bluuebunny/crossref_metadata_2025 huggingface dataset:
Impaired expression of BCAT1 relates to muscle atrophy of mouse model of sarcopenia
Authors: Ouyang Hui , Gao Xuguang , Zhang Jun
Published: May 2022

Background

The underlying mechanism of muscle atrophy in sarcopenia is still not fully understood; branched chain aminotransferase 1(BCAT1) isocitrate dehydrogenase-1 encodes an evolutionarily conserved cytoplasmic aminotransferase for glutamate and branched-chain amino acids (BCAAs), thus constituting a regulatory component of cytoplasmic amino and keto acid metabolism. In human gliomas carrying wild-type isocitrate dehydrogenase-1, BCAT1 promotes cell proliferation through amino acid catabolism. Hence, the goals of this study were to unravel the potential role of BCAT1 expression in muscle atrophy and to explore the mechanisms underlying this process.

Methods

We first measured Bcat1 expression by RT-qPCR and western blotting in murine and cellular models of muscle atrophy. To understand how the Bcat1-driven changes sustained muscle cell growth, we analyzed reactive oxygen species (ROS) levels and activation of the mTORC1/S6K1 pathway in muscle cells. Furthermore, we performed Cell Counting Kit-8(CCK8) assays and fluorescence staining to evaluate growth rate of cells and ROS levels. Finally, we verified that depletion of Bcat1 impairs the growth rate of muscle cells and increases ROS levels, indicating that muscle atrophy resulted from the downregulation of the mTORC1/S6K1 pathway. Data were analyzed by two-tailed unpaired Student’s t-test or Mann-Whitney U test for two groups to determine statistical significance. Statistical analyses were performed using GraphPad Prism version 6.0 and SPSS 16.0 software.

Results

Bcat1 expression level in skeletal muscles was lower in murine and cellular models of sarcopenia than in the control groups. Bcat1 knockdown not only suppressed the growth of muscle cells but also increased the production of ROS. Impaired cell growth and increased ROS production was rescued by co-introduction of an shRNA-resistant Bcat1 cDNA or addition of the mTORC1 stimulator MYH1485. Muscle cells with Bcat1 knockdown featured lower mTORC1 and S6K1 phosphorylation (pS6K1) than NT muscle cells. Addition of either shRNA-resistant Bcat1 cDNA or MYH1485 rescued the suppression of cell growth, increase in ROS production, and decrease in pS6K1.

Conclusions

The branched chain amino acids catabolic enzyme BCAT1 is essential for the growth of muscle cells. BCAT1 expression contributes to sustained growth of muscle cells by activating mTOR signaling and reducing ROS production.
Effect of phytochemical-filled microcapsules with antifungal activity on material properties and dimensional accuracy of denture base resin for three-dimensional printing
Authors: Jeon Sol , Jo Ye-Hyeon , Yoon Hyung-In , Han Jung-Suk
Published: May 2022

Background

Studies on the material properties and dimensional accuracy of three-dimensionally (3D) printed denture base containing microcapsules with antifungal phytochemicals are lacking.

Methods

Two types of phytochemicals (phytoncide A and B) with antifungal activity were microencapsulated. The 3D-printed denture base specimens with minimum and maximum effective concentrations of microcapsules (6 and 8 wt% for phytoncide A; 15 and 25 wt% for phytoncide B) were prepared. The morphological changes ofC. albicanson 3D-printed denture base with microcapsules was microscopically observed. The degree of conversion of 3D-printed denture base with microcapsules investigated. The microhardness and flexural strength values were also measured to evaluate the mechanical properties of 3D-printed denture bases. The dimensional accuracy (trueness) of the specimens with microcapsules was measured as root-mean-square values (RMS) for the whole, upper, and side surfaces of the specimens as well as their total height. For the degree of conversion, microhardness, and flexural strength values, the Kruskal–Wallis analysis and a post-hoc comparison using Mann–Whitney U test was performed. For the analysis of trueness (RMS), the one-way analysis of variance and a post-hoc comparison using Tukey’s method was conducted (α = 0.05).

Results

At both maximum and minimum effective concentrations of microcapsules, cell surface disruption or membrane breakdown of fungal cells were observed in the specimens. The groups with microcapsules (both phytoncide A- and B-filled) showed significantly lower microhardness and elastic modulus values than the control group (all, P = 0.001). For the trueness, all the RMS values of the whole, upper, and side surfaces of the specimens with microcapsules were less than 100 µm, although significantly higher than those without (all, P = 0.001). The mean flexural strength values of the groups with phytoncide A-filled microcapsule were higher than 65 MPa, not statistically different from that of the control group (all, P > 0.05). However, the groups with phytoncide B-filled microcapsules showed significantly lower values than the control (all, P = 0.001).

Conclusions

Within the limitations of this in-vitro study, the 3D-printed denture base containing 6 wt% of phytoncide A-filled microcapsules was clinically acceptable in terms of antifungal activity, dimensional accuracy, and flexural strength.
A social network intervention to improve connectivity and burnout among psychiatry residents in an academic institution: a quasi-experimental study
Authors: Aghaei Ardavan Mohammad , Sharifi Vandad , Tabatabaee Maryam , Abdi-Masouleh Fattaneh , Nooraie Reza Yousefi
Published: May 2022

Background

Burnout is common among residents, which could be associated with their professional network characteristics. This study aimed to assess the social networks of psychiatry residents and develop an intervention to improve their network characteristics, burnout, and perception of the educational environment.

