bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of Methamphetamine-Related Attention Bias by Intermittent Theta-Burst Stimulation on Left Dorsolateral Prefrontal Cortex
Authors: Chen Tianzhen , Su Hang , Wang Lihui , Li Xiaotong , Wu Qianying , Zhong Na , Du Jiang , Meng Yiran , Duan Chunmei , Zhang Congbin , Shi Wen , Xu Ding , Song Weidong , Zhao Min , Jiang Haifeng
Published: August 2021

Background

Previous studies have identified the treatment effect of repetitive transcranial magnetic stimulation (rTMS) on cravings of patients with methamphetamine use disorder (MUD). However, the mechanism underlying the treatment effect remains largely unknown. A potential candidate mechanism could be that rTMS over the dorsolateral prefrontal cortex (DLPFC) modulates the attention bias to methamphetamine-related cues. The purpose of this study is therefore to determine the modulation of rTMS on methamphetamine-related attention bias and the corresponding electrophysiological changes.

Methods

Forty-nine patients with severe MUD were included for analysis. The subjects were randomized to receive the active intermittent theta-burst stimulation (iTBS) or sham iTBS targeting DLPFC for 20 sessions. Participants performed the Addiction Stroop Task before and after the treatment while being recorded by a 64-channel electroencephalogram. Baseline characteristics were collected through the Addiction Severity Index.

Results

Post-treatment evaluations showed a reduced error rate in discriminating the color of methamphetamine words in the active iTBS group compared with the sham iTBS group. Following rTMS treatment, we found the significant time-by-group effect for the N1 amplitude (methamphetamine words > neutral words) and P3 latency (methamphetamine words > neutral words). The change of N1 amplitude was positively correlated with cravings in the active group. Moreover, reduced power of neural oscillation in the beta band, manifesting at frontal central areas, was also found in the active group.

Conclusion

This study suggests that attention bias and the beta oscillation during the attentional processing of methamphetamine words in patients with MUD could be modulated by iTBS applied to left DLPFC.
Phytochemicals: Targeting Mitophagy to Treat Metabolic Disorders
Authors: Su Zuqing , Guo Yanru , Huang Xiufang , Feng Bing , Tang Lipeng , Zheng Guangjuan , Zhu Ying
Published: August 2021

Metabolic disorders include metabolic syndrome, obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease and cardiovascular diseases. Due to unhealthy lifestyles such as high-calorie diet, sedentary and physical inactivity, the prevalence of metabolic disorders poses a huge challenge to global human health, which is the leading cause of global human death. Mitochondrion is the major site of adenosine triphosphate synthesis, fatty acid β−oxidation and ROS production. Accumulating evidence suggests that mitochondrial dysfunction-related oxidative stress and inflammation is involved in the development of metabolic disorders. Mitophagy, a catabolic process, selectively degrades damaged or superfluous mitochondria to reverse mitochondrial dysfunction and preserve mitochondrial function. It is considered to be one of the major mechanisms responsible for mitochondrial quality control. Growing evidence shows that mitophagy can prevent and treat metabolic disorders through suppressing mitochondrial dysfunction-induced oxidative stress and inflammation. In the past decade, in order to expand the range of pharmaceutical options, more and more phytochemicals have been proven to have therapeutic effects on metabolic disorders. Many of these phytochemicals have been proved to activate mitophagy to ameliorate metabolic disorders. Given the ongoing epidemic of metabolic disorders, it is of great significance to explore the contribution and underlying mechanisms of mitophagy in metabolic disorders, and to understand the effects and molecular mechanisms of phytochemicals on the treatment of metabolic disorders. Here, we investigate the mechanism of mitochondrial dysfunction in metabolic disorders and discuss the potential of targeting mitophagy with phytochemicals for the treatment of metabolic disorders, with a view to providing a direction for finding phytochemicals that target mitophagy to prevent or treat metabolic disorders.
Non-coding RNA Regulated Cross-Talk Between Mitochondria and Other Cellular Compartments
Authors: Huang Jinliang , Wu Sipeng , Wang Pengcheng , Wang Geng
Published: August 2021

Mitochondria are the main hubs for cellular energy production. Metabolites produced in mitochondria not only feed many important biosynthesis pathways but also function as signaling molecules. Mitochondrial biosynthesis requires collaboration of both nuclear and mitochondrial gene expression systems. In addition, mitochondria have to quickly respond to changes inside and outside the cells and have their own functional states reported to the nucleus and other cellular compartments. The underlying molecular mechanisms of these complex regulations have not been well understood. Recent evidence indicates that in addition to small molecules, non-coding RNAs may contribute to the communication between mitochondria and other cellular compartments and may even serve as signals. In this review, we summarize the current knowledge about mitochondrial non-coding RNAs (including nucleus-encoded non-coding RNAs that are imported into mitochondria and mitochondrion-encoded non-coding RNAs that are exported), their trafficking and their functions in co-regulation of mitochondrial and other cellular processes.
Identification of Biomarkers for Cervical Cancer Radiotherapy Resistance Based on RNA Sequencing Data
Authors: Feng Yue , Wang Zhao , Yang Nan , Liu Sijia , Yan Jiazhuo , Song Jiayu , Yang Shanshan , Zhang Yunyan
Published: August 2021

