bluuebunny/crossref_metadata_2025 huggingface dataset:
Organisational and staff-related effects on cultural competence in the hospital setting: a cross-sectional online survey of nursing and medical staff
Authors: Schenk Liane , Sonntag Pia-Theresa , Beck Patricia , Khan Zohra , Peppler Lisa , Schouler-Ocak Meryam
Published: May 2022

Background

Cultural competence is considered a core qualification for dealing with socio-cultural diversity and balancing disparities in health care.

Objectives

To explore features supporting and inhibiting cultural competence in the hospital at both organisational and staff levels.

Design

Cross-sectional online survey in the form of a full census from May to November 2018.

Setting

Two organisations that run a total of 22 hospitals in Germany.

Participants

Eight hundred nursing and medical professionals [nurses: n = 557; doctors: n = 243].

Methods

Using the Short Form Cultural Intelligence SCALE (SFCQ), cultural competence was measured and its relation to potential influencing factors at staff level and organisational level examined, using bivariate (t-Test, one-way ANOVA, Pearson and Spearman correlations) and multivariate (multiple linear regression) approaches. Model 1 examined features at organisational level, Model 2 at individual level and Model 3 included organisational and individual features.

Results

The mean cultural competence measured was 3.49 [min.: 1.3; max.: 5.0]. In the bivariate and isolated multivariate models [Models 1 and 2], factors on both organisational and individual levels were significantly related to the hospital staff’s cultural competence. The multivariate overview [Model 3], however, revealed that individual features at staff level were the statistically relevant predictors. Positive influencing features included staff’s assessment of the importance of cultural competence in their professional context [B: 0.368, 95% confidence interval 0.307; 0.429], participation in competence training [B: 0.193; 95% confidence interval 0.112; 0.276] and having a migration background [B: 0.175; 95% confidence interval 0.074; 0.278], while negative features included length of medical service [B: -0.004; 95% confidence interval -0.007; -0.001].

Conclusions

The development and practice of cultural competence appear to be determined less by organisational features and more on the level of individual actors. In addition to staff development, adequate organisational structures and an economic incentive system are required to promote sociocultural diversity in hospitals.
A case report of fatal feline babesiosis caused by Babesia canis in north western Spain
Authors: Remesar Susana , Arnal Jose Luis , Gómez Andrea , Prieto Alberto , García-Dios David , Benito Alfredo , Panadero Rosario , Morrondo Patrocinio , Díaz Pablo
Published: May 2022

Background

In Europe, Babesia infections in cats are sporadic and only partial knowledge is currently available since the number of described cases including both the clinical presentation and the molecular identification of the Babesia species involved is limited. In the present case report, the clinical signs, the epidemiological data and the molecular results suggest that this is the first reported fatal case of feline babesiosis caused by Babesia canis.

Case presentation

A six month old female European shorthair cat from north-western Spain died after being hospitalized for two days. This animal was pregnant and showed anorexia, lethargy, weakness, jaundice and fever with increased respiratory and heart rates. Haematological analysis revealed haemolytic regenerative anaemia, thrombocytopenia and leukocytosis. The presence of piroplasms was assessed using a PCR targeting the 18S rRNA gene of Babesia spp. and Theileria spp.; the sample resulted positive and B. canis was identified by DNA sequence analysis. The possible existence of co-infections with other vector-borne pathogens such as Anaplasma spp., Bartonella spp., Borrelia burgdorferi s.l., Cytauxzoon spp., Ehrlichia spp., Hepatozoon canis, Mycoplasma spp. or Rickettsia spp. was excluded by qPCR.

Conclusions

Our results together with previous reports on Babesia infections in cats from Europe suggest that feline babesiosis should be included in the differential diagnosis of animals with anaemia, thrombocytopenia, anorexia and lethargy, especially in young or immunocompromised animals from endemic areas for canine babesiosis.
Genomic profiling of sporadic multiple meningiomas
Authors: Erson-Omay E. Zeynep , Vetsa Shaurey , Vasandani Sagar , Barak Tanyeri , Nadar Arushii , Marianayagam Neelan J. , Yalcin Kanat , Miyagishima Danielle , Aguilera Stephanie Marie , Robert Stephanie , Mishra-Gorur Ketu , Fulbright Robert K. , McGuone Declan , Günel Murat , Moliterno Jennifer
Published: May 2022

Background

Multiple meningiomas (MMs) rarely occur sporadically. It is unclear whether each individual tumor in a single patient behaves similarly. Moreover, the molecular mechanisms underlying the formation of sporadic MMs and clonal formation etiology of these tumors are poorly understood.

Methods

Patients with spatially separated MMs without prior radiation exposure or a family history who underwent surgical resection of at least two meningiomas were included. Unbiased, comprehensive next generation sequencing was performed, and relevant clinical data was analyzed.

Results

Fifteen meningiomas and one dural specimen from six patients were included. The majority of tumors (12/15) were WHO Grade I; one patient had bilateral MMs, one of which was Grade II, while the other was Grade I. We found 11/15 of our cohort specimens were of NF2-loss subtype. Meningiomas from 5/6 patients had a monoclonal origin, with the tumor from the remaining patient showing evidence for independent clonal formation. We identified a novel case of non-NF2 mutant MM with monoclonal etiology. MMs due to a monoclonal origin did not always display a homogenous genomic profile, but rather exhibited heterogeneity due to branching evolution.

