bluuebunny/crossref_metadata_2025 huggingface dataset:
In vivo antiviral effect of plant essential oils against avian infectious bronchitis virus
Authors: Zhang Yu , Li Xiao-Yan , Zhang Bing-Sha , Ren Li-Na , Lu Yan-Peng , Tang Jin-Wen , Lv Di , Yong Lu , Lin Li-Ting , Lin Zi-Xue , Mo Qin , Mo Mei-Lan
Published: March 2022

Background

Infectious bronchitis virus (IBV) leads to huge economic losses in the poultry industry worldwide. The high levels of mutations of IBV render vaccines partially protective. Therefore, it is urgent to explore an effective antiviral drug or agent. The present study aimed to investigate the in vivo anti-IBV activity of a mixture of plant essential oils (PEO) of cinnamaldehyde (CA) and glycerol monolaurate (GML), designated as Jin-Jing-Zi.

Results

The antiviral effects were evaluated by clinical signs, viral loads, immune organ indices, antibody levels, and cytokine levels. The infection rates in the PEO-M (middle dose) and PEO-H (high dose) groups were significantly lower than those in the prevention, positive drug, and PEO-L (low dose) groups. The cure rates in the PEO-M and PEO-H groups were significantly higher than those in the prevention, positive drug, and PEO-L groups, and the PEO-M group had the highest cure rate of 92.31%. The symptom scores and IBV mRNA expression levels were significantly reduced in the PEO-M group. PEO significantly improved the immune organ indices and IBV-specific antibody titers of infected chickens. The anti-inflammatory factor levels of IL-4 and IFN-γ in the PEO-M group maintained high concentrations for a long time. The IL-6 levels in the PEO-M group were lower than those in prevention, positive drug, and PEO-L groups.

Conclusion

The PEO had remarkable inhibition against IBV and the PEO acts by inhibiting virus multiplication and promoting immune function, suggesting that the PEO has great potential as a novel anti-IBV agent for inhibiting IBV infection.
Cell factory for γ-aminobutyric acid (GABA) production using Bifidobacterium adolescentis
Authors: Altaib Hend , Kozakai Tomoya , Badr Yassien , Nakao Hazuki , El-Nouby Mahmoud A. M. , Yanase Emiko , Nomura Izumi , Suzuki Tohru
Published: March 2022

Background

Bifidobacteria are gram-positive, probiotic, and generally regarded as safe bacteria. Techniques such as transformation, gene knockout, and heterologous gene expression have been established for Bifidobacterium, indicating that this bacterium can be used as a cell factory platform. However, there are limited previous reports in this field, likely because of factors such as the highly anaerobic nature of this bacterium. Bifidobacterium adolescentis is among the most oxygen-sensitive Bifidobacterium species. It shows strain-specific gamma-aminobutyric acid (GABA) production. GABA is a potent bioactive compound with numerous physiological and psychological functions. In this study, we investigated whether B. adolesentis could be used for mass production of GABA.

Results

The B. adolescentis 4–2 strain isolated from a healthy adult human produced approximately 14 mM GABA. It carried gadB and gadC, which encode glutamate decarboxylase and glutamate GABA antiporter, respectively. We constructed pKKT427::Pori-gadBC and pKKT427::Pgap-gadBC plasmids carrying gadBC driven by the original gadB (ori) and gap promoters, respectively. Recombinants of Bifidobacterium were then constructed. Two recombinants with high production abilities, monitored by two different promoters, were investigated. GABA production was improved by adjusting the fermentation parameters, including the substrate concentration, initial culture pH, and co-factor supplementation, using response surface methodology. The optimum initial cultivation pH varied when the promoter region was changed. The ori promoter was induced under acidic conditions (pH 5.2:4.4), whereas the constitutive gap promoter showed enhanced GABA production at pH 6.0. Fed-batch fermentation was used to validate the optimum fermentation parameters, in which approximately 415 mM GABA was produced. The conversion ratio of glutamate to GABA was 92–100%.

Conclusion

We report high GABA production in recombinant B. adolescentis. This study provides a foundation for using Bifidobacterium as a cell factory platform for industrial production of GABA.
DNA methyltransferase 1 inhibits microRNA-497 and elevates GPRC5A expression to promote chemotherapy resistance and metastasis in breast cancer
Authors: Liu Yaobang , Bai Zhengyang , Chai Dahai , Gao Yali , Li Ting , Ma Yinling , Li Jinping
Published: March 2022

Background

Abnormal DNA methylation of tumor suppressor gene promoter has been found in breast cancer. Therefore, the current study set out to explore how DNA methyltransferase 1 (DNMT1) affects breast cancer through mediating miR-497/GPRC5A axis.

Methods

After loss and gain-of-function approaches were conducted in MCF-7/ADR and MCF-7 cells, cell viability, IC50 value, invasion, migration and apoptosis were measured, respectively. In addition, drug resistance, metastasis and apoptosis-related protein expression were examined using immunoblotting. ChIP and dual-luciferase reporter gene assays were carried out to validate relationship among DNMT1, miR-497, and GPRC5RA. Subcutaneous xenograft tumor model in nude mice was established to detect effects of DNMT1 on growth and metastasis of breast cancer in vivo.

Results

It was found that DNMT1 was notably increased, while miR-497 was poorly-expressed in breast cancer. Highly-expressed DNMT1 could promote chemotherapy resistance and metastasis of breast cancer. Meanwhile, DNMT1 modified methylation of CpG island in miR-497 promoter region, thereby repressing miR-497 level. In addition, miR-497 targeted GPRC5A expression to curb chemotherapy resistance and metastasis of breast cancer cells. Lastly, in vivo experiments showed that knockdown of DNMT1 could suppress breast cancer growth and metastasis.