Cervical cancer as a common gynecological malignancy threatens the health and lives of women. Resistance to radiotherapy is the primary cause of treatment failure and is mainly related to difference in the inherent vulnerability of tumors after radiotherapy. Here, we investigated signature genes associated with poor response to radiotherapy by analyzing an independent cervical cancer dataset from the Gene Expression Omnibus, including pre-irradiation and mid-irradiation information. A total of 316 differentially expressed genes were significantly identified. The correlations between these genes were investigated through the Pearson correlation analysis. Subsequently, random forest model was used in determining cancer-related genes, and all genes were ranked by random forest scoring. The top 30 candidate genes were selected for uncovering their biological functions. Functional enrichment analysis revealed that the biological functions chiefly enriched in tumor immune responses, such as cellular defense response, negative regulation of immune system process, T cell activation, neutrophil activation involved in immune response, regulation of antigen processing and presentation, and peptidyl-tyrosine autophosphorylation. Finally, the top 30 genes were screened and analyzed through literature verification. After validation, 10 genes (KLRK1, LCK, KIF20A, CD247, FASLG, CD163, ZAP70, CD8B, ZNF683, and F10) were to our objective. Overall, the present research confirmed that integrated bioinformatics methods can contribute to the understanding of the molecular mechanisms and potential therapeutic targets underlying radiotherapy resistance in cervical cancer.
Alterations of Vaginal Microbiota in Women With Infertility and Chlamydia trachomatis Infection
Authors: Chen Hongliang , Wang Li , Zhao Lanhua , Luo Lipei , Min Shuling , Wen Yating , Lei Wenbo , Shu Mingyi , Li Zhongyu
Published: August 2021

Chlamydia trachomatis (C. trachomatis) is the most common etiological agent of bacterial sexually transmitted infections (STIs) worldwide and causes serious health sequelae such as cervicitis, pelvic inflammatory disease, and even infertility if ascending from the lower to the upper female genital tract. Previous studies have revealed the pivotal role of vaginal microbiota in susceptibility to STIs. However, alterations in the vaginal microbiota in women who are infertile and infected with C. trachomatis remain unknown. This study used metagenomic analysis of sequenced 16S rRNA gene amplicons to examine the vaginal microbial profiles of women with tubal infertility who were C. trachomatis-negative and those who were C. trachomatis-positive pre- and post-antibiotic treatment. Women who were C. trachomatis-negative and deemed healthy were recruited as references of eubiosis and dysbiosis. Women with tubal infertility and C. trachomatis infection presented a unique Lactobacillus iners-dominated vaginal microbiota rather than one dominated by Lactobacillus crispatus and displayed a decrease in Lactobacillus, Bifidobacterium, Enterobacter, Atopobium, and Streptococcus, accompanied by decreased levels of cytokines such as interferon (IFN)-γ and interleukin (IL)-10. This altered vaginal microbiota could be restored with varying degrees after standard treatment for C. trachomatis. This shift could be a predictive vaginal microbiota signature for C. trachomatis infection among females with tubal infertility, while no significant differences in phylum, class, and operational taxonomic unit (OTU) levels were observed between women with tubal infertility who were C. trachomatis-negative and healthy controls. This is the first study to provide data on the association of vaginal microbiota with C. trachomatis infection among women with tubal infertility and highlights unprecedented potential opportunities to predict C. trachomatis infection.
Dysbiosis of Gut Microbiota Is an Independent Risk Factor of Stroke-Associated Pneumonia: A Chinese Pilot Study
Authors: Xia Geng-Hong , Zhang Ming-Si , Wu Qi-Heng , Wang Hui-Di , Zhou Hong-Wei , He Yan , Yin Jia
Published: August 2021

Background and Purpose

Identifying risks of stroke-associated pneumonia (SAP) is important for clinical management. We aimed to evaluate the association between gut microbiome composition and SAP in patients with acute ischemic stroke (AIS).

Methods

A prospective observational study was conducted, and 188 AIS patients were enrolled as the training cohort. Fecal and serum samples were collected at admission. SAP was diagnosed by specialized physicians, and disease severity scores were recorded. Fecal samples were subjected to 16S rRNA V4 tag sequencing and analysed with QIIME and LEfSe. Associations between the most relevant taxa and SAP were analysed and validated with an independent cohort. Fecal short-chain fatty acid (SCFA), serum D-lactate (D-LA), intestinal fatty acid-binding protein (iFABP) and lipopolysaccharide binding protein (LBP) levels were measured.

Results

Overall, 52 patients (27.7%) had SAP in the training cohort. The gut microbiome differed between SAP and non-SAP patients; specifically,Roseburiadepletion and opportunistic pathogen enrichment were noted in SAP patients, as confirmed in the validation cohort (n=144, 28 SAP [19.4%]). Based on multivariate analysis,Roseburiawas identified as a protective factor against SAP in both cohorts (training, aOR 0.52; 95% CI, 0.30-0.90; validation, aOR 0.44; 95% CI, 0.23-0.85). The combination of these taxa into a microbial dysbiosis index (MDI) revealed that dysbiosis increased nearly 2 times risk of SAP (training, aOR 1.95; 95% CI, 1.19-3.20; validation, aOR 2.22; 95% CI, 1.15-4.26). Lower fecal SCFA levels and higher serum D-LA levels were observed in SAP patients. Furthermore, SAP was an independent risk factor of 30-day death and 90-day unfavorable outcome.