Conclusions

Both NF2-loss and non-NF2 driven MMs can form due to monoclonal expansion and those tumors can acquire inter-tumoral heterogeneity through branched evolution. Grade I and II meningiomas can occur in the same patient. Thus, the molecular make-up and clinical behavior of one tumor in MMs, cannot reliably lend insight into that of the others and suggests the clinical management strategy for MMs should be tailored individually.
Diagnosis of pulmonary tuberculosis via identification of core genes and pathways utilizing blood transcriptional signatures: a multicohort analysis
Authors: Qiu Qian , Peng Anzhou , Zhao Yanlin , Liu Dongxin , Liu Chunfa , Qiu Shi , Xu Jinhong , Cheng Hongguang , Xiong Wei , Chen Yaokai
Published: May 2022

Background

Blood transcriptomics can be used for confirmation of tuberculosis diagnosis or sputumless triage, and a comparison of their practical diagnostic accuracy is needed to assess their usefulness. In this study, we investigated potential biomarkers to improve our understanding of the pathogenesis of active pulmonary tuberculosis (PTB) using bioinformatics methods.

Methods

Differentially expressed genes (DEGs) were analyzed between PTB and healthy controls (HCs) based on two microarray datasets. Pathways and functional annotation of DEGs were identified and ten hub genes were selected. They were further analyzed and selected, then verified with an independent sample set. Finally, their diagnostic power was further evaluated between PTB and HCs or other diseases.

Results

62 DEGs mostly related to type I IFN pathway, IFN-γ-mediated pathway, etc. in GO term and immune process, and especially RIG-I-like receptor pathway were acquired. Among them, OAS1, IFIT1 and IFIT3 were upregulated and were the main risk factors for predicting PTB, with adjusted risk ratios of 1.36, 3.10, and 1.32, respectively. These results further verified that peripheral blood mRNA expression levels of OAS1, IFIT1 and IFIT3 were significantly higher in PTB patients than HCs (all P < 0.01). The performance of a combination of these three genes (three-gene set) had exceeded that of all pairwise combinations of them in discriminating TB from HCs, with mean AUC reaching as high as 0.975 with a sensitivity of 94.4% and a specificity of 100%. The good discernibility capacity was evaluated d via 7 independent datasets with an AUC of 0.902, as well as mean sensitivity of 87.9% and mean specificity of 90.2%. In regards to discriminating PTB from other diseases (i.e., initially considered to be possible TB, but rejected in differential diagnosis), the three-gene set equally exhibited an overall strong ability to separate PTB from other diseases with an AUC of 0.999 (sensitivity: 99.0%; specificity: 100%) in the training set, and 0.974 with a sensitivity of 96.4% and a specificity of 98.6% in the test set.

Conclusion

The described commonalities and unique signatures in the blood profiles of PTB and the other control samples have considerable implications for PTB biosignature design and future diagnosis, and provide insights into the biological processes underlying PTB.
Behavioural and psychological patterns of patients with idiopathic pulmonary fibrosis: a prospective study
Authors: Delameillieure Anouk , Dobbels Fabienne , Fieuws Steffen , Leceuvre Katleen , Vanderauwera Sara , Wuyts Wim A.
Published: May 2022

Background

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung condition. Currently, care models predominantly focus on acute medical and pharmacological needs. As a step towards holistic care, the aim of this prospective study was to investigate the psychological and behavioural needs of IPF patients treated with pirfenidone from diagnosis until two years of follow-up.

Methods

The following variables were selected from the literature on patients’ needs and the COM-B model, a theoretical model explaining behaviour: medication adherence, barriers to adherence, importance and intentions of medication adherence, anxiety, depression, health literacy, knowledge, reported side effects, adherence to sun protection recommendations, alcohol use, physical activity, quality of life and health status. Linear and generalised linear models for longitudinal data were used to evaluate the evolution since treatment initiation.

Results

We included 66 outpatients: 72.7% men, mean age of 70.3 years (range 50–87), predicted mean forced vital capacity of 85.8% (SD 17.4) and predicted mean diffusing capacity for monoxide of 56.9% (SD 15.7). The participants placed considerable importance on following the treatment recommendations. We noticed difficulties regarding health literacy, alcohol use, pirfenidone adherence (decline over time) and adherence to sun protection recommendations (early in follow-up care). There were low levels of physical activity (no effect of time), high body mass indices (decline over time) and moderate levels of depression and anxiety.

Conclusion

When providing care to IPF patients, behavioural issues, health literacy and psychological well-being should be taken into consideration. There is a need to further explore interventions and care models to tackle these difficulties.

Trial registration This study was registered in the ClinicalTrials.gov database (identifier NCT03567785) on May 9th, 2018
A TetR family transcriptional regulator, SP_2854 can affect the butenyl-spinosyn biosynthesis by regulating glucose metabolism in Saccharopolyspora pogona
Authors: Rang Jie , Xia Ziyuan , Shuai Ling , Cao Li , Liu Yang , Li Xiaomin , Xie Jiao , Li Yunlong , Hu Shengbiao , Xie Qingji , Xia Liqiu
Published: May 2022

Background

Butenyl-spinosyn produced by Saccharopolyspora pogona exhibits strong insecticidal activity and a broad pesticidal spectrum. Currently, important functional genes involve in butenyl-spinosyn biosynthesis remain unknown, which leads to difficulty in efficiently understanding its regulatory mechanism, and improving its production by metabolic engineering.

Results

Here, we identified a TetR family transcriptional regulator, SP_2854, that can positively regulate butenyl-spinosyn biosynthesis and affect strain growth, glucose consumption, and mycelial morphology in S. pogona. Using targeted metabolomic analyses, we found that SP_2854 overexpression enhanced glucose metabolism, while SP_2854 deletion had the opposite effect. To decipher the overproduction mechanism in detail, comparative proteomic analysis was carried out in the SP-2854 overexpressing mutant and the original strain, and we found that SP_2854 overexpression promoted the expression of proteins involved in glucose metabolism.