Conclusions

Collectively, our findings indicated that DNMT1 may inhibit miR-497 and boost the expression of GPRC5A through methylation, thus augmenting breast cancer chemotherapy resistance and metastasis, which provides novel mechanistic insight into the unrecognized roles of DNMT1 in breast cancer.
Reconstructing asynchrony for mechanical ventilation using a hysteresis loop virtual patient model
Authors: Zhou Cong , Chase J. Geoffrey , Sun Qianhui , Knopp Jennifer , Tawhai Merryn H. , Desaive Thomas , Möller Knut , Shaw Geoffrey M. , Chiew Yeong Shiong , Benyo Balazs
Published: March 2022

Background

Patient-specific lung mechanics during mechanical ventilation (MV) can be identified from measured waveforms of fully ventilated, sedated patients. However, asynchrony due to spontaneous breathing (SB) effort can be common, altering these waveforms and reducing the accuracy of identified, model-based, and patient-specific lung mechanics.

Methods

Changes in patient-specific lung elastance over a pressure–volume (PV) loop, identified using hysteresis loop analysis (HLA), are used to detect the occurrence of asynchrony and identify its type and pattern. The identified HLA parameters are then combined with a nonlinear mechanics hysteresis loop model (HLM) to extract and reconstruct ventilated waveforms unaffected by asynchronous breaths. Asynchrony magnitude can then be quantified using an energy-dissipation metric, Easyn, comparing PV loop area between model-reconstructed and original, altered asynchronous breathing cycles. Performance is evaluated using both test-lung experimental data with a known ground truth and clinical data from four patients with varying levels of asynchrony.

Results

Root mean square errors for reconstructed PV loops are within 5% for test-lung experimental data, and 10% for over 90% of clinical data. Easyn clearly matches known asynchrony magnitude for experimental data with RMS errors < 4.1%. Clinical data performance shows 57% breaths having Easyn > 50% for Patient 1 and 13% for Patient 2. Patient 3 only presents 20% breaths with Easyn > 10%. Patient 4 has Easyn = 0 for 96% breaths showing accuracy in a case without asynchrony.

Conclusions

Experimental test-lung validation demonstrates the method’s reconstruction accuracy and generality in controlled scenarios. Clinical validation matches direct observations of asynchrony in incidence and quantifies magnitude, including cases without asynchrony, validating its robustness and potential efficacy as a clinical real-time asynchrony monitoring tool.
Air pollution in association with mental and self-rated health and the mediating effect of physical activity
Authors: Hautekiet Pauline , Saenen Nelly D. , Demarest Stefaan , Keune Hans , Pelgrims Ingrid , Van der Heyden Johan , De Clercq Eva M. , Nawrot Tim S.
Published: March 2022

Background

Recent studies showed that air pollution might play a role in the etiology of mental disorders. In this study we evaluated the association between air pollution and mental and self-rated health and the possible mediating effect of physical activity in this association.

Methods

In 2008, 2013 and 2018 the Belgian Health Interview Survey (BHIS) enrolled 16,455 participants who completed following mental health dimensions: psychological distress, suboptimal vitality, suicidal ideation, and depressive and generalized anxiety disorder and self-rated health. Annual exposure to nitrogen dioxide (NO2), particulate matter ≤ 2.5 µm (PM2.5) and black carbon (BC) were estimated at the participants’ residence by a high resolution spatiotemporal model. Multivariate logistic regressions were carried out taking into account a priori selected covariates.

Results

Long-term exposure to PM2.5, BC and NO2 averaged 14.5, 1.4, and 21.8 µg/m3, respectively. An interquartile range (IQR) increment in PM2.5 exposure was associated with higher odds of suboptimal vitality (OR = 1.27; 95% CI: 1.13, 1.42), poor self-rated health (OR = 1.20; 95% CI: 1.09, 1.32) and depressive disorder (OR = 1.19; 95% CI: 1.00, 1.41). Secondly, an association was found between BC exposure and higher odds of poor self-rated health and depressive and generalized anxiety disorder and between NO2 exposure and higher odds of psychological distress, suboptimal vitality and poor self-rated health. No association was found between long-term ambient air pollution and suicidal ideation or severe psychological distress. The mediation analysis suggested that between 15.2% (PM2.5-generalized anxiety disorder) and 40.1% (NO2-poor self-rated health) of the association may be mediated by a difference in physical activity.

Conclusions

Long-term exposure to PM2.5, BC or NO2 was adversely associated with multiple mental health dimensions and self-rated health and part of the association was mediated by physical activity. Our results suggest that policies aiming to reduce air pollution levels could also reduce the burden of mental health disorders in Belgium.
Clinical considerations for the design of PROTACs in cancer
Authors: Nieto-Jiménez Cristina , Morafraile Esther Cabañas , Alonso-Moreno Carlos , Ocaña Alberto
Published: March 2022