Conclusion

We demonstrate that a microbial community with depletedRoseburiaand enriched opportunistic pathogens is associated with increased risk of SAP among AIS patients. Gut microbiota screening might be useful for identifying patients at high risk for SAP and provide clues for stroke treatment.
Ivabradine: A Potential Therapeutic for Children With Refractory SVT
Authors: Younis Nour K. , Abi-Saleh Bernard , Al Amin Farah , El Sedawi Omar , Tayeh Christelle , Bitar Fadi , Arabi Mariam
Published: August 2021

Background: In April 2015, ivabradine was approved by the Food and Drug Administration for the treatment of patients with coronary artery disease and heart failure (HF). The use of this medication has been linked with improved clinical outcomes and reduced rates of hospitalization in patients with symptomatic HF and a baseline heart rate of 70 bpm and above. Nonetheless, little is known about the use of ivabradine in pediatric patients with supraventricular tachycardia (SVT). This use is not well-studied and is only endorsed by a few case reports and case series.

Aim: This study discusses the off-label utilization of ivabradine in pediatric patients with SVT, and highlights its efficacy in treating treatment-resistant (refractory) SVT.

Methods: We conducted a retrospective single-center observational study involving pediatric patients with SVT treated at our center between January 2016 and October 2020. We identified the total number of patients with SVT, and the number of patients with refractory SVT treated with Ivabradine. Similarly, we performed a thorough review of the databases of PubMed, Medline and Google Scholar to compare the clinical course of our patients to those described in the literature.

Results: Between January 2016 and October 2020, 79 pediatric patients with SVT were seen and treated at our center. A treatment-resistant SVT was noted only in three patients (4%). Ivabradine was used in these patients as a single or combined therapy. The rest (96%) were successfully treated with conventional anti-arrhythmics such as β-blockers, flecainide, and other approved medications. In the ivabradine group, successful reversal to sinus rhythm was achieved in two of the three patients (66%), one patient was treated with a combination therapy of amiodarone and ivabradine, and the other patient was treated only with ivabradine.

Conclusion: Overall, promissory results are associated with the use of ivabradine in pediatric patients with refractory SVT. Ivabradine appears to be a safe and well-tolerated medication that can induce adequate suppression of SVT, complete reversal to sinus rhythm, and effective enhancement of left ventricular function.
Antidepressant Drugs Effects on Blood Pressure
Authors: Calvi Anna , Fischetti Ilaria , Verzicco Ignazio , Belvederi Murri Martino , Zanetidou Stamatula , Volpi Riccardo , Coghi Pietro , Tedeschi Stefano , Amore Mario , Cabassi Aderville
Published: August 2021

Individuals suffering from depressive disorders display a greater incidence of hypertension compared with the general population, despite reports of the association between depression and hypotension. This phenomenon may depend, at least in part, on the use of antidepressant drugs, which may influence blood pressure through different effects on adrenergic and serotoninergic pathways, as well as on histaminergic, dopaminergic, and cholinergic systems. This review summarizes extant literature on the effect of antidepressant drugs on blood pressure. Selective serotonin reuptake inhibitors are characterized by limited effects on autonomic system activity and a lower impact on blood pressure. Thus, they represent the safest class—particularly among elderly and cardiovascular patients. Serotonin–norepinephrine reuptake inhibitors, particularly venlafaxine, carry a greater risk of hypertension, possibly related to greater effects on the sympathetic nervous system. The norepinephrine reuptake inhibitor reboxetine is considered a safe option because of its neutral effects on blood pressure in long-term studies, even if both hypotensive and hypertensive effects are reported. The dopamine–norepinephrine reuptake inhibitor bupropion can lead to blood pressure increases, usually at high doses, but may also cause orthostatic hypotension, especially in patients with cardiovascular diseases. The norepinephrine–serotonin modulators, mirtazapine and mianserin, have minimal effects on blood pressure but may rarely lead to orthostatic hypotension and falls. These adverse effects are also observed with the serotonin-reuptake modulators, nefazodone and trazodone, but seldomly with vortioxetine and vilazodone. Agomelatine, the only melatonergic antidepressant drug, may also have limited effects on blood pressure. Tricyclic antidepressants have been associated with increases in blood pressure, as well as orthostatic hypotension, particularly imipramine. Oral monoamine–oxidase inhibitors, less frequently skin patch formulations, have been associated with orthostatic hypotension or, conversely, with hypertensive crisis due to ingestion of tyramine-containing food (i.e., cheese reaction). Lastly, a hypertensive crisis may complicate antidepressant treatment as a part of the serotonin syndrome, also including neuromuscular, cognitive, and autonomic dysfunctions. Clinicians treating depressive patients should carefully consider their blood pressure status and cardiovascular comorbidities because of the effects of antidepressant drugs on blood pressure profiles and potential interactions with antihypertensive treatments.
The Impact of Mindset on Self-Tracking Experience
Authors: Hancı Elçin , Ruijten Peter A. M. , Lacroix Joyca , IJsselsteijn Wijnand A.
Published: August 2021

Self-tracking technologies aim to offer a better understanding of ourselves through data, create self-awareness, and facilitate healthy behavior change. Despite such promising objectives, very little is known about whether the implicit beliefs users may have about the changeability of their own behavior influence the way they experience self-tracking. These implicit beliefs about the permanence of the abilities are called mindsets; someone with a fixed mindset typically perceives human qualities (e.g., intelligence) as fixed, while someone with a growth mindset perceives them as amenable to change and improvement through learning. This paper investigates the concept of mindset in the context of self-tracking and uses online survey data from individuals wearing a self-tracking device (n = 290) to explore the ways in which users with different mindsets experience self-tracking. A combination of qualitative and quantitative approaches indicates that implicit beliefs about the changeability of behavior influence the extent to which users are self-determined toward self-tracking use. Moreover, differences were found in how users perceive and respond to failure, and how self-judgmental vs. self-compassionate they are toward their own mistakes. Overall, considering that how users respond to the self-tracking data is one of the core dimensions of self-tracking, our results suggest that mindset is one of the important determinants in shaping the self-tracking experience. This paper concludes by presenting design considerations and directions for future research.
Older Adult Use and Outcomes in a Digital Musculoskeletal (MSK) Program, by Generation
Authors: Wang Grace , Bailey Jeannie F. , Yang Manshu , Krauss Jeffrey
Published: August 2021

Objective: We investigated use and clinical outcomes in a digital musculoskeletal (MSK) program, by generation.