Conclusion

Our findings suggest that SP_2854 can affect strain growth and development and butenyl-spinosyn biosynthesis in S. pogona by controlling glucose metabolism. The strategy reported here will be valuable in paving the way for genetic engineering of regulatory elements in actinomycetes to improve important natural products production.
Versatile aliphatic polyester biosynthesis system for producing random and block copolymers composed of 2-, 3-, 4-, 5-, and 6-hydroxyalkanoates using the sequence-regulating polyhydroxyalkanoate synthase PhaCAR
Authors: Satoh Keigo , Kawakami Tomoya , Isobe Nagi , Pasquier Loïc , Tomita Hiroya , Zinn Manfred , Matsumoto Ken’ichiro
Published: May 2022

Background

Polyhydroxyalkanoates (PHAs) are microbial polyesters synthesized by PHA synthases. Naturally occurring PHA copolymers possess a random monomer sequence. The development of PhaCAR, a unique sequence-regulating PHA synthase, has enabled the spontaneous biosynthesis of PHA block copolymers. PhaCAR synthesizes both a block copolymer poly(2-hydroxybutyrate)-b-poly(3-hydroxybutyrate) [P(2HB)-b-P(3HB)], and a random copolymer, poly(3HB-co-3-hydroxyhexanoate), indicating that the combination of monomers determines the monomer sequence. Therefore, in this study, we explored the substrate scope of PhaCAR and the monomer sequences of the resulting copolymers to identify the determinants of the monomer sequence. PhaCAR is a class I PHA synthase that is thought to incorporate long-main-chain hydroxyalkanoates (LMC HAs, > C3 in the main [backbone] chain). Thus, the LMC monomers, 4-hydroxy-2-methylbutyrate (4H2MB), 5-hydroxyvalerate (5HV), and 6-hydroxyhexanoate (6HHx), as well as 2HB, 3HB, and 3-hydroxypropionate (3HP) were tested.

Results

Recombinant Escherichia coli harboring PhaCAR, CoA transferase and CoA ligase genes was used for PHA production. The medium contained the monomer precursors, 2HB, 3HB, 3HP, 4H2MB, 5HV, and 6HHx, either individually or in combination. As a result, homopolymers were obtained only for 3HB and 3HP. Moreover, 3HB and 3HP were randomly copolymerized by PhaCAR. 3HB-based binary copolymers P(3HB-co-LMC HA)s containing up to 2.9 mol% 4H2MB, 4.8 mol% 5HV, or 1.8 mol% 6HHx were produced. Differential scanning calorimetry analysis of the copolymers indicated that P(3HB-co-LMC HA)s had a random sequence. In contrast, combining 3HP and 2HB induced the synthesis of P(3HP)-b-P(2HB). Similarly, P(2HB) segment-containing block copolymers P(3HB-co-LMC HA)-b-P(2HB)s were synthesized. Binary copolymers of LMC HAs and 2HB were not obtained, indicating that the 3HB or 3HP unit is essential to the polymer synthesis.

Conclusion

PhaCAR possesses a wide substrate scope towards 2-, 3-, 4-, 5-, and 6-hydroxyalkanoates. 3HB or 3HP units are essential for polymer synthesis using PhaCAR. The presence of a 2HB monomer is key to synthesizing block copolymers, such as P(3HP)-b-P(2HB) and P(3HB-co-LMC HA)-b-P(2HB)s. The copolymers that did not contain 2HB units had a random sequence. This study’s results provide insights into the mechanism of sequence regulation by PhaCAR and pave the way for designing PHA block copolymers.
Biosynthesis of eriodictyol from tyrosine by Corynebacterium glutamicum
Authors: Wu Xia , Liu Jingyi , Liu Dan , Yuwen Miaomiao , Koffas Mattheos A. G. , Zha Jian
Published: May 2022

Background

Eriodictyol is a bioactive flavonoid compound that shows potential applications in medicine development and food processing. Microbial synthesis of eriodictyol has been attracting increasing attention due to several benefits. In this study, we employed a GRAS strainCorynebacterium glutamicumas the host to produce eriodictyol directly from tyrosine.

Results

We firstly optimized the biosynthetic module of naringenin, the upstream intermediate for eriodictyol production, through screening of different gene orthologues. Next, to improve the level of the precursor malonyl-CoA necessary for naringenin production, we introducedmatBandmatCfromRhizobium trifoliiintoC. glutamicumto convert extracellular malonate to intracellular malonyl-CoA. This combinatorial engineering resulted in around 35-fold increase in naringenin production from tyrosine compared to the initial recombinantC. glutamicum. Subsequently, thehpaBCgenes fromE. coliencoding 4-hydroxyphenylacetate 3-hydroxylase were expressed inC. glutamicumto synthesize eriodictyol from naringenin. Further optimization of the biotransformation process parameters led to the production of 14.10 mg/L eriodictyol.

Conclusions

The biosynthesis of theortho-hydroxylated flavonoid eriodictyol inC. glutamicumwas achieved for the first time via functional expression ofE. coli hpaBC, providing a baseline strain for biosynthesis of other complex flavonoids. Our study demonstrates the potential application ofC. glutamicumas a host microbe for the biosynthesis of value-added natural compounds from tyrosine.
Decreased INPP5B expression predicts poor prognosis in lung adenocarcinoma
Authors: Deng Jun , Lin Xu , Li Qi , Cai Xiao-yu , Wu Lin-wen , Wang Wei , Zhang Bo , Li Yang-ling , Hu Jian , Lin Neng-ming
Published: May 2022

Background

Inositol Polyphosphate-5-Phosphatase B (INPP5B), a inositol 5-phosphatase, plays an important role in many biological processes through phosphorylating PI(4,5)P2 and/or PI(3,4,5)P3 at the 5-position. Nevertheless, little is known about its function and cellular pathways in tumors. This study aims to investigate the potential role of INPP5B as a diagnostic and prognostic biomarker for lung adenocarcinoma (LUAD), as well as its biological functions and molecular mechanisms in LUAD.