Degradation of targeted proteins using proteolysis targeting chimeras (PROTACs) has gained momentum. A PROTAC is a bifunctional molecule that consists of three parts: a ligand that interacts with the protein to be degraded, another ligand that binds to an E3 ubiquitin ligase and a linker that connects both. Identification of the right proteins as targets to be degraded and a ligase that is highly expressed in tumors compare with normal tissue is mandatory, as can augment efficacy reducing toxicity. In this article we review the current development stage of PROTACs in cancer to categorize the best PROTAC construction. Targets including BCL2, CDK4 and MCL1 were highly expressed in all tumors; MCL1 was significantly increased in breast cancer and lung adenocarcinoma and CDK4 in colon adenocarcinoma. Degradation of CDK9, AURKA or PLK1, followed by BCL2, MCL1, PTPN11, BRD4, PTK2, showed a high dependency. Most ligases evaluated were not highly present in tumors except for MDM2 in breast, lung, prostate and gastric cancer. In non-transformed tissue MDM2 was the most abundant ligase, followed by cIAP and CRBN, and those with low expression included XIAP and VHL. MDM2 ligase coupled with inhibitors of the targets BCL2, BRD4, CDK9, PLK1 and MCL1 in stomach tumor, and MDM2 with PIK3C3 inhibitors in breast cancer, seems to be the best therapeutic strategy. Our results suggest potential options for the design of PROTACS in specific medical indications.
Effect of spermidine on ameliorating spermatogenic disorders in diabetic mice via regulating glycolysis pathway
Authors: Wang Jin-Yuan , Ma Duo , Luo Min , Tan Yong-Peng , Ou Zhong  , Tian Ge , Lv Yong-Ting , Li Mei-Xiang , Chen Xi , Tang Zhi-Han , Hu Lin-Lin , Lei Xiao-Can
Published: March 2022

Diabetes mellitus (DM), a high incidence metabolic disease, is related to the impairment of male spermatogenic function. Spermidine (SPM), one of the biogenic amines, was identified from human seminal plasma and believed to have multiple pharmacological functions. However, there exists little evidence that reported SPM’s effects on moderating diabetic male spermatogenic function. Thus, the objective of this study was to investigate the SPM’s protective effects on testicular spermatogenic function in streptozotocin (STZ)-induced type 1 diabetic mice. Therefore, 40 mature male C57BL/6 J mice were divided into four main groups: the control group (n = 10), the diabetic group (n = 10), the 2.5 mg/kg SPM-treated diabetic group (n = 10) and the 5 mg/kg SPM-treated diabetic group (n = 10), which was given intraperitoneally for 8 weeks. The type 1 diabetic mice model was established by a single intraperitoneal injection of STZ 120 mg/kg. The results showed that, compare to the control group, the body and testis weight, as well the number of sperm were decreased, while the rate of sperm malformation was significantly increased in STZ-induced diabetic mice. Then the testicular morphology was observed, which showed that seminiferous tubule of testis were arranged in mess, the area and diameter of which was decreased, along with downregulated anti-apoptotic factor (Bcl-2) expression, and upregulated pro-apoptotic factor (Bax) expression in the testes. Furthermore, testicular genetic expression levels of Sertoli cells (SCs) markers (WT1, GATA4 and Vimentin) detected that the pathological changes aggravated observably, such as the severity of tubule degeneration increased. Compared to the saline-treated DM mice, SPM treatment markedly improved testicular function, with an increment in the body and testis weight as well as sperm count. Pro-apoptotic factor (Bax) was down-regulated expression with the up-regulated expression of Bcl-2 and suppression of apoptosis in the testes. What’s more, expression of WT1, GATA4, Vimentin and the expressions of glycolytic rate-limiting enzyme genes (HK2, PKM2, LDHA) in diabetic testes were also upregulated by SPM supplement. The evidence derived from this study indicated that the SMP’s positive effect on moderating spermatogenic disorder in T1DM mice’s testis. This positive effect is delivered via promoting spermatogenic cell proliferation and participating in the glycolytic pathway’s activation.
Exosomes in the tumor microenvironment of cholangiocarcinoma: current status and future perspectives
Authors: Zhao Kai , Li Xiangyu , Shi Yuanxin , Lu Yun , Qiu Peng , Deng Zhengdong , Yao Wei , Wang Jianming
Published: March 2022

Cholangiocarcinoma (CCA) refers to an aggressive malignancy with a high fatality rate and poor prognosis. Globally, the morbidity of CCA is increasing for the past few decades, which has progressed into a disease that gravely endangers human health. Exosomes belong to a class of extracellular vesicles (EVs) with diameters ranging from 40 to 150 nm that can be discharged by all living cells. As communication messengers of the intercellular network, exosomes carry a diverse range of cargoes such as proteins, nucleic acids, lipids, and metabolic substances, which are capable of conveying biological information across different cell types to mediate various physiological activities or pathological changes. Increasing studies have demonstrated that exosomes in the tumor microenvironment participate in regulating tumorigenesis and progression via multiple approaches in the tumor microenvironment. Here, we reviewed the current research progress of exosomes in the context of cancer and particularly highlighted their functions in modulating the development of CCA. Furthermore, the potential values of exosomes as diagnostic and therapeutic targets in CCA were overviewed as well.
Tumor-B-cell interactions promote isotype switching to an immunosuppressive IgG4 antibody response through upregulation of IL-10 in triple negative breast cancers
Authors: Toney Nicole J. , Opdenaker Lynn M. , Cicek Kader , Frerichs Lisa , Kennington Christopher Ryan , Oberly Samuel , Archinal Holly , Somasundaram Rajasekharan , Sims-Mourtada Jennifer
Published: March 2022

Background

Triple negative breast cancer (TNBC) is an aggressive breast cancer for which there is currently no targeted therapy. Tumor-infiltrating B-cells (TIB) have been observed in tumor tissues of TNBC patients, but their functional role is unclear. IgG4 is one of four antibody subclasses of IgG expressed and secreted by B cells. Unlike other IgG isotypes, IgG4 has an immunosuppressive function and is induced by Th2-type cytokines. In cancers such as melanoma, IgG4 has been linked with advanced disease and poor patient survival. Therefore, we sought to determine if IgG4 + B cells are present and determine the mechanisms driving isotype switching in TNBC.

