall activity of 315 U/g dry cell mass. We demonstrated that bioconversion catalyzed by a semi-permeabilized whole-cell catalyst achieved an industrial relevant COS product titer of 125 g/L and a space–time yield of 20 g/L/h. With CbP as the cellobiose providing enzyme, flux into higher oligosaccharides (DP ≥ 6) was prevented and no insoluble products were formed after 6 h of conversion.

Conclusions
A whole-cell catalyst for COS biosynthesis was developed. The coordinated co-expression of the three biosynthesis enzymes balanced the activities of the individual enzymes such that COS production was maximized. With the flux control set to minimize the share of insolubles in the product, the whole-cell synthesis shows a performance with respect to yield, productivity, product concentration and quality that is promising for industrial production.
AdpA, a developmental regulator, promotes ε-poly-l-lysine biosynthesis in Streptomyces albulus
Authors: Huang Rui , Liu Honglu , Zhao Wanwan , Wang Siqi , Wang Shufang , Cai Jun , Yang Chao 
Published: April 2022

AbstractBackgroundAdpA is a global regulator of morphological differentiation and secondary metabolism inStreptomyces,but the regulatory roles of theStreptomycesAdpA family on the biosynthesis of the natural product ε-poly-l-lysine (ε-PL) remain unidentified, and few studies have focused on increasing the production of ε-PL by manipulating transcription factors inStreptomyces.ResultsIn this study, we revealed the regulatory roles of different AdpA homologs in ε-PL biosynthesis and morphological differentiation and effectively promoted ε-PL production and sporulation inStreptomycesalbulusNK660 by heterologously expressingadpAfromS.neyagawaensisNRRLB-3092 (adpASn). First, we identified a novel AdpA homolog named AdpASainS.albulusNK660 and characterized its function as an activator of ε-PL biosynthesis and morphological differentiation. Subsequently, four heterologous AdpA homologs were selected to investigate their phylogenetic relationships and regulatory roles inS.albulus, and AdpASnwas demonstrated to have the strongest ability to promote both ε-PL production and sporulation among these five AdpA proteins. The ε-PL yield ofS.albulusheterologously expressingadpASnwas approximately 3.6-fold higher than that of the control strain. Finally, we clarified the mechanism of AdpASnin enhancing ε-PL biosynthesis and its effect on ε-PL polymerization degree using real-time quantitative PCR, microscale thermophoresis and MALDI-TOF–MS. AdpASnwas purified, and its seven direct targets,zwf,tal,pyk2,pta,ack,pepcand a transketolase gene (DC74_2409), were identified, suggesting that AdpASnmay cause the redistribution of metabolic flux in central metabolism pathways, which subsequently provides more carbon skeletons and ATP for ε-PL biosynthesis inS.albulus.ConclusionsHere, we characterized the positive regulatory roles ofStreptomycesAdpA homologs in ε-PL biosynthesis and their effects on morphological differentiation and reported for the first time that AdpASnpromotes ε-PL biosynthesis by affecting the transcription of its target genes in central metabolism pathways. These findings supply valuable insights into the regulatory roles of theStreptomycesAdpA family on ε-PL biosynthesis and morphological differentiation and suggest that AdpASnmay be an effective global regulator for enhanced production of ε-PL and other valuable secondary metabolites inStreptomyces.
The m6A demethylase ALKBH5 promotes tumor progression by inhibiting RIG-I expression and interferon alpha production through the IKKε/TBK1/IRF3 pathway in head and neck squamous cell carcinoma
Authors: Jin Shufang , Li Mingyu , Chang Hanyue , Wang Ruijie , Zhang Zhiyuan , Zhang Jianjun , He Yue , Ma Hailong 
Published: April 2022

Abstract
Background
N6-methyladenosine (m6A) RNA modification plays a critical role in various physiological and pathological conditions. However, the role of m6A modification in head and neck squamous cell carcinoma (HNSCC) remains elusive.

Methods
In this study, the expression of m6A demethylases was detected by HNSCC tissue microarray. m6A-RNA immunoprecipitation (MeRIP) sequencing and RNA sequencing were used to identify downstream targets of ALKBH5. Comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) was used to explore the m6A “readers”. Tumor-infiltrating lymphocytes were analyzed in SCC7-bearing xenografts in C3H mice.