Methods

TCGA, GEO, CTPAC, and HPA datasets were used for differential expression analysis and pathological stratification comparison. The prognostic and diagnostic role of INPP5B was determined by Kaplan–Meier curves, univariate and multivariate Cox regression analysis, and receiver operating characteristics (ROC) curve analyses. The potential mechanism of INPP5B was explored through GO, KEGG, and GSEA enrichment analysis, as well as GeneMANIA and STRING protein–protein interaction (PPI) network. PicTar, PITA, and miRmap databases were used for exploring miRNA targeting INPP5B. In molecular biology experiments, immunohistochemical analyses and Western blot analyses were used to determine protein expression. Co-immunoprecipitation assay was used to detect protein–protein interactions. CCK8 assays and colony formation assays were used for the measurement of cell proliferation. Cell cycle was assessed by PI staining with flow cytometry. Cell migration was performed by Transwell assays and wound healing assays.

Result

INPP5B was decreased in LUAD tissues compared with normal adjacent tissues. And the low expression of INPP5B was associated with late-stage pathological features. In addition, INPP5B was found to be a significant independent prognostic and diagnostic factor for LUAD patients. Hsa-miR-582-5p was predicted as a negative regulator of INPP5B mRNA expression. INPP5B was significantly correlated with the expression of PTEN and the activity of PI3K/AKT signaling pathways, as determined by enrichment analysis and PPI network. In vitro experiments partially confirmed the aforementioned findings. INPP5B could interact directly with PTEN. INPP5B overexpression inhibited LUAD cell proliferation and migration while downregulating the AKT pathway.

Conclusion

Our results demonstrated that INPP5B could inhibit the proliferation and metastasis of LUAD cells. It could serve as a novel diagnostic and prognostic biomarker for LUAD patients.

Trial registration LUAD tissues and corresponding para-cancerous tissues were collected from 10 different LUAD patients at Hangzhou First People’s Hospital. The Ethics Committee of Hangzhou First People’s Hospital has approved this study. (registration number: IIT-20210907-0031-01; registration date: 2021.09.13)
An injectable photo-cross-linking silk hydrogel system augments diabetic wound healing in orthopaedic surgery through spatiotemporal immunomodulation
Authors: Mei Jiawei , Zhou Jun , Kong Lingtong , Dai Yong , Zhang Xianzuo , Song Wenqi , Zhu Chen
Published: May 2022

Background

The complicated hyperglycaemic and chronic inflammation of diabetic wounds in orthopaedic surgery leads to dysregulated immune cell function and potential infection risk. Immune interventions in diabetic wounds face a possible contradiction between simultaneous establishment of the pro-inflammatory microenvironment in response to potential bacterial invasion and the anti-inflammatory microenvironment required for tissue repair. To study this contradiction and accelerate diabetic-wound healing, we developed a photocurable methacryloxylated silk fibroin hydrogel (Sil-MA) system, co-encapsulated with metformin-loaded mesoporous silica microspheres (MET@MSNs) and silver nanoparticles (Ag NPs).

Results

The hydrogel system (M@M–Ag–Sil-MA) enhanced diabetic-wound healing via spatiotemporal immunomodulation. Sil-MA imparts a hydrogel system with rapid in situ Ultra-Violet-photocurable capability and allows preliminary controlled release of Ag NPs, which can inhibit bacterial aggregation and create a stable, sterile microenvironment. The results confirmed the involvement of Met in the immunomodulatory effects following spatiotemporal dual-controlled release via the mesoporous silica and Sil-MA. Hysteresis-released from Met shifts the M1 phenotype of macrophages in regions of diabetic trauma to an anti-inflammatory M2 phenotype. Simultaneously, the M@M–Ag–Sil-MA system inhibited the formation of neutrophil extracellular traps (NETs) and decreased the release of neutrophil elastase, myeloperoxidase, and NETs-induced pro-inflammatory factors. As a result of modulating the immune microenvironmental, the M@M–Ag–Sil-MA system promoted fibroblast migration and endothelial cell angiogenesis in vivo, with verification of enhanced diabetic-wound healing accompanied with the spatiotemporal immunoregulation of macrophages and NETs in a diabetic mouse model.

Conclusions

Our findings demonstrated that the M@M–Ag–Sil-MA hydrogel system resolved the immune contradiction in diabetic wounds through spatiotemporal immunomodulation of macrophages and NETs, suggesting its potential as a promising engineered nano-dressing for the treatment of diabetic wounds in orthopaedic surgery.

Graphical Abstract
BCOR-CCNB3 sarcoma with concurrent RNF213-SLC26A11 gene fusion: a rare sarcoma with altered histopathological features after chemotherapy
Authors: Huang Wen , Wang Wei , Huang Liang-Liang , Li Heng , Zhou Wen-Chao , Wu Hai-Bo
Published: May 2022

Background

Chemotherapy is a common approach for cancer treatment, but intrinsic genetic mutations in different individuals may cause different responses to chemotherapy, resulting in unique histopathological changes. The genetic mutation along with the distinct histopathological features may indicate new tumor entities. BCOR-CCNB3 sarcomas is a kind of Ewing-like sarcomas (ELS) occurring mostly in bone and soft tissues. No gene fusion other than BCOR-CCNB3 has been found in this type of tumor.