Methods

We recruited a cohort of 17 PGY-2 residents and assessed their social networks, burnout, and perception of the educational environment. After the baseline survey, we held a focus group with PGY-2 residents to discuss the results, their network characteristics, and interventions that can improve their relationships. The PGY-2 residents indicated that offering extracurricular opportunities to facilitate friendly interactions among the residents and faculty members would be the most feasible and acceptable intervention. Therefore, four “interest groups” for extracurricular activities were established. Residents and faculty members were invited to participate in interest groups to improve the network characteristics. Some PGY-2 residents and faculty members agreed to moderate interest group sessions (active members).

Results

After the intervention, active residents improved significantly in the perceived personal accomplishment subscale of the burnout inventory and their perception of the educational environment. Active faculty members also had a significant increase in their relationships with PGY-2 residents in one domain of social networks.

Conclusions

Enhancing relationships between residents and faculty members through participatory intervention and extracurricular activities can improve faculty-resident connectivity and residents’ perception of personal accomplishment and educational environment quality.
The development of a patient decision aid to reduce decisional conflict about antidepressant use in pregnancy
Authors: Hussain-Shamsy Neesha , Somerton Sarah , Stewart Donna E. , Grigoriadis Sophie , Metcalfe Kelly , Oberlander Tim F. , Schram Carrie , Taylor Valerie H. , Dennis Cindy-Lee , Vigod Simone N.
Published: May 2022

Background

People with moderate to severe depression in pregnancy must weigh potential risks of untreated or incompletely treated depression against the small, but uncertain risks of fetal antidepressant drug exposure. Clinical support alone appears insufficient for helping individuals with this complex decision. A patient decision aid (PDA) has the potential to be a useful tool for this population. The objective of our work was to use internationally recognized guidelines from the International Patient Decision Aids Standards Collaboration to develop an evidence-based PDA for antidepressant use in pregnancy.

Methods

A three-phased development process was used whereby, informed by patient and physician perspectives and evidence synthesis, a steering committee commissioned a web-based PDA for those deciding whether or not to start or continue antidepressant treatment for depression in pregnancy (Phase 1). A prototype was developed (Phase 2) and iteratively revised based on feedback during field testing based on a user-centred process (Phase 3).

Results

We developed a web-based PDA for people deciding whether to start or continue antidepressant use for depression in pregnancy. It has five interactive sections: (1) information on depression and treatment; (2) reasons to start/continue an antidepressant and to start/stop antidepressant medication; (3) user assessment of values regarding each issue; (4) opportunity to reflect on factors that contribute to decision making; and (5) a printable PDF that summarizes the user’s journey through the PDA.

Conclusions

This tool, which exclusively focuses on depression treatment with Selective Serotonin Reuptake Inhibitors and Serotonin–Norepinephrine Reuptake Inhibitors, can be used by individuals making decisions about antidepressant use to treat depression during pregnancy. Limitations of the PDA are that it is not for other conditions, nor other medications that can be used for depression, and in its pilot form cannot be used by women who do not speak English or who have a visual impairment. Pending further study, it has the potential to enhance quality of care and patient experience.
Barriers and facilitators to implementing a continuing medical education intervention in a primary health care setting
Authors: Reis Teresa , Faria Inês , Serra Helena , Xavier Miguel
Published: May 2022

Background

Continuing medical education (CME), as a systematic attempt to facilitate change in General Practitioners’ (GPs) practices, is considered crucial, assuming that if physicians are up-to-date, they will change and improve their practice, resulting in better performance and ultimately better patient care. However, studies continue to demonstrate considerable gaps between the real and ideal performance and patient-related outcomes. The objective of this study was to explore GP’s perception of the factors affecting the implementation of a CME digital platform in a primary health care setting in Portugal.

Methods

Our work is framed in a larger effectiveness-implementation hybrid type 1 study, where a Digital Behaviour Change Intervention (DBCI), called ePrimaPrescribe, was developed and implemented with the aim of changing benzodiazepines (BZD) prescribing patterns. Our design used mixed methodologies to obtain an enriched knowledge on GPs’ perspectives on the facilitators and barriers to implementing a Digital Behaviour Change Intervention (DBCI) applied to CME. To do so, we used data coming from an onsite questionnaire, an adapted version of the Barriers and Facilitators Assessment Instrument (BaFAI) and in-depth interviews.

Results

From the 47 GPs successfully included in the intervention arm of our cluster-randomized effectiveness study, we collected 37 onsite questionnaires, 24 BaFAIs, and performed 12 in-depth interviews. GPs reported as the main barriers to CME a lack of time, a perception of work overload, a lack of digital competence, a lack of digital infrastructure, and motivational and emotional factors. They reported as facilitators to CME delivered through a DBCI the convenience of the delivery method, the practical and pragmatic characteristics of the content, and the possibility for CME to be mandatory.

Conclusions

The perceptions of the barriers and facilitators reported by GPs represent an important contribution to improving knowledge regarding the factors influencing the implementation of CME in primary health care settings. We consider that our study might bring useful insights to other countries where primary health care plays a central role in the provision of care.

Trial registration

ClinicalTrials.gov number NCT04925596.
Opsin1 regulates light-evoked avoidance behavior in Aedes albopictus
Authors: Liu Xinyi , Yang Shuzhen , Yao Yuan , Wu Si , Wu Pa , Zhai Zongzhao
Published: May 2022

Background

Mosquitoes locate a human host by integrating various sensory cues including odor, thermo, and vision. However, their innate light preference and its genetic basis that may predict the spatial distribution of mosquitoes, a prerequisite to encounter a potential host and initiate host-seeking behaviors, remains elusive.