Method: This longitudinal study uses retrospective data collected online or by app. The study included adults with 12 or more weeks of pain who took part in a digital MSK program. We compared Gen Z and Millennials, Gen X, working age Baby Boomers, and retiree age Baby Boomer and Silent Generation. Program use outcomes were program start, program completion, and number of exercises, educational articles, and messages to coaches. Clinical outcomes were changes in pain, depression, and anxiety from baseline to 12 weeks. We calculated descriptive statistics and conducted adjusted regression models.

Results: Odds of starting the program were significantly higher for Gen Xers (OR: 1.12) and working age Baby Boomers (OR: 1.37) vs. Gen Zers and Millennials. Compared to Gen Zers and Millennials, we observed significantly higher odds of program completion among Gen Xers (OR: 1.62), working age Baby Boomers (OR: 2.24), and retirees (OR: 2.36). Compared to Gen Zers and Millennials, retirees had 19 more exercise sessions (IRR: 1.69), accessed 11 more articles (IRR: 1.84), and sent 4 more messages to coaches (IRR: 1.26). Compared to Gen Z and Millennials, we observed no significant differences in change in pain for Gen Xers, working age Baby Boomers, or retirees.

Conclusions: Adults from multiple generations took part in a digital MSK program. Findings suggest that older generations used a digital MSK program more than younger generations, but had similar pain outcomes.
Experimental Study on Influencing Factors of Aerosol Retention by Pool Scrubbing
Authors: Li Yuxiang , Tong Lili , Cao Xuewu
Published: August 2021

During the process of containment depressurization venting, a high-temperature and high-pressure carrier gas with aerosol may be released into the spent fuel pool by a multihole injector. This aerosol in the carrier gas can be removed by pool scrubbing. A small-scale pool scrubbing facility was built to study the aerosol pool scrubbing phenomenon using a multihole injector. In this study, a gaseous mixture of nitrogen and steam is used to simulate a carrier gas, and insoluble solid particles of TiO2 are used to simulate aerosols in the carrier gas. Seven tests were performed to examine the dependence of the decontamination factor (DF) on the pool depth, particle diameter, and steam mass fraction. The results show that log(1/(1–Xm)) has a linear relationship with log(DF). DF varies exponentially with the pool depth, which has an influence on the retention of aerosols with a larger particle diameter. Particle diameters in the range of 0.2–0.52 μm have little effect on the DF. For a low-depth pool scrubbing, the steam condensation mechanism is dominant and the particle diameter does not have a significant effect on the DF. Moreover, the pool scrubbing model is discussed, and an empirical correlation is proposed to evaluate the DF of a pool.
Earlier Snowmelt Advances Breeding Phenology of the Common Frog (Rana temporaria) but Increases the Risk of Frost Exposure and Wetland Drying
Authors: Bison Marjorie , Yoccoz Nigel G. , Carlson Bradley Z. , Klein Geoffrey , Laigle Idaline , Van Reeth Colin , Delestrade Anne
Published: August 2021

The alarming decline of amphibians around the world calls for complementary studies to better understand their responses to climate change. In mountain environments, water resources linked to snowmelt play a major role in allowing amphibians to complete tadpole metamorphosis. As snow cover duration has significantly decreased since the 1970s, amphibian populations could be strongly impacted by climate warming, and even more in high elevation sites where air temperatures are increasing at a higher rate than at low elevation. In this context, we investigated common frog (Rana temporaria) breeding phenology at two different elevations and explored the threats that this species faces in a climate change context. Our objectives were to understand how environmental variables influence the timing of breeding phenology of the common frog, and explore the threats that amphibians face in the context of climate change in mountain areas. To address these questions, we collected 11 years (2009–2019) of data on egg-spawning date, tadpole development stages, snowmelt date, air temperature, rainfall and drying up of wetland pools at ∼1,300 and ∼1,900 m a.s.l. in the French Alps. We found an advancement of the egg-spawning date and snowmelt date at low elevation but a delay at high elevations for both variables. Our results demonstrated a strong positive relationship between egg-spawning date and snowmelt date at both elevations. We also observed that the risk of frost exposure increased faster at high elevation as egg-spawning date advanced than at low elevation, and that drying up of wetland pools led to tadpole mortality at the high elevation site. Within the context of climate change, egg-spawning date is expected to happen earlier in the future and eggs and tadpoles of common frogs may face higher risk of frost exposure, while wetland drying may lead to higher larval mortality. However, population dynamics studies are needed to test these hypotheses and to assess impacts at the population level. Our results highlight climate-related threats to common frog populations in mountain environments, but additional research should be conducted to forecast how climate change may benefit or harm amphibian populations, and inform conservation and land management plans in the future.
Contemporary Oyster Reef Restoration: Responding to a Changing World
Authors: Howie Alice H. , Bishop Melanie J.
Published: August 2021