Case presentation

We herein report a case of 17-year-old male patient, presented with a mass on his left shoulder that was diagnosed as undifferentiated small round cell sarcoma according to core biopsy. The patient received 5 courses of preoperational chemotherapy, and the tumor was resected and analyzed. Primitive small round cells and larger myoid cells in the resected tumor tissue but not in biopsy were observed, and arterioles stenosis and occlusion were also detected, indicating a dramatic change of histopathological features of this tumor. In addition, the immunohistochemical results showed the altered staining patterns of BCOR, bcl2, CyclinD1, TLE1, AR, SMA, CD117, STAB2, CD56, and CD99 in tumor tissues after chemotherapy. Notably, RNA sequencing revealed a RNF213-SLC26A11 fusion in the tumor sample.

Conclusions

The BCOR-CCNB3 sarcoma with RNF213-SLC26A11 fusion may indicate a subset of tumors that undergo histopathological changes in response to chemotherapy. More similar cases in the future may help to clarify the clinical meanings of RNF213-SLC26A11 fusion in BCOR-CCNB3 sarcomas and the underlying mechanisms.
Circulating miRNAs in extracellular vesicles related to treatment response in patients with idiopathic membranous nephropathy
Authors: Sun In O. , Bae Yun-Ui , Lee Haekyung , Kim Hyoungnae , Jeon Jin Seok , Noh Hyunjin , Choi Jong-Soo , Doh Kyung-Oh , Kwon Soon Hyo
Published: May 2022

Background

Extracellular vesicle (EV)-microRNAs (miRNAs) are potential biomarkers for various renal diseases. This study attempted to identify the circulating EV-miRNA signature not only for discriminating idiopathic membranous nephropathy (IMN) from idiopathic nephrotic syndrome (INS), but also to predict the treatment response of patients with IMN.

Methods

We prospectively enrolled 60 participants, including those with IMN (n = 19) and INS (n = 21) and healthy volunteers (HVs; n = 20) in this study. Using RNA sequencing, we assessed the serum EV-miRNA profiles of all participants. To identify the EV-miRNAs predictive of treatment response in IMN, we also analyzed EV-miRNAs among patients with IMN with and without clinical remission.

Results

The expression levels of 3 miRNAs differed between IMN patients, INS patients and HVs. In addition, compared to HVs, RNA sequencing revealed differential expression of 77 and 44 EV-miRNAs in patients with IMN without and with remission, respectively. We also identified statistically significant (|fold change ≥ 2, p < 0.05) differences in the expression levels of 23 miRNAs in IMN without remission. Biological pathway analysis of miRNAs in IMN without remission indicated that they are likely involved in various pathways, including renal fibrosis.

Conclusion

Our study identified EV-miRNAs associated with IMN as well as those associations with therapeutic response. Therefore, these circulating EV-miRNAs may be used as potential markers for the diagnosis and prediction of treatment response in patients with IMN.
Exploring the association between birthweight and breast cancer using summary statistics from a perspective of genetic correlation, mediation, and causality
Authors: Zhang Meng , Qiao Jiahao , Zhang Shuo , Zeng Ping
Published: May 2022

Background

Previous studies demonstrated a positive relationship between birthweight and breast cancer; however, inconsistent, sometimes even controversial, observations also emerged, and the nature of such relationship remains unknown.

Methods

Using summary statistics of birthweight and breast cancer, we assessed the fetal/maternal-specific genetic correlation between them via LDSC and prioritized fetal/maternal-specific pleiotropic genes through MAIUP. Relying on summary statistics we conducted Mendelian randomization (MR) to evaluate the fetal/maternal-specific origin of causal relationship between birthweight, age of menarche, age at menopause and breast cancer.

Results

With summary statistics we identified a positive genetic correlation between fetal-specific birthweight and breast cancer (rg = 0.123 andP = 0.013) as well as a negative but insignificant correlation between maternal-specific birthweight and breast cancer (rg = − 0.068,P = 0.206); and detected 84 pleiotropic genes shared by fetal-specific birthweight and breast cancer, 49 shared by maternal-specific birthweight and breast cancer. We also revealed fetal-specific birthweight indirectly influenced breast cancer risk in adulthood via the path of age of menarche or age at menopause in terms of MR-based mediation analysis.

Conclusion

This study reveals that shared genetic foundation and causal mediation commonly drive the connection between the two traits, and that fetal/maternal-specific birthweight plays substantially distinct roles in such relationship. However, our work offers little supportive evidence for the fetal origins hypothesis of breast cancer originating in utero.
Epigenetic regulation of innate immune memory in microglia
Authors: Zhang Xiaoming , Kracht Laura , Lerario Antonio M. , Dubbelaar Marissa L. , Brouwer Nieske , Wesseling Evelyn M. , Boddeke Erik W. G. M. , Eggen Bart J. L. , Kooistra Susanne M.
Published: May 2022

Background

Microglia are the tissue-resident macrophages of the CNS. They originate in the yolk sac, colonize the CNS during embryonic development and form a self-sustaining population with limited turnover. A consequence of their relative slow turnover is that microglia can serve as a long-term memory for inflammatory or neurodegenerative events.

Methods

Using ATAC-, ChIP- and RNA-sequencing, we characterized the epigenomes and transcriptomes of FACS-purified microglia from mice exposed to different stimuli. A repeated endotoxin challenge (LPS) was used to induce tolerance in microglia, while genotoxic stress (DNA repair deficiency-induced accelerated aging through Ercc1 deficiency) resulted in primed (hypersensitive) microglia.