Results
Here, we demonstrate the downregulation of m6A status and upregulation of two demethylases in HNSCC. Silencing the m6A demethylase alkB homolog 5, RNA demethylase (ALKBH5) suppresses tumor progression in vitro and in vivo. m6A-RNA immunoprecipitation sequencing reveals that ALKBH5 downregulates the m6A modification of DDX58 mRNA. Moreover, RIG-I, encoded by the DDX58 mRNA, reverses the protumorigenic characteristics of ALKBH5. ChIRP-MS demonstrates that HNRNPC binds to the m6A sites of DDX58 mRNA to promote its maturation. ALKBH5 overexpression inhibits RIG-I-mediated IFNα secretion through the IKKε/TBK1/IRF3 pathway. The number of tumor-infiltrating lymphocytes in C3H immunocompetent mice is reduced by ALKBH5 overexpression and restored by IFNα administration. Upregulation of AKLBH5 negatively correlates with RIG-I and IFNα expression in HNSCC patients.

Conclusions
These findings unveil a novel mechanism of immune microenvironment regulation mediated by m6A modification through the ALKBH5/RIG-I/IFNα axis, providing a rationale for therapeutically targeting epitranscriptomic modulators in HNSCC.
Integrative proteomic characterization of trace FFPE samples in early-stage gastrointestinal cancer
Authors: Li Lingling , Liu Hui , Li Yan , Guo Chunmei , Wang Bing , Shen Dan , Zhang Qiao , Ding Chen 
Published: April 2022

Abstract
Background
The surveillance and therapy of early-stage cancer would be better for patients’ prognosis. However, the extreme trace amount of tissue samples in different stages have limited in portraying the characterization of early-stage cancer. Therefore, we focused on and presented comprehensive proteomic and phosphoproproteomic profiling of the trace FFPE samples from early-stage gastrointestinal cancer, and then explored the potential biomarkers of early-stage gastrointestinal cancer.

Methods
In this study, a quantitative proteomic method with chromatography with mass spectrometry (LC-MS/MS) was used to analyse the proteomic difference between the trace early-stage esophageal squamous cell carcinoma (EESCC) and early-stage duodenum adenocarcinoma cancer (EDAC).

Results
We identified ~ 6000 proteins and > 10,000 phosphosites in single trace FFPE samples. Comparative analysis disclosed the diverse proteomic features of tumor tissues compared with paired normal tissue of EESCC and EDAC, and revealed the difference of EESCC and EDAC was derived from their origin normal tissue. The distinct separation of EESCC and EDAC illustrated the functions of cell cycle (RB1 T373, EGFR T693) in EESCC, and the positive impacts of apoptosis, metabolic processes (MTOR and MTOR S1261) in EDAC. Furthermore, we deconvoluted the immune infiltration of early-stage gastrointestinal cancer, in which higher immune cell signatures were detected in EDAC, and showed the specific cytokines in EESCC and EDAC. We performed kinases-substates relationship analysis and elucidated the specific proteomic kinase characterization of EESCC and EDAC, and proposed the medicative effects and corresponding drugs for EESCC and EDAC at the clinic.

Conclusion
We disclosed the specific immune characterization of the early-stage gastrointestinal cancer, and presented potential makers of EESCC (EGFR, PDGFRB, CDK4, WEE1) and EDAC (MTOR, MAP2K1, MAPK3). This study represents a major stepping stone towards investigating the carcinogenesis mechanism of gastrointestinal cancer, and providing a rich resource for medicative strategy in the clinic.

Graphical Abstract
Evaluating machine learning-powered classification algorithms which utilize variants in the GCKR gene to predict metabolic syndrome: Tehran Cardio-metabolic Genetics Study
Authors: Akbarzadeh Mahdi , Alipour Nadia , Moheimani Hamed , Zahedi Asieh Sadat , Hosseini-Esfahani Firoozeh , Lanjanian Hossein , Azizi Fereidoun , Daneshpour Maryam S. 
Published: April 2022

Abstract
Background
Metabolic syndrome (MetS) is a prevalent multifactorial disorder that can increase the risk of developing diabetes, cardiovascular diseases, and cancer. We aimed to compare different machine learning classification methods in predicting metabolic syndrome status as well as identifying influential genetic or environmental risk factors.

Methods
This candidate gene study was conducted on 4756 eligible participants from the Tehran Cardio-metabolic Genetic study (TCGS). We compared predictive models using logistic regression (LR), Random Forest (RF), decision tree (DT), support vector machines (SVM), and discriminant analyses. Demographic and clinical features, as well as variables regarding common GCKR gene polymorphisms, were included in the models. We used a 10-repeated tenfold cross-validation to evaluate model performance.