Globally, there is growing interest in restoring previously widespread oyster reefs to reinstate key ecosystem services such as shoreline protection, fisheries productivity and water filtration. Yet, since peak expiration of oysters in the 1800s, significant and ongoing environmental change has occurred. Estuaries and coasts are undergoing some of the highest rates of urbanization, warming and ocean acidification on the planet, necessitating novel approaches to restoration. Here, we review key design considerations for oyster reef restoration projects that maximize the probability that they will meet biological and socio-economic goals not only under present-day conditions, but into the future. This includes selection of sites, and where required, substrates and oyster species and genotypes for seeding, not only on the basis of their present and future suitability in supporting oyster survival, growth and reproduction, but also based on their match to specific goals of ecosystem service delivery. Based on this review, we provide a road map of design considerations to maximize the success of future restoration projects.
Phenotype and Genotype Study of Chinese POMT2-Related α-Dystroglycanopathy
Authors: Chen Xiao-Yu , Song Dan-Yu , Jiang Li , Tan Dan-Dan , Liu Yi-Dan , Liu Jie-Yu , Chang Xing-Zhi , Xing Guo-Gang , Toda Tatsushi , Xiong Hui
Published: August 2021

Objective

Alpha-dystroglycanopathy (α-DGP) is a subtype of muscular dystrophy caused by defects in the posttranslational glycosylation of α-dystroglycan (α-DG). Our study aimed to summarize the clinical and genetic features of POMT2-related α-DGP in a cohort of patients in China.

Methods

Pedigrees, clinical data, and laboratory tests of patients diagnosed with POMT2-related α-DGP were analyzed retrospectively. The pathogenicity of variants in POMT2 were predicted by bioinformatics software. The variants with uncertain significance were verified by further analysis.

Results

The 11 patients, comprising eight males and three females, were from nine non-consanguineous families. They exhibited different degrees of muscle weakness, ambulation, and intellectual impairment. Among them, three had a muscle-eye-brain disease (MEB)-like phenotype, five presented congenital muscular dystrophy with intellectual disability (CMD-ID), and three presented limb-girdle muscular dystrophy (LGMD). Overall, nine novel variants of POMT2, including two non-sense, one frameshift and six missense variants, were identified. The pathogenicity of two missense variants, c.1891G > C and c.874G > C, was uncertain based on bioinformatics software prediction. In vitro minigene analysis showed that c.1891G > C affects the splicing of POMT2. Immunofluorescence staining with the IIH6C4 antibody of muscle biopsy from the patient carrying the c.874G > C variant showed an apparent lack of expression.

Conclusion

This study summarizes the clinical and genetic characteristics of a cohort of POMT2-related α-DGP patients in China for the first time, expanding the mutational spectrum of the disease. Further study of the pathogenicity of some missense variants based on enzyme activity detection is needed.
Novel Immune Cell-Based Therapies to Eradicate High-Risk Acute Myeloid Leukemia
Authors: Limongello Roberto , Marra Andrea , Mancusi Antonella , Bonato Samanta , Hoxha Eni , Ruggeri Loredana , Hui Susanta , Velardi Andrea , Pierini Antonio
Published: August 2021

Adverse genetic risk acute myeloid leukemia (AML) includes a wide range of clinical-pathological entities with extremely poor outcomes; thus, novel therapeutic approaches are needed. Promising results achieved by engineered chimeric antigen receptor (CAR) T cells in other blood neoplasms have paved the way for the development of immune cell-based therapies for adverse genetic risk AML. Among these, adoptive cell immunotherapies with single/multiple CAR-T cells, CAR-natural killer (NK) cells, cytokine-induced killer cells (CIK), and NK cells are subjects of ongoing clinical trials. On the other hand, allogeneic hematopoietic stem cell transplantation (allo-HSCT) still represents the only curative option for adverse genetic risk AML patients. Unfortunately, high relapse rates (above 50%) and associated dismal outcomes (reported survival ~10–20%) even question the role of current allo-HSCT protocols and emphasize the urgency of adopting novel effective transplant strategies. We have recently demonstrated that haploidentical allo-HSCT combined with regulatory and conventional T cells adoptive immunotherapy (Treg-Tcon haplo-HSCT) is able to overcome disease-intrinsic chemoresistance, prevent leukemia-relapse, and improve survival of adverse genetic risk AML patients. In this Perspective, we briefly review the recent advancements with immune cell-based strategies against adverse genetic risk AML and discuss how such approaches could favorably impact on patients’ outcomes.
Case Report: Acquired Disseminated BCG in the Context of a Delayed Immune Reconstitution After Hematological Malignancy
Authors: Gies Vincent , Dieudonné Yannick , Morel Florence , Sougakoff Wladimir , Carapito Raphaël , Martin Aurélie , Weingertner Noëlle , Jacquel Léa , Hubele Fabrice , Kuhnert Cornelia , Jung Sophie , Schramm Frederic , Boyer Pierre , Hansmann Yves , Danion François , Korganow Anne-Sophie , Guffroy Aurélien
Published: August 2021

Context

Disseminated infections due to Mycobacterium bovis Bacillus Calmette-Guérin (BCG) are unusual and occur mostly in patients with inborn error of immunity (IEI) or acquired immunodeficiency. However, cases of secondary BCGosis due to intravesical BCG instillation have been described. Herein, we present a case of severe BCGosis occurring in an unusual situation.