Results

Whereas the enrichment of permissive epigenetic marks at enhancer regions could explain training (hyper-responsiveness) of primed microglia to an LPS challenge, the tolerized response of microglia seems to be regulated by loss of permissive epigenetic marks. We identify that inflammatory stimuli and accelerated aging as a result of genotoxic stress activate distinct gene networks. These gene networks and associated biological processes are partially overlapping, which is likely driven by specific transcription factor networks, resulting in altered epigenetic signatures and distinct functional (desensitized vs. primed) microglia phenotypes.

Conclusion

This study provides insight into epigenetic profiles and transcription factor networks associated with transcriptional signatures of tolerized and trained microglia in vivo, leading to a better understanding of innate immune memory of microglia.
Epidemiologic analysis of 8000 acute vertebral fractures: evolution of treatment and complications at 10-year follow-up
Authors: Bigdon Sebastian F. , Saldarriaga Yannis , Oswald Katharina A. C. , Müller Martin , Deml Moritz C. , Benneker Lorin M. , M. Ecker Timo , Albers Christoph E.
Published: May 2022

Study design

This is a retrospective cohort study.

Objectives

This study aims to determine the proportional incidence, clinical characteristics, treatment patterns with complications and changes in treatment of vertebral fractures over 10 years at a Swiss university hospital.

Methods

A retrospective cohort study was performed. All patients with an acute vertebral fracture were included in this study. The extracted anonymized data from the medical records were manually assessed. Demographic data, exact location, etiology, type of treatment and complications related to the treatment were obtained.

Results

Of 330,225 treated patients, 4772 presented with at least one vertebral fracture. In total 8307 vertebral fractures were identified, leading to a proportional incidence of 25 vertebral fractures in 1000 patients. Fractures were equally distributed between genders. Male patients were significantly younger and more likely to sustain a traumatic fracture, while female patients more commonly presented with osteoporotic fractures. The thoracolumbar junction (Th11-L2) was the most frequent fracture site in all etiologies. More than two-thirds of vertebral fractures were treated surgically (68.6%). Out of 4622 performed surgeries, we found 290 complications (6.3%). The odds for surgical treatment in osteoporotic fractures were two times higher before 2010 compared to 2010 and after (odds ratio: 2.1, 95% CI 1.5–2.9,p < 0.001).

Conclusion

Twenty-five out of 1000 patients presented with a vertebral fracture. More than 4000 patients with over 8307 vertebral body fractures were treated in 10 years. Over two-thirds of all fractures were treated surgically with 6.3% complications. There was a substantial decrease in surgeries for osteoporotic fractures after 2009.
Association between obesity and bone mineral density in middle-aged adults
Authors: Li Yue
Published: May 2022

Background

The relationship between obesity and bone mineral density (BMD) varies in different studies. Our aim in this study was to explore the association between obesity (body mass index ≥ 30) and BMD among adults 40–59 years of age.

Methods

This study was conducted on a sample of 2218 participants (986 men and 1232 women) aged 40 to 59 years from the National Health and Nutrition Examination Survey 2011–2018. The independent variable was body mass index (BMI). The outcome variable was lumbar BMD. The associations of BMI with lumbar BMD were examined using multivariable linear regression models.

Results

BMI was positively associated with lumbar BMD after adjusting for other covariates [β 0.006; 95% confidence interval (CI) 0.003–0.008]. An inverted U-shaped association between BMI and lumbar BMD was further identified, with the point of infection at approximately 50 kg/m2. In the subgroup analyses, the relationship between BMI and lumbar BMD in women and blacks was an inverted U-shape.

Conclusion

Based on the results, it may be beneficial to appropriately increase BMI to promote BMD. However, considering the inverted U-shaped association, excessive BMI may be harmful to bone health in women and blacks.
A positive feedback loop between gastric cancer cells and tumor-associated macrophage induces malignancy progression
Authors: Piao Haiyan , Fu Lingfeng , Wang Yuxin , Liu Yang , Wang Yue , Meng Xiangyu , Yang Dong , Xiao Xiang , Zhang Jun
Published: May 2022

Background

Hypoxia and inflammation tumor microenvironment (TME) play a crucial role in tumor development and progression. Although increased understanding of TME contributed to gastric cancer (GC) progression and prognosis, the direct interaction between macrophage and GC cells was not fully understood.

Methods

Hypoxia and normoxia macrophage microarrays of GEO database was analyzed. The peripheral blood mononuclear cell acquired from the healthy volunteers. The expression of C-X-C Motif Chemokine Ligand 8 (CXCL8) in GC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR), western-blot, Elisa and immunofluorescence. Cell proliferation, migration, and invasion were evaluated by cell counting kit 8 (CCK8), colony formation, real-time imaging of cell migration and transwell. Flow Cytometers was applied to identify the source of cytokines. Luciferase reporter assays and chromatin immunoprecipitation were used to identify the interaction between transcription factor and target gene. Especially, a series of truncated and mutation reporter genes were applied to identify precise binding sites. The corresponding functions were verified in the complementation test and in vivo animal experiment.

Results

Our results revealed that hypoxia triggered macrophage secreted CXCL8, which induced GC invasion and proliferation. This macrophage-induced GC progression was CXCL8 activated C-X-C Motif Chemokine Receptor 1/2 (CXCR1/2) on the GC cell membrane subsequently hyperactivated Janus kinase 1/ Signal transducer and activator of transcription 1 (JAK/STAT1) signaling pathway. Then, the transcription factor STAT1 directly led to the overexpression and secretion of Interleukin 10 (IL-10). Correspondingly, IL-10 induced the M2-type polarization of macrophages and continued to increase the expression and secretion of CXCL8. It suggested a positive feedback loop between macrophage and GC. In clinical GC samples, increased CXCL8 predicted a patient’s pessimistic outcome.