Results

Here, we first studied mosquito visual features and surprisingly uncovered that both diurnal (Aedes aegypti and Aedes albopictus) and nocturnal (Culex quinquefasciatus) mosquitoes significantly avoided stronger light when given choices. With consistent results from multiple assays, we found that such negative phototaxis maintained throughout development to adult stages. Notably, female mosquitoes significantly preferred to bite hosts in a shaded versus illuminated area. Furthermore, silencing Opsin1, a G protein-coupled receptor that is most enriched in compound eyes, abolished light-evoked avoidance behavior of Aedes albopictus and attenuated photonegative behavior in Aedes aegypti. Finally, we found that field-collected Aedes albopictus also prefers darker area in an Opsin1-dependent manner.

Conclusions

This study reveals that mosquitoes consistently prefer darker environment and identifies the first example of a visual molecule that modulates mosquito photobehavior.
Sucking and drinking behaviour in preweaned dairy calves in the first five weeks of life
Authors: Braun Ueli , Kochan Manon , Kaske Martin , Gerspach Christian , Bleul Ulrich
Published: May 2022

Background

Nursing and sucking are essential for adequate nourishment of preweaned calves and the relationship between sucking indices has not been studied. The goal of this study was to investigate the number of sucks per litre of milk and per minute of drinking and the amount of milk ingested per suck in healthy preweaned calves. Correlation coefficients were calculated for the relationships between these variables. Eighteen healthy calves were used from birth to 5 weeks of age, and five measurements were made at the end of weeks 1 to 5. The calves were randomly divided into three groups and offered milk twice daily in a bucket with a rubber nipple. The amount of milk offered per day was equal to 12% of body weight in group A and 16% of body weight in group B. Calves in group C were offered as much milk as they wanted during each feeding period. The duration of drinking was determined with a stopwatch, and the number of sucks was counted with a handheld tally counter. The variables drinking duration, total amount consumed and the number of sucks required were used to calculate the number of sucks/min, the number of sucks/L, the amount ingested per suck and drinking speed.

Results

The number of sucks/min ranged from 113 to 133 and increased significantly during the study period. The mean number of sucks/L decreased from 204 in week 1 to 141 in week 5 and drinking speed increased from 0.6 to 1.0 L/min. There were significant correlations between the number of sucks/L of milk and the amount of milk ingested per suck, drinking duration, total amount consumed and drinking speed. Drinking speed was positively correlated with the amount of milk ingested per suck and the total amount of milk consumed, and negatively correlated with drinking duration.

Conclusions

These findings show that drinking variables of calves offered different amounts of milk vary little and significant changes occur during the same period with respect to the number of sucks/L of milk and the amount of milk ingested per suck. Several drinking variables are significantly correlated with other variables.
Construction of an immune-related lncRNA signature pair for predicting oncologic outcomes and the sensitivity of immunosuppressor in treatment of lung adenocarcinoma
Authors: Zhuang Jinman , Chen Zhongwu , Chen Zishan , Chen Jin , Liu Maolin , Xu Xinying , Liu Yuhang , Yang Shuyan , Hu Zhijian , He Fei
Published: May 2022

Background

Although immunotherapy has shown clinical activity in lung adenocarcinoma (LUAD), LUAD prognosis has been a perplexing problem. We aimed to construct an immune-related lncRNA pairs (IRLPs) score for LUAD and identify what immunosuppressor are appropriate for which group of people with LUAD.

Methods

Based on The Cancer Genome Atlas (TCGA)-LUAD cohort, IRLPs were identified to construct an IRLPs scoring system by Cox regression and validated in the Gene Expression Omnibus (GEO) dataset using log-rank test and the receiver operating characteristic curve (ROC). Next, we used spearman’s correlation analysis, t-test, signaling pathways analysis and gene mutation analysis to explore immune and molecular characteristics in different IRLP subgroups. The “pRRophetic” package was used to predict the sensitivity of immunosuppressant.

Results

The IRLPs score was constructed based on eight IRLPs calculated as 2.12 × (MIR31HG|RRN3P2) + 0.43 × (NKX2-1-AS1|AC083949.1) + 1.79 × (TMPO-AS1|LPP-AS2) + 1.60 × (TMPO-AS1|MGC32805) + 1.79 × (TMPO-AS1|PINK1-AS) + 0.65 × (SH3BP5-AS1|LINC01137) + 0.51 × (LINC01004|SH3PXD2A-AS1) + 0.62 × (LINC00339|AGAP2-AS1). Patients with a lower IRLPs risk score had a better overall survival (OS) (Log-rank test PTCGA train dataset < 0.001, PTCGA test dataset = 0.017, PGEO dataset = 0.027) and similar results were observed in the AUCs of TCGA dataset and GEO dataset (AUC TCGA train dataset = 0.777, AUC TCGA test dataset = 0.685, AUC TCGA total dataset = 0.733, AUC GEO dataset = 0.680). Immune score (Cor = -0.18893, P < 0.001), stoma score (Cor = -0.24804, P < 0.001), and microenvironment score (Cor = -0.22338, P < 0.001) were significantly decreased in the patients with the higher IRLP risk score. The gene set enrichment analysis found that high-risk group enriched in molecular changes in DNA and chromosomes signaling pathways, and in this group the tumor mutation burden (TMB) was higher than in the low-risk group (P = 0.0015). Immunosuppressor methotrexate sensitivity was higher in the high-risk group (P = 0.0052), whereas parthenolide (P < 0.001) and rapamycin (P = 0.013) sensitivity were lower in the high-risk group.