Methods

We performed co-culture assays to examine expression of Th2 cytokines by TNBC cells with and without the presence of B cells. We also performed in vitro class switching experiments with peripheral B cells with and without co-culture with TNBC cells in the presence or absence of an IL-10 blocking antibody. We examined expression of CD20+TIB, IgG4 and Th2 cytokines by immunohistochemistry in 152 TNBC samples. Statistical analysis was done using Log-Rank and Cox-proportional hazards tests.

Results

Our findings indicate that B cells interact with TNBC to drive chronic inflammatory responses through increased expression of inflammatory cytokines including the TH2 cytokines IL-4 and IL-10. In vitro class switching studies show that interactions between TNBC cell lines and B cells drive isotype switching to the IgG4 isotype in an IL-10 dependent manner. In patient tissues, expression of IgG4 correlates with CD20 and tumor expression of IL-10. Both IgG4 and tumor IL-10 are associated to shorter recurrence free survival (RFS) and overall survival (OS) in TNBC. In a multi-variant analysis, IL-10 was associated with poor outcomes indicating that tumor IL-10 may drive immune escape.

Conclusions

These findings indicate that interactions between TIB and TNBC results in activation of chronic inflammatory signals such as IL-10 and IL-4 that drive class switching to an IgG4 + subtype which may suppress antibody driven immune responses. The presence of IgG4 + B cells may serve as a biomarker for poor prognosis.
Connexin 43 gap junction-mediated astrocytic network reconstruction attenuates isoflurane-induced cognitive dysfunction in mice
Authors: Dong Rui , Han Yuqiang , Jiang Linhao , Liu Shuai , Zhang Fujun , Peng Liangyu , Wang Zimo , Ma Zhengliang , Xia Tianjiao , Gu Xiaoping
Published: March 2022

Background

Postoperative cognitive dysfunction (POCD) is a common complication following anesthesia and surgery. General anesthetic isoflurane has potential neurotoxicity and induces cognitive impairments, but the exact mechanism remains unclear. Astrocytes form interconnected networks in the adult brain through gap junctions (GJs), which primarily comprise connexin 43 (Cx43), and play important roles in brain homeostasis and functions such as memory. However, the role of the GJ-Cx43-mediated astrocytic network in isoflurane-induced cognitive dysfunction has not been defined.

Methods

4-month-old male C57BL/6 mice were exposure to long-term isoflurane to induce cognitive impairment. To simulate an in vitro isoflurane-induced cognitive dysfunction‐like condition, primary mouse astrocytes were subjected to long-term isoflurane exposure. Cognitive function was assessed by Y-maze and fear conditioning tests. Western blot was used to determine the expression levels of different functional configurations of Cx43. The morphology of the GJs-Cx43 was evaluated by immunofluorescence staining. Levels of IL-1β and IL-6 were examined by ELISA. The ability of GJs-Cx43-mediated intercellular communication was examined by lucifer yellow dye transfer assay. Ethidium bromide uptake assays were used to measure the activity of Cx43 hemichannels. The ultrastructural morphology of astrocyte gap junctions and tripartite synapse were observed by transmission electron microscopy.

Results

After long-term isoflurane anesthesia, the GJs formed by Cx43 in the mouse hippocampus and primary mouse astrocytes were significantly reduced, GJs function was impaired, hemichannel activity was enhanced, the levels of IL-1β and IL-6 were increased, and mice showed significant cognitive impairment. After treatment with the novel GJ-Cx43 enhancer ZP1609, GJ-Cx43-mediated astrocytic network function was enhanced, neuroinflammation was alleviated, and ameliorated cognition dysfunction induced by long-term isoflurane exposure. However, ZP1609 enhances the astrocytic network by promoting Cx43 to form GJs without affecting hemichannel activity. Additionally, our data showed that long-term isoflurane exposure does not alter the structure of tripartite synapse.

Conclusion

Our results reveal a novel mechanism of the GJ-Cx43-mediated astrocytic network involved in isoflurane-induced neuroinflammation and cognitive impairments, which provides new mechanistic insight into the pathogenesis of POCD and identifies potential targets for its treatment.
Longitudinal association of cytokine-producing CMV-specific T cells with frailty in HIV-infected and -uninfected men who have sex with men
Authors: Zhang Weiying , Li Huifen , Bream Jay H. , Nilles Tricia L. , Leng Sean X. , Margolick Joseph B.
Published: March 2022

Background

Chronic cytomegalovirus (CMV) infection has been postulated as a driver of chronic inflammation that has been associated with frailty and other age-related conditions in both HIV-infected (HIV+) and -uninfected (HIV-) people.

Methods

To study the T cell response to CMV as a predictor of onset and maintenance of frailty, baseline CMV-specific T cell responses of 42 men (20 HIV-, 22 HIV+; 21 frail, 21 nonfrail) in the Multicenter AIDS Cohort Study (MACS) were assessed by flow cytometric analysis of cytokine production (IFN-γ, TNF-⍺, and IL-2) in response to overlapping peptide pools spanning 19 CMV open reading frames. The Fried frailty phenotype was assessed at baseline and semiannually thereafter. Times to transition into or out of frailty were compared by tertiles of percentages of cytokine-producing T cells using Kaplan-Meier estimators and the exact log-rank test.