Conclusion

Our work identified a positive feedback loop governing cancer cells and macrophage in GC that contributed to tumor progression and patient outcome.
Beta 2 adrenergic receptor and mu opioid receptor interact to potentiate the aggressiveness of human breast cancer cell by activating the glycogen synthase kinase 3 signaling
Authors: Rousseau Bénédicte , Murugan Sengottuvelan , Palagani Ajay , Sarkar Dipak K.
Published: May 2022

Background

Opioid and beta-adrenergic receptors are recently shown to cross talk via formation of receptor heterodimers to control the growth and proliferation of breast cancer cells. However, the underlying cell signaling mechanism remained unclear.

Methods

To determine the effect of the interaction of the two systems in breast cancer, we employed triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468, CRISPR or chemical inhibition or activation of beta-adrenergic receptors (B2AR) and mu-opioid receptors (MOR) gene, and PCR array technology and studied aggressive tumor phenotype and signaling cascades.

Results

We show here that in triple-negative breast cancer cells, the reduction in expression B2AR and MOR by genetic and pharmacological tools leads to a less aggressive phenotype of triple-negative breast cancer cells in vitro and in animal xenografts. Genomic analysis indicates the glycogen synthase kinase 3 (GSK3) pathway as a possible candidate messenger system involved in B2AR and MOR cross talk. GSK3 inactivation in MDA-MB-231 and MDA-MB-468 cells induced similar phenotypic changes as the inhibition of B2AR and/or MOR, while a GSK3 activation by wortmannin reversed the effects of B2AR and/or MOR knockdown on these cells. GSK3 inactivation also prevents B2AR agonist norepinephrine or MOR agonist DAMGO from affecting MDA-MB-231 and MDA-MB-468 cell proliferation.

Conclusions

These data confirm a role of B2AR and MOR interaction in the control of breast cancer cell growth and identify a possible role of the GSK3 signaling system in mediation of these two receptors’ cross talk. Screening for ligands targeting B2AR and MOR interaction and/or the GSK3 system may help to identify novel drugs for the prevention of triple-negative breast cancer cell growth and metastasis.
Analgesic effect of auricular point acupressure for acute pain in patients with dementia: study protocol for a randomized controlled trial
Authors: Chai Xiao-Min , Shi Hong-Yan , Zhang Jun-Jun , Wang Lei , Gao Hai-Xiang , Dai Ya-Liang , Gao Lu-Lu , Yu Jian-Qiang , Li Yu-Xiang , Wang Carol Chunfeng
Published: May 2022

Background

Common and frequent as acute pain is, it is often underestimated and undertreated in older people with dementia in nursing homes and inadequate pain management remains an issue.

Methods

The study is designed to be a randomized, sham-controlled trial and is underway in nursing homes located in China. A total of 206 dementia patients are being recruited from nursing homes in Yinchuan, China. They are randomly allocated to an intervention or a controlled group in a 1:1 ratio. The intervention group will be treated with true APP therapy, while the other group will receive APP at sham point stimulation therapy. The patients will be assessed at baseline (T0), at 5 min during performing the intervention (T1), and at 5 min after completion of the intervention (T2). The primary outcome is the level of pain relief at T1 and T2. Physiological parameters, side effects and additional use of analgesics during the procedure, satisfaction from caregivers, and acceptance of patients are evaluated as secondary outcomes.

Discussion

The results of this study are expected to verify the analgesic effect of APP for acute pain in patients with mild dementia in nursing homes. It has the potential to prompt APP therapy to be implemented widely in dementia patients with acute pain in nursing homes.

Trial registration

Chinese Clinical Trial Registry ChiCTR2100047932. Registered on 27 June 2021. Currently, patient recruitment is ongoing. Recruitment is expected to take place from December 2020 to December 2021.
Development and validation of a HPLC-UV method for methadone hydrochloride quantification in a new oral solution with preservatives to be implemented in physicochemical stability studies
Authors: Álvaro-Alonso Elena Alba , Lorenzo Mª Paz , Escobar-Rodríguez Ismael , Aguilar-Ros Antonio
Published: May 2022

Purpose

The Pharmacy Service of the Infanta Leonor University Hospital acquires, compounds, distributes and dispenses more than 3000 L of methadone oral solution to Drug Addiction Patients Centers per year. Our purpose is to develop and validate an improved high performance liquid chromatography (HPLC) method to quantify methadone hydrochloride in a new oral solution with methylhydroxybenzoate (methylparaben) and propylhydroxybenzoate (propylparaben) to be implemented in physicochemical stability studies that allow to provide more information and even to increase the beyond-use date.

Methods

A HPLC-Agilent® 1100 equipment, comprising a quaternary pump and an ultraviolet diode-array-detector (DAD) was used. An analytical method development and validation was completed. The curve was constructed from methadone working concentrations of 75–125% (7.5, 9.0, 10.0, 11.0 and 12.5 mg/mL) to assess the linear relationship between the concentration of the analyte and the obtained areas. Precision and accuracy were calculated. Detection and quantification limit (LD, LQ) were estimated using the EURACHEM method. Forced-degradation studies were also performed.

Results

Chromatographic conditions were: flow rate 1.6 mL/min; mobile phase 55% acetonitrile and 45% sodium phosphate 25 mM (pH = 10); injection volume was 5 µL. The column was a Waters-XTerra™ RP18, maintained at 40 °C. DAD was λ = 254 nm. Retention times for methadone, methylparaben and propylparaben were 4.34, 0.70 and 0.88 min respectively.

The method was linear (y = 284.3x − 97.8, r = 0.996). Instrumental precision was 0.33% for standards (n = 10); intra-assay precision 0.53% (n = 6) and inter-assay precision 1.95% (n = 12). The relative standard deviation percentage for accuracy was 1.28%. The recovery percentage was 101.5 ± 1.5%. LQ and LD were 2.18 µg/mL and 2.0 µg/mL respectively. The most destabilizing conditions were oxidizing and alkaline. The chromatograms confirmed no interference with the methadone signal.