Conclusions

Our study established an IRLPs scoring system as a biomarker to help in the prognosis, the identification of molecular and immune characteristics, and the patient-tailored selection of the most suitable immunosuppressor for LUAD therapy.
Extracellular vesicles from the inflammatory microenvironment regulate the osteogenic and odontogenic differentiation of periodontal ligament stem cells by miR-758-5p/LMBR1/BMP2/4 axis
Authors: Yan Chaoting , Li Na , Xiao Tong , Ye Xiaying , Fu Lin , Ye Yu , Xu Tao , Yu Jinhua
Published: May 2022

Background

Extracellular vesicles (EVs) play a key role in constructing a microenvironment that favors the differentiation of stem cells. The present work aimed to determine the molecular mechanisms by which EV derived from inflammatory dental pulp stem cell (iDPSC-EV) influence periodontal ligament stem cells (PDLSCs) and provide a potential strategy for bone and dental pulp regeneration.

Methods

The osteogenic and odontogenic differentiation was assessed by quantitative real-time polymerase chain reaction (qRT-PCR), western blot, alkaline phosphatase (ALP) activity assay, ALP staining, alizarin red S (ARS) staining, and immunofluorescence staining. To detect proliferation, the Cell Counting Kit-8 (CCK-8) assay, and flow cytometry analysis were used. EVs were isolated by the Exoperfect kit and ultrafiltration and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blot. The expression profile of miRNAs in EVs was studied using miRNA sequence and bioinformatics, and one of the upregulated miRNAs was evaluated on PDLSCs.

Results

The inflammatory microenvironment stimulated osteogenic and odontogenic differentiation of DPSCs and iDPSC-EV behaved alike on PDLSCs. MiR-758-5p was upregulated in iDPSC-EV and was demonstrated to play a significant role in the osteogenic and odontogenic commitment of PDLSCs. A dual-luciferase reporter assay confirmed the binding site between miR-758-5p and limb development membrane protein 1 (LMBR1). The knockdown of LMBR1 also enhanced the above potential. Mechanically, bone morphogenetic protein (BMP) signaling was activated.

Conclusions

EVs from the inflammatory microenvironment enhanced the osteogenic and odontogenic differentiation of PDLSCs partly by shuttering LMBR1-targeting miR-758-5p via BMP signaling.
Identification of mutation patterns and circulating tumour DNA-derived prognostic markers in advanced breast cancer patients
Authors: Liao Hao , Zhang Jiayang , Zheng Tiantian , Liu Xiaoran , Zhong Jianxin , Shao Bin , Dong Xiaoxi , Wang Xiaohong , Du Pan , King Bonnie L. , Jia Shidong , Yu Jianjun , Li Huiping
Published: May 2022

Background

The correlations between circulating tumour DNA (ctDNA)-derived genomic markers and treatment response and survival outcome in Chinese patients with advanced breast cancer (ABC) have not been extensively characterized.

Methods

Blood samples from 141 ABC patients who underwent first-line standard treatment in Peking University Cancer Hospital were collected. A next-generation sequencing based liquid biopsy assay (PredicineCARE) was used to detect somatic mutations and copy number variations (CNVs) in ctDNA. A subset of matched blood samples and tumour tissue biopsies were compared to evaluate the concordance.

Results

Overall, TP53 (44.0%) and PIK3CA (28.4%) were the top two altered genes. Frequent CNVs included amplifications of ERBB2 (24.8%) and FGFR1 (8.5%) and deletions of CDKN2A (3.5%). PIK3CA/TP53 and FGFR1/2/3 variants were associated with drug resistance in hormone receptor-positive (HR +) and human epidermal growth factor receptor 2-positive (HER2 +) patients. The comparison of genomic variants across matched tumour tissue and ctDNA samples revealed a moderate to high concordance that was gene dependent. Triple-negative breast cancer (TNBC) patients harbouring TP53 or PIK3CA alterations had a shorter overall survival than those without corresponding mutations (P = 0.03 and 0.008). A high ctDNA fraction was correlated with a shorter progression-free survival (PFS) (P = 0.005) in TNBC patients. High blood-based tumor mutation burden (bTMB) was associated with a shorter PFS for HER2 + and TNBC patients (P = 0.009 and 0.05). Moreover, disease monitoring revealed several acquired genomic variants such as ESR1 mutations, CDKN2A deletions, and FGFR1 amplifications.

Conclusions

This study revealed the molecular profiles of Chinese patients with ABC and the clinical validity of ctDNA-derived markers, including the ctDNA fraction and bTMB, for predicting treatment response, prognosis, and disease progression.

Trial registration: ClinicalTrials.gov ID: NCT03792529. Registered January 3rd 2019,https://clinicaltrials.gov/ct2/show/NCT03792529.
Z-DNA binding protein 1 mediates necroptotic and apoptotic cell death pathways in murine astrocytes following herpes simplex virus-1 infection
Authors: Jeffries Austin M. , Suptela Alexander J. , Marriott Ian
Published: May 2022

Background

The mechanisms by which glia respond to viral central nervous system (CNS) pathogens are now becoming apparent with the demonstration that microglia and astrocytes express an array of pattern recognition receptors that include intracellular RNA and DNA sensors. We have previously demonstrated that glia express Z-DNA binding protein 1 (ZBP1) and showed that this cytosolic nucleic acid sensor contributes to the inflammatory/neurotoxic responses of these cells to herpes simplex virus-1 (HSV-1). However, the relative contribution made by ZBP1- to HSV-1-mediated cell death in glia has not been determined.