Results

Over a median follow-up of 6.5 (interquartile range: 2) years, faster onset of frailty was significantly predicted by higher (HIV- men) or lower (HIV+ men) percentages of CD4 T cells producing only IFN-γ (IFN-γ-single-producing (SP)), and by lower percentages of IFN-γ-, TNF-⍺-, and IL-2-triple-producing CD8 T cells (HIV- men). Greater maintenance of frailty was significantly predicted by lower percentages of both these T cell subsets in HIV- men, and by lower percentages of IFN-γ-SP CD4 T cells in HIV+ men. The antigenic specificity of IFN-γ-SP CD4 T cells was different between HIV- and HIV+ nonfrail men, as were the correlations between these cells and serum inflammatory markers.

Conclusions

In this pilot study, percentages of CMV-specific T cells predicted the onset and maintenance of frailty in HIV- and HIV+ men. Predictive responses differed by HIV status, which may relate to differential control of CMV reactivation and inflammation by anti-CMV T cell responses.
Manual therapy interventions in the management of adults with prior cervical spine surgery for degenerative conditions: a scoping review
Authors: Gliedt Jordan A. , Dawson Aprill Z. , Daniels Clinton J. , Spector Antoinette L. , Cupler Zachary A. , King Jeff , Egede Leonard E.
Published: March 2022

Objective

Cervical spine surgeries for degenerative conditions are rapidly increasing. Cervical post-surgery syndrome consisting of chronic pain, adjacent segment disease, recurrent disc herniation, facet joint pain, and/or epidural scarring is common. Repeat surgery is regularly recommended, though patients are often unable to undergo or decline further surgery. Manual therapy is included in clinical practice guidelines for neck pain and related disorders, however clinical guidance for utilization of manual therapy in adults with prior cervical spine surgery is lacking. This study aimed to synthesize available literature and characterize outcomes and adverse events for manual therapy interventions in adults with prior cervical spine surgery due to degenerative conditions.

Methods

Preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews was followed. PubMed, Cumulative Index of Nursing and Allied Health Literature, physiotherapy evidence database, and Index to Chiropractic Literature were searched from inception through October 2021. English-language literature comprised of randomized clinical trials (RCT), case–control, cohort, and case report designs were included. Adults undergoing manual therapy, with or without combination of other interventions, with prior cervical spine surgery due to degenerative conditions were included.

Results

Twelve articles were identified, including 10 case reports, 1 low-quality RCT, and 1 acceptable-quality RCT. Eight case reports described 9 patients with history of fusion surgery. Two case reports described 2 patients with history of discectomy. One case report described one patient with separate operations of a discectomy at one level and a fusion at another level. One case report described 2 patients with history of cervical disc replacement surgery. The two RCTs included 63 and 86 participants, respectively. Use of manual joint mobilization/manipulation, table/instrument assisted mobilization/manipulation, and multimodal interventions were described in eligible studies. Favorable clinical outcomes were reported in 10 studies. Six case reports/series involving 8 patients described use of unclassified forms of manual therapy. Eight studies described the use of multimodal interventions along with manual therapy. One study described high patient satisfaction. Two studies, accounting for 3 patients, reported serious adverse events.

Conclusions

There is a lack of literature informing evidence related to clinical outcomes, patient satisfaction, and adverse events associated with manual therapy for patients with prior cervical spine surgery due to degenerative conditions. High-quality studies of higher-level hierarchical study design are needed to understand the clinical utility and safety profile of manual therapy for this population.
The patterns of acceptance, mindfulness, and values for Japanese patients with type 2 diabetes mellitus: a web-based survey
Authors: Saito Junichi , Kumano Hiroaki
Published: March 2022

Background

The Acceptance and Commitment Therapy (ACT) model of human functioning uses the behavioral processes of acceptance, mindfulness, and values, which together compose psychological flexibility, the ability to contact the present moment more fully as a conscious human being and to either change or persist when doing so serves valued ends. To increase the effectiveness of interventions in the medical treatment of diabetes, it is important to examine the effects on patients with type 2 diabetes of promoting the active component patterns of ACT. This study explores these points.

Methods

Questionnaires were administered to type 2 diabetes patients who were registered in the database of a research service provider, and data was collected and analyzed from a total of 211 patients (mean age ± SD was 58.84 years old ±10.25, 14.69% were females).

Results

Cluster analysis yielded four clusters: “Average” (average levels of acceptance, mindfulness, and values), “Flexibility” (high levels of acceptance, mindfulness, and values), “Values/low” (average levels of acceptance and mindfulness, and a low level of values), “Values/high” (average levels of acceptance and mindfulness and a high level of values). Patients in the “Flexibility” and “Values/high” clusters had significantly fewer depressive symptoms than the other clusters. However, members of the “Values/high” cluster demonstrated significantly higher glycated hemoglobin levels than those in the other clusters.

Conclusions

The results above indicate that each part of the ACT model is necessary for managing diabetes treatment while improving quality of life. The importance of values is emphasized in ACT for diabetes patients, but we argue, given our results, that acceptance and mindfulness are very important for Japanese patients with type 2 diabetes. This study is limited to Japanese patients with type 2 diabetes. In further research, the subject population must be expanded to people from other areas and of different racial backgrounds.
Multiple endocrine neoplasia type 1: a new germline “homozygous” variant (c.201delC) caused by detection errors
Authors: Zhang Fan , Yu Xiaohui , Wang Xiaoli , Shao Hua
Published: March 2022

Background

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary cancer syndrome caused by germline variants in theMEN1gene located on chromosome 11q13. We found a Chinese woman who had a pancreatic tumor, parathyroid tumor, adrenal tumor, and suspicion of gastrinoma.