Results
50.6% of participants had MetS. MetS was significantly associated with age, gender, schooling years, BMI, physical activity, rs780094, and rs780093 (P < 0.05) as indicated by LR. RF showed the best performance overall (AUC-ROC = 0.804, AUC-PR = 0.776, and Accuracy = 0.743) and indicated BMI, physical activity, and age to be the most influential model features. According to the DT, a person with BMI < 24 and physical activity < 8.8 possesses a 4% chance for MetS. In contrast, a person with BMI ≥ 25, physical activity < 2.7, and age ≥ 33, has 77% probability of suffering from MetS.

Conclusion
Our findings indicated that, on average, machine learning models outperformed conventional statistical approaches for patient classification. These well-performing models may be used to develop future support systems that use a variety of data sources to identify persons at high risk of getting MetS.
Personality disorders (PD) and interpersonal violence (IV) during COVID-19 pandemic: a systematic review
Authors: Di Stefano Ramona , Di Pietro Angelica , Talevi Dalila , Rossi Alessandro , Socci Valentina , Pacitti Francesca , Rossi Rodolfo 
Published: April 2022

AbstractNot only did the ongoing CoronaVIrus Disease-19 (COVID-19) pandemic cause a massive number of casualties, but also there is growing concern that the burden of its psychological aftermaths will only show up years down the road. This systematic review summarises the existing literature reporting the impact of COVID-19 on personality disorders (PDs)-related violence. MEDLINE and APA PsycINFO were independently searched for relevant studies by two authors. Eligible studies had to be identifiable through database searching, published and fully accessible. This systematic review was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. An initial pool of 241 studies were found, out of which 69 met the selection criteria and were, therefore, included. The majority reported a worse Mental Health Outcome (MHO) during the pandemic as related to dysfunctional personality and positive personality traits predicting a better outcome. Furthermore, increased levels of interpersonal violence (IV) and self-directed violence were reported. Further research should be conducted on the reciprocal interaction of PDs and IV during the time of pandemic. Nevertheless, the dramatic impact of restrictive measures on PDs has still to be appropriately addressed.
Root-TRAPR: a modular plant growth device to visualize root development and monitor growth parameters, as applied to an elicitor response of Cannabis sativa
Authors: Suwanchaikasem Pipob , Idnurm Alexander , Selby-Pham Jamie , Walker Robert , Boughton Berin A. 
Published: April 2022

AbstractBackgroundPlant growth devices, for example, rhizoponics, rhizoboxes, and ecosystem fabrication (EcoFAB), have been developed to facilitate studies of plant root morphology and plant-microbe interactions in controlled laboratory settings. However, several of these designs are suitable only for studying small model plants such asArabidopsis thalianaandBrachypodium distachyonand therefore require modification to be extended to larger plant species like crop plants. In addition, specific tools and technical skills needed for fabricating these devices may not be available to researchers. Hence, this study aimed to establish an alternative protocol to generate a larger, modular and reusable plant growth device based on different available resources.ResultsRoot-TRAPR (Root-Transparent, Reusable, Affordable three-dimensional Printed Rhizo-hydroponic) system was successfully developed. It consists of two main parts, an internal root growth chamber and an external structural frame. The internal root growth chamber comprises a polydimethylsiloxane (PDMS) gasket, microscope slide and acrylic sheet, while the external frame is printed from a three-dimensional (3D) printer and secured with nylon screws. To test the efficiency and applicability of the system, industrial hemp (Cannabis sativa) was grown with or without exposure to chitosan, a well-known plant elicitor used for stimulating plant defense. Plant root morphology was detected in the system, and plant tissues were easily collected and processed to examine plant biological responses. Upon chitosan treatment, chitinase and peroxidase activities increased in root tissues (1.7- and 2.3-fold, respectively) and exudates (7.2- and 21.6-fold, respectively). In addition, root to shoot ratio of phytohormone contents were increased in response to chitosan. Within 2 weeks of observation, hemp plants exhibited dwarf growth in the Root-TRAPR system, easing plant handling and allowing increased replication under limited growing space.ConclusionThe Root-TRAPR system facilitates the exploration of root morphology and root exudate ofC. sativaunder controlled conditions and at a smaller scale. The device is easy to fabricate and applicable for investigating plant responses toward elicitor challenge. In addition, this fabrication protocol is adaptable to study other plants and can be applied to investigate plant physiology in different biological contexts, such as plant responses against biotic and abiotic stresses.
Disappointment and frustration, but long-term satisfaction: patient experiences undergoing treatment for a chronic Achilles tendon rupture—a qualitative study
Authors: Nordenholm Anna , Nilsson Niklas , Krupic Ferid , Hamrin Senorski Eric , Nilsson Helander Katarina , Westin Olof , Karlsson Jón 
Published: April 2022