Methods

We have investigated the relative contribution made by ZBP1- to HSV-1-mediated cell death in primary astrocytes derived from mice genetically deficient in this sensor. We have used capture ELISAs and immunoblot analysis to assess inflammatory cytokine production and ZBP1 and phosphorylated mixed lineage kinase domain-like protein (MLKL) expression levels, respectively, following HSV-1 challenge. Furthermore, we have used a commercially available cell viability assay to determine the proportion and rate of cell death in cells following infection with laboratory and neuroinvasive clinical strains of HSV-1, and pharmacological inhibitors of necroptotic and apoptotic pathway components to assess the relative role of each.

Results

We show that the loss of ZBP1 in astrocytes results in an increase in the number of viral particles released following HSV-1 infection. Importantly, we have confirmed that HSV-1 induces necroptosis in astrocytes and have established the ability of ZBP1 to mediate this cell death pathway. Interestingly, while ZBP1 is best known for its role in necroptotic signaling, our findings indicate that this sensor can also contribute to virally induced apoptosis in these glia.

Conclusions

Our findings indicate that ZBP1 serves as a restriction factor for HSV-1 infection and is associated with the induction of both necroptotic and apoptotic cell death pathways in primary murine astrocytes. While it remains to be seen whether ZBP1-mediated activation of cell death in astrocytes contributes significantly to host protection or, rather, exacerbates HSV-1 encephalitis pathology, the identification of such a role in resident CNS cells may represent a novel target for therapeutic intervention to reduce HSV encephalitis-associated morbidity and mortality.
The correlation between cutout and eccentric distance (ED) of the cephalic fixator tip in geriatric intertrochanteric fractures with internal fixation
Authors: Yang Yun-fa , Huang Jian-wen , Gao Xiao-sheng , Xu Zhong-he
Published: May 2022

Background

The location of cephalic fixator tip with different eccentric distance (ED) should have different risks of cutout. This study aims to evaluate the cephalic fixator tip position by measuring ED of the cephalic fixator tip in geriatric ITF patients with single-screw cephalomedullary nail (SCMN) fixation and analyze the correlation between the cutout and the ED.

Methods

Firstly, we assumed all the femoral head was a regular sphere and standardized the radius of the femoral head (RFD) as “3” no matter how big the RFD was for complete match of the Cleveland zone system and convenient identification of artificial intelligence. Secondly, we measured the ED of the cephalic fixator tip by calculating the distances from the cephalic fixator tip to the geometric central axis of the femoral neck and head on both AP view and lateral view radiographs. Thirdly, we evaluated all the ED of the cephalic fixator tip in the eligible 123 geriatric ITF patients and analyzed the correlation between the cutout and the ED.

Results

The ED in cutout group (1.25 ± 0.43) is much bigger than that in non-cutout group (0.64 ± 0.34) with significant difference (OR = 50.01, 95% CI 8.42–297.19, p < 0.001). The probability of cutout increased with ED increasing, especially when “ED ≥ 1.” The best cutoff value of ED for predicting cutout was “1.022” (“1.022” was just a little bit more than 1/3 times of RFD because “RFD = 3,” sensitivity = 73.3%, specificity = 86.1%, and AUC = 0.867, p < 0.001).

Conclusion

ED is suitable for evaluation of the cephalic fixator tip position for predicting cutout in geriatric ITF patients with SCMN fixation, and ED can potentially be used as artificial intelligence application during surgery. The smaller the ED, the lower the cutout rate. For avoiding cutout, the ED of the cephalic fixator tip should be less than one-third times of the radius of the femoral head.
Microdeletions in 1q21 and 8q12.1 depict two additional molecular subgroups of Silver-Russell syndrome like phenotypes
Authors: Baba Naomi , Lengyel Anna , Pinti Eva , Yapici Elzem , Schreyer Isolde , Liehr Thomas , Fekete György , Eggermann Thomas
Published: May 2022

Background

Silver-Russell syndrome (SRS) is a genetic disorder characterized by intrauterine and postnatal growth restriction, relative macrocephaly at birth, body asymmetry and typical facial features. Clinical and molecular heterogeneity is described in SRS. Common causes are loss of methylation of the imprinting center 1 in 11p15 and maternal uniparental disomy of chromosome 7. Other genetic alterations include disturbances of imprinted regions in 14q32, 7q32 and 11p15 as well as submicroscopic deletions and duplications. Single nucleotide variants in genes like IGF2, HMGA2, PLAG1, CDKN1C have also been identified in patients with SRS phenotypes. However, routine molecular diagnostics usually focus on 11p15 and chromosome 7, while less frequent causes are not systematically addressed.

Results

Here we report two patients with SRS features in which molecular karyotyping revealed microdeletions in 1q21 and 8q12.1 respectively. In a 3.5-year-old girl with postnatal growth restriction, feeding difficulties, relative macrocephaly and distinct SRS features a 2 Mb deletion in 1q21.1q21.2 was identified. Our second case is a 1.5-year-old boy with intrauterine and postnatal growth restriction, feeding difficulties and distinct facial features with a 77 kb deletion in 8q12.1 affecting PLAG1 as the only protein-encoding gene with known function.