Case presentation

The proband and her immediate family members underwent genetic detection. The results showed that two of the proband’s six relatives had the same variants as the proband, and her sister also had the typical symptoms of MEN1. However, the first- and second-time genetic detection results showed that they were homozygous variants, which did not conform to Mendelian inheritance laws. Multiplex ligation-dependent probe amplification (MLPA) was used to rule out homozygous variants caused by a deletion of gene fragments in the proband and her immediate family members. The MLPA results showed that the gene deletion was absent in theMEN1. The results from the third genetic detection (redesigned the primer) showed that they had a heterozygous variant. A newMEN1germline variant [c.201delC (p.Ala68Profs*51)], which could induce MEN1, was found in this study.

Conclusions

This newly identified germline variant could improve the identification of clinical phenotypes and the early diagnosis of MEN1. Clinician should consider the present of situation that intron variant causing detection error. Re-designing the primers close to the variant site for gene detection could avoid this situation.
TraSig: inferring cell-cell interactions from pseudotime ordering of scRNA-Seq data
Authors: Li Dongshunyi , Velazquez Jeremy J. , Ding Jun , Hislop Joshua , Ebrahimkhani Mo R. , Bar-Joseph Ziv
Published: March 2022

A major advantage of single cell RNA-sequencing (scRNA-Seq) data is the ability to reconstruct continuous ordering and trajectories for cells. Here we present TraSig, a computational method for improving the inference of cell-cell interactions in scRNA-Seq studies that utilizes the dynamic information to identify significant ligand-receptor pairs with similar trajectories, which in turn are used to score interacting cell clusters. We applied TraSig to several scRNA-Seq datasets and obtained unique predictions that improve upon those identified by prior methods. Functional experiments validate the ability of TraSig to identify novel signaling interactions that impact vascular development in liver organoids.

Software

https://github.com/doraadong/TraSig.
Angiopoietin-2/-1 ratios and MMP-3 levels as an early warning sign for the presence of giant cell arteritis in patients with polymyalgia rheumatica
Authors: van Sleen Yannick , Therkildsen Philip , Nielsen Berit Dalsgaard , van der Geest Kornelis S. M. , Hansen Ib , Heeringa Peter , Posthumus Marcel D. , Sandovici Maria , Toonen Erik J. M. , Zijlstra Jannik , Boots Annemieke M. H. , Hauge Ellen-Margrethe , Brouwer Elisabeth
Published: March 2022

Background

Diagnosing patients with giant cell arteritis (GCA) remains difficult. Due to its non-specific symptoms, it is challenging to identify GCA in patients presenting with symptoms of polymyalgia rheumatica (PMR), which is a more common disease. Also, commonly used acute-phase markers CRP and ESR fail to discriminate GCA patients from PMR and (infectious) mimicry patients. Therefore, we investigated biomarkers reflecting vessel wall inflammation for their utility in the accurate diagnosis of GCA in two international cohorts.

Methods

Treatment-naïve GCA patients participated in the Aarhus AGP cohort (N = 52) and the Groningen GPS cohort (N = 48). The AGP and GPS biomarker levels and symptoms were compared to patients presenting phenotypically as isolated PMR, infectious mimicry controls and healthy controls (HCs). Serum/plasma levels of 12 biomarkers were measured by ELISA or Luminex.

Results

In both the AGP and the GPS cohort, we found that weight loss, elevated erythrocyte sedimentation rate (ESR) and higher angiopoietin-2/-1 ratios but lower matrix metalloproteinase (MMP)-3 levels identify concomitant GCA in PMR patients. In addition, we confirmed that elevated platelet counts are characteristic of GCA but not of GCA mimicry controls and that low MMP-3 and proteinase 3 (PR3) levels may help to discriminate GCA from infections.

Conclusion

This study, performed in two independent international cohorts, consistently shows the potential of angiopoietin-2/-1 ratios and MMP-3 levels to identify GCA in patients presenting with PMR. These biomarkers may be used to select which PMR patients require further diagnostic workup. Platelet counts may be used to discriminate GCA from GCA look-alike patients.
SnakeCube: containerized and automated pipeline for de novo genome assembly in HPC environments
Authors: Angelova Nelina , Danis Theodoros , Lagnel Jacques , Tsigenopoulos Costas S. , Manousaki Tereza
Published: March 2022

Objective

The rapid progress in sequencing technology and related bioinformatics tools aims at disentangling diversity and conservation issues through genome analyses. The foremost challenges of the field involve coping with questions emerging from the swift development and application of new algorithms, as well as the establishment of standardized analysis approaches that promote transparency and transferability in research.

Results

Here, we present SnakeCube, an automated and containerized whole de novo genome assembly pipeline that runs within isolated, secured environments and scales for use in High Performance Computing (HPC) domains. SnakeCube was optimized for its performance and tested for its effectiveness with various inputs, highlighting its safe and robust universal use in the field.
Phenotypic differences between female and male individuals with suspicion of autism spectrum disorder
Authors: Stroth Sanna , Tauscher Johannes , Wolff Nicole , Küpper Charlotte , Poustka Luise , Roepke Stefan , Roessner Veit , Heider Dominik , Kamp-Becker Inge
Published: March 2022

Background

Although autism spectrum disorder (ASD) is a common developmental disorder, our knowledge about a behavioral and neurobiological female phenotype is still scarce. As the conceptualization and understanding of ASD are mainly based on the investigation of male individuals, females with ASD may not be adequately identified by routine clinical diagnostics. The present machine learning approach aimed to identify diagnostic information from the Autism Diagnostic Observation Schedule (ADOS) that discriminates best between ASD and non-ASD in females and males.