Case Description

We report one case of severe disseminated BCG disease occurring after hematological malignancy in a 48-year-old man without BCG instillation and previously vaccinated in infancy with no complication. Laboratory investigations demonstrated that he was not affected by any known or candidate gene of IEI or intrinsic cellular defect involving IFNγ pathway. Whole genome sequencing of the BCG strain showed that it was most closely related to the M. bovis BCG Tice strain, suggesting an unexpected relationship between the secondary immunodeficiency of the patient and the acquired BCG infection.

Conclusion

This case highlights the fact that, in addition to the IEI, physicians, as well as microbiologists and pharmacists should be aware of possible acquired disseminated BCG disease in secondary immunocompromised patients treated in centers that administrate BCG for bladder cancers.
Granzyme A Produced by γ9δ2 T Cells Activates ER Stress Responses and ATP Production, and Protects Against Intracellular Mycobacterial Replication Independent of Enzymatic Activity
Authors: Rasi Valerio , Wood David C. , Eickhoff Christopher S. , Xia Mei , Pozzi Nicola , Edwards Rachel L. , Walch Michael , Bovenschen Niels , Hoft Daniel F.
Published: August 2021

Mycobacterium tuberculosis(Mtb), the pathological agent that causes tuberculosis (TB) is the number one infectious killer worldwide with one fourth of the world’s population currently infected. Data indicate that γ9δ2T cells secrete Granzyme A (GzmA) in the extracellular space triggering the infected monocyte to inhibit growth of intracellular mycobacteria. Accordingly, deletion ofGZMAfrom γ9δ2T cells reverses their inhibitory capacity. Through mechanistic studies, GzmA’s action was investigated in monocytes from human PBMCs. The use of recombinant human GzmA expressed in a mammalian system induced inhibition of intracellular mycobacteria to the same degree as previous human native protein findings. Our data indicate that: 1) GzmA is internalized within mycobacteria-infected cells, suggesting that GzmA uptake could prevent infection and 2) that the active site is not required to inhibit intracellular replication. Global proteomic analysis demonstrated that the ER stress response and ATP producing proteins were upregulated after GzmA treatment, and these proteins abundancies were confirmed by examining their expression in an independent set of patient samples. Our data suggest that immunotherapeutic host interventions of these pathways may contribute to better control of the current TB epidemic.
Downregulation of CD45 Signaling in COVID-19 Patients Is Reversed by C24D, a Novel CD45 Targeting Peptide
Authors: Alon Danny , Paitan Yossi , Robinson Eyal , Ganor Nirit , Lipovetsky Julia , Yerushalmi Rinat , Cohen Cyrille J. , Raiter Annat
Published: August 2021

CD45, the predominant transmembrane tyrosine phosphatase in leukocytes, is required for the efficient induction of T cell receptor signaling and activation. We recently reported that the CD45-intracellular signals in peripheral blood mononuclear cells (PBMCs) of triple negative breast cancer (TNBC) patients are inhibited. We also reported that C24D, an immune modulating therapeutic peptide, binds to CD45 on immune-suppressed cells and resets the functionality of the immune system via the CD45 signaling pathway. Various studies have demonstrated that also viruses can interfere with the functions of CD45 and that patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are immune-suppressed. Given the similarity between the role of CD45 in viral immune suppression and our findings on TNBC, we hypothesized that the C24D peptide may have a similar “immune-resetting” effect on PBMCs from COVID-19 patients as it did on PBMCs from TNBC patients. We tested this hypothesis by comparing the CD45/TCR intracellular signaling in PBMCs from ten COVID-19 patients vs. PBMCs from ten healthy volunteers. Herein, we report our findings, demonstrating the immune reactivating effect of C24D via the phosphorylation of the tyrosine 505 and 394 in Lck, the tyrosine 493 in ZAP-70 and the tyrosine 172 in VAV-1 proteins in the CD45 signaling pathway. Despite the relatively small number of patients in this report, the results demonstrate that C24D rescued CD45 signaling. Given the central role played by CD45 in the immune system, we suggest CD45 as a potential therapeutic target.
Decisive Effects of Life Stage on the Gut Microbiota Discrepancy Between Two Wild Populations of Hibernating Asiatic Toads (Bufo gargarizans)
Authors: Song Xiaowei , Zhang Jingwei , Song Jinghan , Zhai Yuanyuan
Published: August 2021

Until now, the effects of driving factors on the gut microbiota of amphibians are still mostly confounded. Due to a long-term fasting, hibernating amphibians are ideal experimental materials to explore this question. In this study, we characterized the small intestine microbiota of adult hibernating Asiatic toads (Bufo gargarizans) collected from two geographical populations using 16S rRNA amplicon sequencing technique and evaluated the effects of non-dietary factors (e.g., sex and host genetic background). Proteobacteria (0.9196 ± 0.0892) was characterized as the most dominant phylum in the small gut microbiota of hibernating Asiatic toads, among which five core OTUs were identified and three were classified into Pseudomonas. In view of the coincidence between the dominant KEGG pathways (such as the two-component system) and Pseudomonas, Pseudomonas appeared to be a key adaptor for small gut microbiota during hibernation. Furthermore, we detected a greater discrepancy of gut microbiota between geographical populations than between sexes. Both sex and host genetic background showed a minor effect on the gut microbiota variation. Finally, life stage was determined to be the decisive factor driving the gut microbiota discrepancy between populations. However, a large proportion of the gut microbiota variation (∼70%) could not be explained by the measured deterministic factors (i.e., sex, location, body length, and routine blood indices). Therefore, other factors and/or stochastic processes may play key roles in shaping gut bacterial community of hibernating amphibians.
Purification and Characterization of a Thermo- and pH-Stable Laccase From the Litter-Decomposing Fungus Gymnopus luxurians and Laccase Mediator Systems for Dye Decolorization
Authors: Sun Yue , Liu Zi-Lu , Hu Bo-Yang , Chen Qing-Jun , Yang Ai-Zhen , Wang Qiu-Ying , Li Xiao-Feng , Zhang Jia-Yan , Zhang Guo-Qing , Zhao Yong-Chang
Published: August 2021