Abstract
Background
Delayed treatment of Achilles tendon ruptures is generally due to either misdiagnosis or patient delay. When the treatment is delayed more than 4 weeks, the rupture is defined as “chronic”, and almost always requires more invasive surgery and longer rehabilitation time compared with acute Achilles tendon ruptures. There is insufficient knowledge of patient experiences of sustaining and recovering from a chronic Achilles tendon rupture.

Methods
To evaluate patients’ experiences of suffering a chronic Achilles tendon rupture, semi-structured group interviews were conducted 4–6 years after surgical treatment using a semi-structured interview guide. The data were analyzed using qualitative content analysis described by Graneheim and Lundman.

Results
The experiences of ten patients (65 ± 14 years, 7 males and 3 females) were summarized into four main categories: (1) “The injury”, where the patients described immediate functional impairments, following either traumatic or non-traumatic injury mechanisms that were misinterpreted by themselves or the health-care system; (2) “The diagnosis”, where the patients expressed relief in receiving the diagnosis, but also disappointment and/or frustration related to the prior misdiagnosis and delay; (3) “The treatment”, where the patients expressed high expectations, consistent satisfaction with the surgical treatment, and addressed the importance of the physical therapist having the right expertise; and (4) “The outcomes”, where the patients expressed an overall satisfaction with the long-term outcome and no obvious limitations in physical activity, although some fear of re-injury emerged.

Conclusions
An Achilles tendon rupture can occur during both major and minor trauma and be misinterpreted by both the assessing health-care professional as well as the patient themselves. Surgical treatment and postoperative rehabilitation for chronic Achilles tendon rupture results in overall patient satisfaction in terms of the long-term outcomes. We emphasize the need for increased awareness of the occurrence of Achilles tendon rupture in patients with an atypical patient history.
Fabrication and characterization of PHEMA–gelatin scaffold enriched with graphene oxide for bone tissue engineering
Authors: Tabatabaee Sara , Baheiraei Nafiseh , Salehnia Mojdeh 
Published: April 2022

Abstract
Background
Growing investigations demonstrate that graphene oxide (GO) has an undeniable impact on repairing damaged bone tissue. Moreover, it has been stated in the literatures that poly(2-hydroxyethyl methacrylate) (PHEMA) and gelatin could provide a biocompatible structure.

Methods
In this research, we fabricated a scaffold using freeze-drying method comprised of PHEMA and gelatin, combined with GO. The validation of the successful fabrication of the scaffolds was performed utilizing Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction assay (XRD). The microstructure of the scaffolds was observed using scanning electron microscopy (SEM). The structural properties of the scaffolds including mechanical strength, hydrophilicity, electrical conductivity, and degradation rate were also evaluated. Human bone marrow‐derived mesenchymal stem cells (hBM-MSCs) were used to evaluate the cytotoxicity of the prepared scaffolds. The osteogenic potential of the GO-containing scaffolds was studied by measuring the alkaline phosphatase (ALP) activity after 7, 14, and 21 days cell culturing.

Results
SEM assay showed a porous interconnected scaffold with approximate pore size of 50–300 μm, appropriate for bone regeneration. The increase in GO concentration from 0.25 to 0.75% w/v exhibited a significant improvement in scaffolds compressive modulus from 9.03 ± 0.36 to 42.82 ± 1.63 MPa. Conventional four-probe analysis confirmed the electrical conductivity of the scaffolds in the semiconductor range. The degradation rate of the samples appeared to be in compliance with bone healing process. The scaffolds exhibited no cytotoxicity using MTT assay against hBM-MSCs. ALP analysis indicated that the PHEMA–Gel–GO scaffolds could efficiently cause the differentiation of hBM-MSCs into osteoblasts after 21 days, even without the addition of the osteogenic differentiation medium.

Conclusion
Based on the results of this research, it can be stated that the PHEMA–Gel–GO composition is a promising platform for bone tissue engineering.