Conclusions

The HPLC method has proved to be valid and reproducible for methadone quantification in a new oral solution with methylparaben and propylparaben. This assay is a rapid, simple and reliable technique that can be used in daily analysis and physicochemical stability studies.
Inhibitory effect of lignin on the hydrolysis of xylan by thermophilic and thermolabile GH11 xylanases
Authors: Kellock Miriam , Rahikainen Jenni , Borisova Anna S. , Voutilainen Sanni , Koivula Anu , Kruus Kristiina , Marjamaa Kaisa
Published: May 2022

Background

Enzymatic hydrolysis of lignocellulosic biomass into platform sugars can be enhanced by the addition of accessory enzymes, such as xylanases. Lignin from steam pretreated biomasses is known to inhibit enzymes by non-productively binding enzymes and limiting access to cellulose. The effect of enzymatically isolated lignin on the hydrolysis of xylan by four glycoside hydrolase (GH) family 11 xylanases was studied. Two xylanases from the mesophilic Trichoderma reesei, TrXyn1, TrXyn2, and two forms of a thermostable metagenomic xylanase Xyl40 were compared.

Results

Lignin isolated from steam pretreated spruce decreased the hydrolysis yields of xylan for all the xylanases at 40 and 50 °C. At elevated hydrolysis temperature of 50 °C, the least thermostable xylanase TrXyn1 was most inhibited by lignin and the most thermostable xylanase, the catalytic domain (CD) of Xyl40, was least inhibited by lignin. Enzyme activity and binding to lignin were studied after incubation of the xylanases with lignin for up to 24 h at 40 °C. All the studied xylanases bound to lignin, but the thermostable xylanases retained 22–39% of activity on the lignin surface for 24 h, whereas the mesophilic T. reesei xylanases become inactive. Removing of N-glycans from the catalytic domain of Xyl40 increased lignin inhibition in hydrolysis of xylan when compared to the glycosylated form. By comparing the 3D structures of these xylanases, features contributing to the increased thermal stability of Xyl40 were identified.

Conclusions

High thermal stability of xylanases Xyl40 and Xyl40-CD enabled the enzymes to remain partially active on the lignin surface. N-glycosylation of the catalytic domain of Xyl40 increased the lignin tolerance of the enzyme. Thermostability of Xyl40 was most likely contributed by a disulphide bond and salt bridge in the N-terminal and α-helix regions.

Graphical Abstract
Recycling industrial food wastes for lipid production by oleaginous yeasts Rhodosporidiobolus azoricus and Cutaneotrichosporon oleaginosum
Authors: Donzella Silvia , Serra Immacolata , Fumagalli Andrea , Pellegrino Luisa , Mosconi Giacomo , Lo Scalzo Roberto , Compagno Concetta
Published: May 2022

Background

Microbial lipids have been emerging as a sustainable alternative to vegetable oils and animal fat to produce biodiesel and industrial relevant chemicals. The use of wastes for microbial processes can represent a way for upgrading low value feedstock to high value products, addressing one of the main goals of circular economy, the reduction of wastes by recycling. Two oleaginous yeasts, Rhodosporidiobolus azoricus and Cutaneotrichosporon oleaginosum, were used in this study to demonstrate the feasibility of the proposed approach.

Results

In this study wastes from industrial food processing, as pumpkin peels and syrup from candied fruits manufacture, were used for yeast cultivation and for lipids production. Evaluation of growth and sugar consumption revealed marked differences between the yeasts in capacity to utilize the main sugars present in the feedstock. In particular, we observed an unexpected limitation in glucose metabolism on mineral defined media by R. azoricus. Both species showed ability to grow and accumulate lipids on media exclusively composed by undiluted pumpkin peel hydrolysate, and R. azoricus was the best performing. By a two-stage process carried out in bioreactor, this species reached a biomass concentration of 45 g/L (dry weight) containing 55% of lipids, corresponding to a lipid concentration of 24 g/L, with a productivity of 0.26 g/L/h and yield of 0.24 g lipids per g of utilized sugar.

Conclusions

Wastes from industrial food processing were sufficient to completely support yeast growth and to induce lipid accumulation. This study provides strong evidence that the concept of valorisation through the production of lipids from the metabolism of nutrients present in agro-industrial wastes by oleaginous yeasts is promising for implementation of biotechnological processes in a circular economy contest.
Mouse Chd4-NURD is required for neonatal spermatogonia survival and normal gonad development
Authors: de Castro Rodrigo O. , Carbajal Agustin , Previato de Almeida Luciana , Goitea Victor , Griffin Courtney T. , Pezza Roberto J.
Published: May 2022

Testis development and sustained germ cell production in adults rely on the establishment and maintenance of spermatogonia stem cells and their proper differentiation into spermatocytes. Chromatin remodeling complexes regulate critical processes during gamete development by restricting or promoting accessibility of DNA repair and gene expression machineries to the chromatin. Here, we investigated the role of Chd4 and Chd3 catalytic subunits of the NURD complex during spermatogenesis. Germ cell-specific deletion of chd4 early in gametogenesis, but not chd3, resulted in arrested early gamete development due to failed cell survival of neonate undifferentiated spermatogonia stem cell population. Candidate assessment revealed that Chd4 controls expression of dmrt1 and its downstream target plzf, both described as prominent regulators of spermatogonia stem cell maintenance. Our results show the requirement of Chd4 in mammalian gametogenesis pointing to functions in gene expression early in the process.