An extracellular laccase (GLL) was purified from fermentation broth of the litter-decomposing fungus Gymnopus luxurians by four chromatography steps, which resulted in a high specific activity of 118.82 U/mg, purification fold of 41.22, and recovery rate of 42.05%. It is a monomeric protein with a molecular weight of 64 kDa and N-terminal amino acid sequence of AIGPV TDLHI, suggesting that GLL is a typical fungal laccase. GLL demonstrated an optimum temperature range of 55°C–65°C and an optimum pH 2.2 toward 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). It displayed considerably high thermostability and pH stability with about 63% activity retained after 24 h at 50°C, and 86% activity retained after 24 h at pH 2.2, respectively. GLL was significantly enhanced in the presence of K+, Na+, and Mg2+ ions. It demonstrated Km of 539 μM and kcat/Km of 140 mM–1⋅s–1 toward ABTS at pH 2.2 and 37°C. Acetosyringone (AS) and syringaldehyde (SA) were the optimal mediators of GLL (0.4 U/ml) for dye decolorization with decolorization rates of about 60%–90% toward 11 of the 14 synthetic dyes. The optimum reaction conditions were determined to be mediator concentration of 0.1 mM, temperature range of 25°C –60°C, and pH 4.0. The purified laccase was the first laccase isolated from genus Gymnopus with high thermostability, pH stability, and effective decolorization toward dyes, suggesting that it has potentials for textile and environmental applications.
Understanding Intra-Species and Inter-Species Prion Conversion and Zoonotic Potential Using Protein Misfolding Cyclic Amplification
Authors: Peden Alexander H. , Suleiman Suzanne , Barria Marcelo A.
Published: August 2021

Prion diseases are fatal neurodegenerative disorders that affect humans and animals, and can also be transmitted from animals to humans. A fundamental event in prion disease pathogenesis is the conversion of normal host prion protein (PrPC) to a disease-associated misfolded form (PrPSc). Whether or not an animal prion disease can infect humans cannot be determineda priori. There is a consensus that classical bovine spongiform encephalopathy (C-type BSE) in cattle transmits to humans, and that classical sheep scrapie is of little or no risk to human health. However, the zoonotic potential of more recently identified animal prion diseases, such as atypical scrapie, H-type and L-type BSE and chronic wasting disease (CWD) in cervids, remains an open question. Important components of the zoonotic barrier are (i) physiological differences between humans and the animal in question, (ii) amino acid sequence differences of the animal and human PrPC, and (iii) the animal prion strain, enciphered in the conformation of PrPSc. Historically, the direct inoculation of experimental animals has provided essential information on the transmissibility and compatibility of prion strains. More recently, cell-free molecular conversion assays have been used to examine the molecular compatibility on prion replication and zoonotic potential. One such assay is Protein Misfolding Cyclic Amplification (PMCA), in which a small amount of infected tissue homogenate, containing PrPSc, is added as a seed to an excess of normal tissue homogenate containing PrPC, and prion conversion is accelerated by cycles of incubation and ultrasonication. PMCA has been used to measure the molecular feasibility of prion transmission in a range of scenarios using genotypically homologous and heterologous combinations of PrPScseed and PrPCsubstrate. Furthermore, this method can be used to speculate on the molecular profile of PrPScthat might arise from a zoonotic transmission. We discuss the experimental approaches that have been used to model both the intra- and inter-species molecular compatibility of prions, and the factors affecting PrPcto PrPScconversion and zoonotic potential. We conclude that cell-free prion protein conversion assays, especially PMCA, are useful, rapid and low-cost approaches for elucidating the mechanisms of prion propagation and assessing the risk of animal prions to humans.
miR-124-3p Inhibits Microglial Secondary Inflammation After Basal Ganglia Hemorrhage by Targeting TRAF6 and Repressing the Activation of NLRP3 Inflammasome
Authors: Fang Yudan , Hong Xiaoqin
Published: August 2021

Objectives: Intracerebral hemorrhage (ICH) represents a serious central nervous system emergency with high morbidity and mortality, and the basal ganglia is the most commonly affected brain region. Differentially expressed microRNAs (miRs) have recently been highlighted to serve as potential diagnostic biomarkers and therapeutic targets for ICH. This study investigated the mechanism of miR-124-3p in microglial secondary inflammation after ICH.