Methods

Random forests (RF) were used to discover patterns of symptoms in diagnostic data from the ADOS (modules 3 and 4) in 1057 participants with ASD (18.1% female) and 1230 participants with non-ASD (17.9% % female). Predictive performances of reduced feature models were explored and compared between females and males without intellectual disabilities.

Results

Reduced feature models relied on considerably fewer features from the ADOS in females compared to males, while still yielding similar classification performance (e.g., sensitivity, specificity).

Limitations

As in previous studies, the current sample of females with ASD is smaller than the male sample and thus, females may still be underrepresented, limiting the statistical power to detect small to moderate effects.

Conclusion

Our results do not suggest the need for new or altered diagnostic algorithms for females with ASD. Although we identified some phenotypic differences between females and males, the existing diagnostic tools seem to sufficiently capture the core autistic features in both groups.
Safety and efficacy study of allogeneic human menstrual blood stromal cells secretome to treat severe COVID-19 patients: clinical trial phase I & II
Authors: Fathi-Kazerooni Mina , Fattah-Ghazi Samrand , Darzi Maryam , Makarem Jalil , Nasiri Reza , Salahshour Faeze , Dehghan-Manshadi Seyed Ali , Kazemnejad Somaieh
Published: March 2022

Background

Cell-free Mesenchymal stromal cells (MSCs) have been considered due to their capacity to modulate the immune system and suppress cytokine storms caused by SARS-CoV-2. This prospective randomized double-blind placebo-controlled clinical trial aimed to assess the safety and efficacy of secretome derived from allogeneic menstrual blood stromal cells (MenSCs) as a treatment in patients with severe COVID-19.

Methods

Patients with severe COVID-19 were randomized (1:1) to either MenSC-derived secretome treatment or the control group. Subjects received five intravenous infusions of 5 mL secretome or the same volume of placebo for five days and were monitored for safety and efficacy for 28 days after treatment. Adverse events, laboratory parameters, duration of hospitalization, clinical symptom improvement, dynamic of O2 saturation, lymphocyte number, and serial chest imaging were analyzed.

Results

All safety endpoints were observed without adverse events after 72 h of secretome injection. Within 28 days after enrollment, 7 patients (50%) were intubated in the treated group versus 12 patients (80%) in the control group. Overall, 64% of patients had improved oxygen levels within 5 days of starting treatment (P < 0.0001) and there was a survival rate of 57% in the treatment group compared to 28% in the control group was (P < 0.0001). Laboratory values revealed that significant acute phase reactants declined, with mean C-reactive protein, ferritin, and D-dimer reduction of 77% (P < 0.001), 43% (P < 0.001), and 42% (P < 0.05), respectively. Significant improvement in lymphopenia was associated with an increase in mean CD4+ and CD8+ lymphocyte counts of 20% (P = 0.06) and 15% (P < 0.05), respectively. Following treatment, percentage of pulmonary involvement showed a significant improvement in the secretome group (P < 0.0001). This improvement differed significantly between survivors and those who were dying (P < 0.005).

Conclusions

For the first time, this study demonstrated that in hospitalized patients with severe COVID-19, therapy with MenSCs-derived secretome leads to reversal of hypoxia, immune reconstitution, and downregulation of cytokine storm, with no adverse effects attributable to the treatment. Given these outcomes, it may be possible to use this type of treatment for serious inflammatory lung disease with a mechanism similar to COVID-19 in the future. However, it is necessary to evaluate the safety and efficacy of MenSCs-derived secretome therapy in clinical trials on a larger population of patients.

Trial registration: ClinicalTrials.gov Identifier: NCT05019287. Registered 24AGUEST 2021, retrospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT05019287. IRCT, IRCT20180619040147N6. Registered 04/01/2021.
Mesenchymal stem cells and natural killer cells interaction mechanisms and potential clinical applications
Authors: Abbasi Batol , Shamsasenjan Karim , Ahmadi Majid , Beheshti Seyedeh Ameneh , Saleh Mahshid
Published: March 2022

Natural killer cells (NK cells) are innate immune cells that are activated to fight tumor cells and virus-infected cells. NK cells also play an important role in the graft versus leukemia response. However, they can over-develop inflammatory reactions by secreting inflammatory cytokines and increasing Th1 differentiation, eventually leading to tissue damage. Today, researchers have attributed some autoimmune diseases and GVHD to NK cells. On the other hand, it has been shown that mesenchymal stem cells (MSCs) can modulate the activity of NK cells, while some researchers have shown that NK cells can cause MSCs to lysis. Therefore, we considered it is necessary to investigate the effect of these two cells and their signaling pathway in contact with each other, also their clinical applications.
Normal values for 18F-FDG uptake in organs and tissues measured by dynamic whole body multiparametric FDG PET in 126 patients
Authors: Dias André H. , Hansen Allan K. , Munk Ole L. , Gormsen Lars C.
Published: March 2022

Background

Dynamic whole-body (D-WB) FDG PET/CT is a recently developed technique that allows direct reconstruction of multiparametric images of metabolic rate of FDG uptake (MRFDG) and “free” FDG (DVFDG). Multiparametric images have a markedly different appearance than the conventional SUV images obtained by static PET imaging, and normal values of MRFDGand DVFDGin frequently used reference tissues and organs are lacking. The aim of this study was therefore to: (1) provide an overview of normal MRFDGand DVFDGvalues and range of variation in organs and tissues; (2) analyse organ time-activity curves (TACs); (3) validate the accuracy of directly reconstructed MRFDGtissue values versus manually calculatedKi(and MRFDG) values; and (4) explore correlations between demographics, blood glucose levels and MRFDGvalues. D-WB data from 126 prospectively recruited patients (100 without diabetes and 26 with diabetes) were retrospectively analysed. Participants were scanned using a 70-min multiparametric PET acquisition protocol on a Siemens Biograph Vision 600 PET/CT scanner. 13 regions (bone, brain grey and white matter, colon, heart, kidney, liver, lung, skeletal muscle of the back and thigh, pancreas, spleen, and stomach) as well as representative pathological findings were manually delineated, and values of static PET (SUV), D-WB PET (Ki, MRFDGand DVFDG) and individual TACs were extracted. Multiparametric values were compared with manual TAC-based calculations ofKiand MRFDG, and correlations with blood glucose, age, weight, BMI, and injected tracer dose were explored.