Conclusions

The 1q21 region has not yet been assigned as an SRS region, although six patients with the same deletion and SRS features including relative macrocephaly have been described before. This new case adds to the evidence that distal 1q21 should be annotated as an SRS candidate region. The PLAGL1 alteration is the smallest deletion in 8q12.1 ever reported in a patient with SRS phenotype and it finally confirms that PLAG1 is the SRS causing gene in 8q12.1. To increase the diagnostic yield in patients with suspected SRS, we recommend both molecular karyotyping and next generation sequencing-based approaches.
Molecular profiling and clinical implications of patients with acute myeloid leukemia and extramedullary manifestations
Authors: Eckardt Jan-Niklas , Stölzel Friedrich , Kunadt Desiree , Röllig Christoph , Stasik Sebastian , Wagenführ Lisa , Jöhrens Korinna , Kuithan Friederike , Krämer Alwin , Scholl Sebastian , Hochhaus Andreas , Crysandt Martina , Brümmendorf Tim H. , Naumann Ralph , Steffen Björn , Kunzmann Volker , Einsele Hermann , Schaich Markus , Burchert Andreas , Neubauer Andreas , Schäfer-Eckart Kerstin , Schliemann Christoph , Krause Stefan W. , Herbst Regina , Hänel Mathias , Hanoun Maher , Kaiser Ulrich , Kaufmann Martin , Rácil Zdenek , Mayer Jiri , Kroschinsky Frank , Berdel Wolfgang E. , Ehninger Gerhard , Serve Hubert , Müller-Tidow Carsten , Platzbecker Uwe , Baldus Claudia D. , Schetelig Johannes , Bornhäuser Martin , Thiede Christian , Middeke Jan Moritz
Published: May 2022

Background

Extramedullary manifestations (EM) are rare in acute myeloid leukemia (AML) and their impact on clinical outcomes is controversially discussed.

Methods

We retrospectively analyzed a large multi-center cohort of 1583 newly diagnosed AML patients, of whom 225 (14.21%) had EM.

Results

AML patients with EM presented with significantly higher counts of white blood cells (p < 0.0001), peripheral blood blasts (p < 0.0001), bone marrow blasts (p = 0.019), and LDH (p < 0.0001). Regarding molecular genetics, EM AML was associated with mutations of NPM1 (OR: 1.66, p < 0.001), FLT3-ITD (OR: 1.72, p < 0.001) and PTPN11 (OR: 2.46, p < 0.001). With regard to clinical outcomes, EM AML patients were less likely to achieve complete remissions (OR: 0.62, p = 0.004), and had a higher early death rate (OR: 2.23, p = 0.003). Multivariable analysis revealed EM as an independent risk factor for reduced overall survival (hazard ratio [HR]: 1.43, p < 0.001), however, for patients who received allogeneic hematopoietic cell transplantation (HCT) survival did not differ. For patients bearing EM AML, multivariable analysis unveiled mutated TP53 and IKZF1 as independent risk factors for reduced event-free (HR: 4.45, p < 0.001, and HR: 2.05, p = 0.044, respectively) and overall survival (HR: 2.48, p = 0.026, and HR: 2.63, p = 0.008, respectively).

Conclusion

Our analysis represents one of the largest cohorts of EM AML and establishes key molecular markers linked to EM, providing new evidence that EM is associated with adverse risk in AML and may warrant allogeneic HCT in eligible patients with EM.
DNA methylation may affect beef tenderness through signal transduction in Bos indicus
Authors: de Souza Marcela Maria , Niciura Simone Cristina Méo , Rocha Marina Ibelli Pereira , Pan Zhangyuan , Zhou Huaijun , Bruscadin Jennifer Jessica , da Silva Diniz Wellison Jarles , Afonso Juliana , de Oliveira Priscila Silva Neubern , Mourão Gerson B. , Zerlotini Adhemar , Coutinho Luiz Lehmann , Koltes James E. , de Almeida Regitano Luciana Correia
Published: May 2022

Background

Beef tenderness is a complex trait of economic importance for the beef industry. Understanding the epigenetic mechanisms underlying this trait may help improve the accuracy of breeding programs. However, little is known about epigenetic effects on Bos taurus muscle and their implications in tenderness, and no studies have been conducted in Bos indicus.

Results

Comparing methylation profile of Bos indicus skeletal muscle with contrasting beef tenderness at 14 days after slaughter, we identified differentially methylated cytosines and regions associated with this trait. Interestingly, muscle that became tender beef had higher levels of hypermethylation compared to the tough group. Enrichment analysis of predicted target genes suggested that differences in methylation between tender and tough beef may affect signal transduction pathways, among which G protein signaling was a key pathway. In addition, different methylation levels were found associated with expression levels of GNAS, PDE4B, EPCAM and EBF3 genes. The differentially methylated elements correlated with EBF3 and GNAS genes overlapped CpG islands and regulatory elements. GNAS, a complex imprinted gene, has a key role on G protein signaling pathways. Moreover, both G protein signaling pathway and the EBF3 gene regulate muscle homeostasis, relaxation, and muscle cell-specificity.

Conclusions

We present differentially methylated loci that may be of interest to decipher the epigenetic mechanisms affecting tenderness. Supported by the previous knowledge about regulatory elements and gene function, the methylation data suggests EBF3 and GNAS as potential candidate genes and G protein signaling as potential candidate pathway associated with beef tenderness via methylation.
Effect of legumes in energy reduced dietary approaches to stop hypertension (DASH) diet on blood pressure among overweight and obese type 2 diabetic patients: a randomized controlled trial
Authors: Hosseinpour-Niazi Somayeh , Hadaegh Farzad , Mirmiran Parvin , Daneshpour Maryam S. , Mahdavi Maryam , Azizi Fereidoun
Published: May 2022

Background

This study aimed to investigate the effects of legumes in dietary approaches to stop hypertension (DASH) on blood pressure and urinary sodium and potassium in participants with type 2 diabetes. We further investigated whether changes in individual dietary food groups in the DASH diet contribute to blood pressure.