Methods: In this study, 48 patients with primary basal ganglia ICH and 48 healthy volunteers were selected and venous blood was collected from all patients on the second morning of admission (within 24 h of stroke onset). The expression of miR-124-3p in serum was detected by RT-qPCR. Three months after ICH, the patients were assessed by modified Rankin Scale (mRS), and the correlation between miR-124-3p expression and mRS score was analyzed by Pearson. The inflammatory response of microglia was induced by lipopolysaccharide (LPS) to establish the cell model of microglial inflammation. miR-124-3p expression patterns were detected in the serum of ICH patients and healthy volunteers, normal microglia, and LPS-induced microglia. The miR-124-3p mimic was transfected into LPS-induced microglia, followed by measurement of the inflammatory factors, apoptosis rate, and cell viability. The target gene of miR-124-3p was predicted and verified. The expression patterns of tumor necrosis factor receptor-associated factor 6 (TRAF6) were detected. pcDNA3.1 and pcDNA3.1-TRAF6 were transfected into LPS-induced HMC3 cells, and nucleotide-binding oligomerization domain-like receptor (NLR) pyrin domain-containing 3 (NLRP3) expression patterns were determined. Lastly, the effects of TRAF6 overexpression on apoptosis, cell viability, and inflammation in HMC3 cells were measured.

Results: miR-124-3p was downregulated in the serum of basal ganglia ICH patients and LPS-induced microglia, and miR-124-3p expression was negatively correlated with mRS. Overexpression of miR-124-3p reduced the inflammatory factors and apoptosis rate and promoted cell activity in LPS-induced microglia. miR-124-3p was found to target TRAF6. Overexpression of TRAF6 enhanced the expression of NLRP3 inflammasome, inflammatory factors and apoptosis rate, and reduced cell viability.

Conclusion: Our findings indicate that miR-124-3p repressed the activation of NLRP3 inflammasome by targeting TRAF6, thus inhibiting microglial secondary inflammation after ICH in basal ganglia.
LncRNA GAS5 as miR-26a-5p Sponge Regulates the PTEN/PI3K/Akt Axis and Affects Extracellular Matrix Synthesis in Degenerative Nucleus Pulposus Cells in vitro
Authors: Tan Liang , Xie Yifang , Yuan Ye , Hu Kai
Published: August 2021

The role of lncRNA growth arrest specific 5 (GAS5) in degenerative nucleus pulposus cell (NPC) apoptosis has been reported, but the mechanism of GAS5 in extracellular matrix (ECM) synthesis in intervertebral disc degeneration (IDD) remains unknown. We aimed to investigate the mechanism of GAS5 in ECM synthesis in degenerative NPCs. GAS5 expression was measured in degenerative NPCs (CP-H170) and normal NPCs (CP-H097). siRNA-mediated GAS5 knockdown was transfected to NPCs to detect cell viability and the expression of ECM-related genes (Collagen II, aggrecan, Collagen I, and MMP-3). Subcellular localization of GAS5 was analyzed. The downstream gene and pathway of GAS5 in degenerative NPCs were explored. As our results indicated, lncRNA GAS5 was upregulated in degenerative NPCs. Silencing GAS5 improved the viability of degenerative NPCs and increased ECM synthesis. GAS5 was mainly located in the cytoplasm of NPCs. LncRNA GAS5 sponged miR-26a-5p to regulate PTEN. Overexpression of miR-26a-5p promoted ECM synthesis in degenerative NPCs. Akt inhibitor LY294002 reversed the promotion of silencing GAS5 on ECM synthesis of degenerative NPCs. In conclusion, lncRNA GAS5 sponged miR-26a-5p to upregulate PTEN and inhibit the PI3K/Akt pathway, thus inhibiting ECM synthesis of degenerative NPCs.
Poor Sleep Quality in Nurses Working or Having Worked Night Shifts: A Cross-Sectional Study
Authors: Huang Qiao , Tian Chong , Zeng Xian-Tao
Published: August 2021

Night shifts are part of clinical care. It is unclear whether poor sleep quality of nurses working both consecutive night shifts and day shifts after quitting night shifts is common. In this cross-sectional study, Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality as study outcome. Univariable and multivariable linear and logistic regressions were performed to compare PSQI score and prevalence of poor sleep quality between 512 nurses currently working consecutive night shifts and 174 nurses having worked night shifts in the past. The prevalence of poor sleep quality was 62.11% in nurses working consecutive night shifts and 55.75% in nurses having worked night shifts before. In multivariable regressions with adjustment for potential confounders, compared with nurses working consecutive night shifts, nurses having worked past night shifts reported decreased PSQI score [mean difference: −0.82 (95% CI: −1.27 to −0.38, p < 0.001)] and lower poor sleep quality [odds ratio (OR): 0.49 (95% CI: 0.29 to 0.80, p = 0.005)]. In nurses working consecutive night shifts, a rising curve that plateaued at the end was observed between years of consecutive night shifts and PSQI score, p = 0.004. To explore the change in PSQI score after quitting night shift, we constructed a hypothetical prospective cohort from the cross-sectional data. Here, 98 pairs of nurses with consecutive and past night shifts were matched for the number of night shift years, religion, marital status, living condition, hypertension, and hyperlipidemia. In each pair, a hypothetical change in PSQI score was calculated between the two types of nurses and hypothetical years after quitting night shifts was obtained from the matched nurse with past night shifts. A U-shaped curve between change in PSQI and years after quitting night shifts was observed, p = 0.007. The rising curve and U-shaped curve together formed an S-shaped curve, which mapped the change in sleep quality. These results based on the hypothetical cohort constructed from cross-sectional data suggested the presence of persistent poor sleep quality in night shift nurses. Also, we support early and continuous sleep hygiene education and reflection for an optimal strategy for when to cease working night shifts with regard to sleep-related problems.