Results

Tissue and organ MRFDGvalues showed little variation, comparable to corresponding SUV variation. All regional TACs were in line with previously published FDG kinetics, and the multiparametric metrics correlated well with manual TAC-based calculations (r2 = 0.97,p < 0.0001). No correlations were observed between glucose levels and MRFDGin tissues known not to be substrate driven, while tissues with substrate driven glucose uptake had significantly correlated glucose levels and MRFDGvalues.

Conclusion

The multiparametric D-WB PET scan protocol provides normal MRFDGvalues with little inter-subject variation and in agreement with manual TAC-based calculations and literature values. The technique therefore facilitates both accurate clinical reports and simpler acquisition of quantitative estimates of whole-body tissue glucose metabolism.
Feasibility of fluorescence imaging at microdosing using a hybrid PSMA tracer during robot-assisted radical prostatectomy in a large animal model
Authors: Dell’Oglio Paolo , van Willigen Danny M. , van Oosterom Matthias N. , Bauwens Kevin , Hensbergen Fabian , Welling Mick M. , van der Stadt Huijbert , Bekers Elise , Pool Martin , van Leeuwen Pim , Maurer Tobias , van Leeuwen Fijs W. B. , Buckle Tessa
Published: March 2022

Background

With the rise of prostate-specific membrane antigen (PSMA) radioguided surgery, which is performed using a microdosing regime, demand for visual target confirmation via fluorescence guidance is growing. While proven very effective for radiotracers, microdosing approaches the detection limit for fluorescence imaging. Thus, utility will be highly dependent on the tracer performance, the sensitivity of the fluorescence camera used, and the degree of background signal. Using a porcine model the ability to perform robot-assisted radical prostatectomy under fluorescence guidance using the bimodal or rather hybrid PSMA tracer (99mTc-EuK-(SO3)Cy5-mas3) was studied, while employing the tracer in a microdosing regime. This was followed by ex vivo evaluation in surgical specimens obtained from prostate cancer patients.

Results

T50% bloodand T50% urinewere reached at 85 min and 390 min, in, respectively, blood and urine. Surgical fluorescence imaging allowed visualization of the prostate gland based on the basal PSMA-expression in porcine prostate. Together, in vivo visualization of the prostate and urinary excretion suggests at least an interval of > 7 h between tracer administration and surgery. Confocal microscopy of excised tissues confirmed tracer uptake in kidney and prostate, which was confirmed with PSMA IHC. No fluorescence was detected in other excised tissues. Tumor identification based on ex vivo fluorescence imaging of human prostate cancer specimens correlated with PSMA IHC.

Conclusion

Intraoperative PSMA-mediated fluorescence imaging with a microdosing approach was shown to be feasible. Furthermore, EuK‐(SO3)Cy5‐mas3allowed tumor identification in human prostate samples, underlining the translational potential of this novel tracer.

Trial registrationApproval for use of biological material for research purposes was provided by the Translational Research Board of the Netherlands Cancer Institute-Antoni van Leeuwenhoek hospital (NKI-AvL) under reference IRBm19-273 (22/10/2019).
Proteases secreted by Trichinella spiralis intestinal infective larvae damage the junctions of the intestinal epithelial cell monolayer and mediate larval invasion
Authors: Song Yan Yan , Lu Qi Qi , Han Lu Lu , Yan Shu Wei , Zhang Xin Zhuo , Liu Ruo Dan , Long Shao Rong , Cui Jing , Wang Zhong Quan
Published: March 2022

The intestinal epithelium is the first natural barrier against Trichinella spiralis larval invasion, but the mechanism of larval invasion of the gut epithelium is not fully elucidated. The aim of this study was to investigate whether the excretory/secretory proteins (ESPs) of T. spiralis intestinal infective larvae (IIL) degrade tight junction (TJ) proteins, to assess the main ESP proteases hydrolysing TJ proteins using various enzyme inhibitors and to define the key invasive factors in IIL invasion of the gut epithelium. The results of immunofluorescence, Western blot and Transwell assays showed that serine proteases and cysteine proteases in the ESPs played main roles in hydrolysing occludin, claudin-1 and E-cad and upregulating claudin-2 expression. Challenge infection results showed that IIL expulsion from the gut at 12 hpi was significantly higher in mice which were infected with muscle larvae (ML) treated with a single inhibitor (PMSF, E-64, 1,10-Phe or pepstatin) or various mixtures containing PMSF and E-64 than in mice in the PBS group or the groups treated with an inhibitor mixture not containing PMSF and E-64 (P < 0.0001). At 6 days post-infection, mice which were infected with ML treated with PMSF, E-64, 1,10-Phe or pepstatin exhibited 56.30, 64.91, 26.42 and 31.85% reductions in intestinal adult worms compared to mice in the PBS group (P < 0.0001). The results indicate that serine proteases and cysteine proteases play key roles in T. spiralis IIL invasion, growth and survival in the host and that they may be main candidate target molecules for vaccines against larval invasion and development.