Methods

Participants were randomized to the traditional DASH diet (n = 150) or the legume-based DASH diet (n = 150). Blood pressure and urinary sodium and potassium were measured at baseline and after 16-week interventions. An intention-to-treat approach with multiple imputations of missing data was applied. The restricted cubic spline (RCS) was applied to assess the linearity and explore the shape of the relationship between the changes in food groups and systolic blood pressure (SBP) in the two intervention groups.

Results

A reduction in SBP and urinary sodium was observed at week 16 in both dietary interventions, and this reduction was more significant in the legume-based DASH diet, than in the DASH diet. In the legume-based DASH diet, SBP decreased with the legume intake of more than 95.8 g/day (Pnonlinear < 0.001). The multivariable RCS analysis showed a U-shaped relationship of refined grains, an L-shaped relationship of fruits, and a linear relationship of sweet, energy, sodium and vegetables intake with SBP.

Conclusions

The DASH diet, enriched in legumes, could improve SBP in participants with type 2 diabetes. In DASH diet, the balance of consumption of refined grains and fruits along with higher vegetable consumption and lower sweet, sodium and energy intake reduced the SBP.

Trial registration:IRCT20090203001640N17.
Influence of combined action observation and motor imagery of walking on lower limb reflex modulation in patients after stroke–preliminary results
Authors: Behrendt Frank , Le-Minh Monika , Schuster-Amft Corina
Published: May 2022

Objective

The combined use of action observation and motor imagery (AOMI) is a promising technique in neurorehabilitation that can be usefully applied in addition to conventional forms of therapy. Previous studies with healthy participants showed that the mere passive observation of walking results in a phase-dependent reflex modulation in the tibialis anterior muscle that resembles the pattern occurring when walking. In patients after stroke, a similar reflex modulation was found in several lower limb muscles during the real execution of walking, but responses were blunted. To clarify whether and how lower limb reflex responses are also modulated in such patients during the combined synchronous observation and imagery of walking, medium-latency cutaneous reflexes from the tibialis anterior muscle were measured. We compared the reflex responses of seven patients after stroke during the AOMI of walking from two different conditions: (a) elicited during the end stance phase and (b) during the end swing phase, both normalized to a baseline condition.

Results

So far, using the identical methodological set-up as in our study with healthy individuals, we could not find any noteworthy reflex response modulation. The study was registered with the German Clinical Trials Register (DRKS00028255).

Trial registration : The study was registered with the German Clinical Trials Register: DRKS00028255.
Identifying potential regulators of JAGGED1 expression in portal mesenchymal cells
Authors: Nishino Teppei , Yoshihara Masaharu , Nakayama Takahiro , Tsuchiya Takaho , Tahara Saeko , Ozaki Haruka , Takahashi Satoru
Published: May 2022

Objective

Portal mesenchymal cells induce the epithelial differentiation of the bile ducts in the developing liver via one of the Delta-Notch signaling components, JAGGED1. Although this differential induction is crucial for normal liver physiology as its genetic disorder (Alagille syndrome) causes jaundice, the molecular mechanism behind JAGGED1 expression remains unknown. Here, we searched for upstream regulatory transcription factors of JAGGED1 using an integrated bioinformatics method.

Results

According to the DoRothEA database, which integrates multiple lines of evidence on the relationship between transcription factors and their downstream target genes, three transcription factors were predicted to be upstream of JAGGED1: SLUG, SOX2, and EGR1. Among these, SLUG and EGR1 were enriched in ACTA2-expressing portal mesenchymal cells in two previously reported human fetal liver single-cell RNA-seq datasets. JAGGED1-expressing portal mesenchymal cells tended to express SLUG rather than EGR1, supporting that SLUG induced JAGGED1 expression. Together with the higher confidentiality of SLUG (DoRothEA level A) over EGR1 (DoRothEA level D), we concluded that SLUG was one of the most important candidate transcription factors upstream of JAGGED1. These results add mechanistic insights into the developmental biology of how portal mesenchymal cells support biliary development in the liver.
Biomimetic hydrogel scaffolds via enzymatic reaction for cartilage tissue engineering
Authors: Khanmohammadi Mehdi , Jalessi Maryam , Asghari Alimohamad
Published: May 2022

Objective

We aimed to evaluate cytocompatibility of hyaluronic acid (HA) and gelatin (Gela) conjugation with phenolic groups (Phs) via enzyme-mediated crosslinking. Phenolic moieties were substituted on the backbone of HA (HA-Ph) and Gela (Gela-Ph) and subsequently were subjected for horseradish peroxidase crosslinking in the presence of H2O2 as an electron donor to create a stable hybrid microenvironment for cellular behavior and cartilage tissue engineering.

Results

Successful synthesis of biopolymers confirmed by NRM and UV–Vis spectrophotometry. The physical characteristic of hydrogels including mechanical properties and water contact angle of hydrogels enhanced with addition of Gela-Ph in HA-based hydrogel. The Gela-Ph showed longest gelation time and highest degradation rate. The cellular studies showed cells did not attach to HA-Ph hydrogel. While, proper cell attachment and proliferation observed on blend hydrogel surface compared with the neat hydrogels which interpret by the existence of cell-adhesive motifs of utilized Gela-Ph in this hydrogel. The encapsulated cells in HA-Ph hydrogel were spheroid and just maintained their viability. Hydrogels containing Gela-Ph, the cells were spindle shape with high degrees of cytoplasmic extension. Overall, the results suggest that hybrid biomimetic hydrogel can provide a superior biological microenvironment for chondrocytes in 3D cartilage tissue engineering.
Effects of environmental enrichment and sexual dimorphism on the expression of cerebellar receptors in C57BL/6 and BTBR + Itpr3tf/J mice
Authors: Monje-Reyna Daniela , Manzo Denes Jorge , Santamaria Fidel
Published: May 2022

Objective

Environmental enrichment is used to treat social, communication, and behavioral deficits and is known to modify the expression of synaptic receptors. We compared the effects of environmental enrichment in the expression of glutamate and endocannabinoid receptors, which are widely expressed in the cerebellar cortex. These two receptors interact to regulate neuronal function and their dysregulation is associated with behavioral changes. We used BTBR + Itpr3tf/J mice, a strain that models behavioral disorders, and C57BL/6 mice for comparison. We studied the effects of genetic background, sex, environmental conditions, and layer of the cerebellar cortex on the expression of each receptor.

Results

The influence of genetic background and environmental enrichment had the same pattern on glutamate and endocannabinoid receptors in males. In contrast, in females, the effect of environmental enrichment and genetic background were different than the ones obtained for males and were also different between the glutamate and endocannabinoid receptors. Furthermore, an analysis of both receptors from tissue obtained from the same animals show that their expression is correlated in males, but not in females. Our results suggest that environmental enrichment has a receptor dependent and sexual dimorphic effect on the molecular expression of different receptors in the cerebellar cortex.
Retinoic acid regulates the ubiquitin–proteasome system in a middle cerebral artery occlusion animal model
Authors: Kang Ju-Bin , Shah Murad-Ali , Park Dong-Ju , Koh Phil-Ok
Published: May 2022

Background

Retinoic acid is a major metabolite of vitamin A and exerts beneficial effects including anti-oxidant and anti-inflammatory activities in neurons. The ubiquitin–proteasome system is an important biological system that regulates cell survival. Ubiquitination regulates protein degradation and plays an important role in oxidative stress. Deubiquitinating enzymes cleave ubiquitin from proteins and control ubiquitination-induced degradation. We detected decreases in ubiquitin carboxy-terminal hydrolase L1, ubiquitin thioesterase OTUB1, and proteasome subunit alpha types 1 and 3 in cerebral ischemic damage. In this study, we investigated whether retinoic acid regulates the expression of deubiquitinating enzymes ubiquitin carboxy-terminal hydrolase L1, ubiquitin thioesterase OTUB1, and proteasome subunit alpha types 1 and 3 in cerebral ischemic injury. Right middle cerebral artery occlusion (MCAO) was performed to induce cerebral ischemic damage in male rats. Retinoic acid (5 mg/kg) or vehicle was intraperitoneally injected every day from 4 days before surgery. Neurological behavioral tests were performed 24 h after MCAO, and right cerebral cortical tissues were collected.

Results

MCAO damage caused neurological behavioral dysfunction, and retinoic acid alleviated these deficits. The identified proteins decreased in MCAO animals with vehicle, while retinoic acid treatment attenuated these decreases. The results of proteomic study were confirmed by a reverse transcription-PCR technique. Expressions of ubiquitin carboxy-terminal hydrolase L1, ubiquitin thioesterase OTUB1, and proteasome subunit alpha types 1 and 3 were decreased in MCAO animals treated with vehicle. Retinoic acid treatment alleviated these MCAO-induced reductions. The ubiquitin–proteasome system plays an essential role in maintaining cell function and preserving cell shape against ischemic damage.

Conclusions

These findings suggest that retinoic acid regulates ubiquitin- and proteasome-related proteins including ubiquitin carboxy-terminal hydrolase L1, ubiquitin thioesterase OTUB1, and proteasome subunit alpha types 1 and 3 in a brain ischemia model. Changes in these proteins are involved in the neuroprotective effects of retinoic acid.
Natriuretic peptides in elderly patients with chronic obstructive pulmonary disease
Authors: Nicolae Bodrug , Ecaterina Luca
Published: May 2022

Background

Natriuretic peptides (NPs) are considered a useful tool for diagnosing the cardiac or pulmonary origin of acute dyspnea in the emergency department. The aim of this study was to evaluate NP in elderly patients with chronic obstructive pulmonary disease (COPD).

Materials and methods

In the PubMed and Hinari databases, we identified 465 comprehensive articles in English, published in the years 1990–2021, which provided information on natriuretic peptides in elderly patients with COPD. The final bibliography contains 49 relevant sources.

Results

NP, specially BNP/NT-proBNP values are frequently elevated in patients with COPD, reflecting three complex aspects of the interrelated cardio-pulmonary continuum: (1) left ventricular systolic and diastolic dysfunction, (2) pulmonary vascular and right heart remodeling, (3) global cardiovascular risk and comorbidities. The additional increase in BNP/NT-proBNP values during acute exacerbation of COPD is probably a marker for both, acute estate of COPD and varying degrees of underlying cardiopulmonary disease.

The results of the studies suggest the role of natriuretic peptides as relevant prognostic biomarkers not only for patients with cardiovascular disease, but also for patients with chronic obstructive pulmonary disease, which has an important clinical implication. The determination of these biomarkers in patients with chronic obstructive pulmonary disease allows stratification for prognosis: it is able to select a subgroup of patients at higher risk, which requires increased attention and optimization of treatment.

Conclusion

NPs, especially BNP/NT-proBNP are relevant prognostic biomarkers not only for patients with cardiovascular disease, but also for patients with COPD, acute exacerbations and haemodynamic disorders like PH and cor pulmonale. Estimating BNP/NT-proBNP in COPD patients has an important clinical implication: it allows the selection of a subgroup of patients at higher risk, which requires increased attention and treatment optimization.