bluuebunny/crossref_metadata_2025 huggingface dataset:
Different Active Microbial Communities in Two Contrasted Subantarctic Fjords
Authors: Maturana-Martínez Claudia , Fernández Camila , González Humberto E. , Galand Pierre E.
Published: June 2021

Microorganisms play a crucial role in biogeochemical processes affecting the primary production and biogeochemical cycles of the ocean. In subpolar areas, the increment of the water temperature induced by climate change could lead to changes in the structure and activity of planktonic microbial communities. To understand how the structure of the microbial community in Chilean Patagonian fjords could be affected by climate change, we analyzed the composition of the prokaryotic community (bacteria-archaea) in two fjords (Pia and Yendegaia) with contrasting morphological and hydrological features. We targeted both the standing stock (16S rRNA genes) and the active fraction (16S rRNA transcripts) of the microbial communities during two consecutive austral winters. Our results showed that in both fjords, the active community had higher diversity and stronger biogeographic patterns when compared to the standing stock. Members of the Alpha-, Gamma-, and Deltaproteobacteria followed by archaea from the Marine Group I (Thaumarchaeota) dominated the active communities in both fjords. However, in Pia fjord, which has a marine-terminating glacier, the composition of the microbial community was directly influenced by the freshwater discharges from the adjacent glacier, and indirectly by a possible upwelling phenomenon that could bring deep sea bacteria such as SAR202 to the surface layer. In turn, in the Yendegaia, which has a land-terminating glacier, microbial communities were more similar to the ones described in oceanic waters. Furthermore, in Yendegaia fjord, inter-annual differences in the taxonomic composition and diversity of the microbial community were observed. In conclusion, Yendegaia fjord, without glacier calving, represents a fjord type that will likely be more common under future climate scenarios. Our results showing distinct Yendegaia communities, with for example more potential nitrogen-fixing microorganisms (Planctomycetes), indicate that as a result of climate change, changing planktonic communities could potentially impact biogeochemical processes and nutrient sources in subantarctic fjords.
Unravelling the Importance of Diazotrophy in Corals – Combined Assessment of Nitrogen Assimilation, Diazotrophic Community and Natural Stable Isotope Signatures
Authors: Bednarz Vanessa N. , van de Water Jeroen A. J. M. , Grover Renaud , Maguer Jean-François , Fine Maoz , Ferrier-Pagès Christine
Published: June 2021

There is an increasing interest in understanding the structure and function of the microbiota associated with marine and terrestrial organisms, because it can play a major role in host nutrition and resistance to environmental stress. Reef-building corals live in association with diazotrophs, which are microbes able to fix dinitrogen. Corals are known to assimilate diazotrophically-derived nitrogen (DDN), but it is still not clear whether this nitrogen source is derived from coral-associated diazotrophs and whether it substantially contributes to the coral’s nitrogen budget. In this study, we aimed to provide a better understanding of the importance of DDN for corals using a holistic approach by simultaneously assessing DDN assimilation rates (using15N2tracer technique), the diazotrophic bacterial community (usingnifHgene amplicon sequencing) and the natural δ15N signature inStylophora pistillatacorals from the Northern Red Sea along a depth gradient in winter and summer. Overall, our results show a discrepancy between the three parameters. DDN was assimilated by the coral holobiont during winter only, with an increased assimilation with depth. Assimilation rates were, however, not linked to the presence of coral-associated diazotrophs, suggesting that the presence ofnifHgenes does not necessarily imply functionality. It also suggests that DDN assimilation was independent from coral-associated diazotrophs and may instead result from nitrogen derived from planktonic diazotrophs. In addition, the δ15N signature presented negative values in almost all coral samples in both seasons, suggesting that nitrogen sources other than DDN contribute to the nitrogen budget of corals from this region. This study yields novel insight into the origin and importance of diazotrophy for scleractinian corals from the Northern Red Sea using multiple proxies.
Temporal Microbial Community Dynamics Within a Unique Acid Saline Lake
Authors: Ghori Noor-Ul-Huda , Wise Michael J. , Whiteley Andrew S.
Published: June 2021

Lake Magic is an extremely acidic, hypersaline lake found in Western Australia, with the highest concentrations of aluminum and silica in the world. Previous studies of Lake Magic diversity have revealed that the lake hosts acid- and halotolerant bacterial and fungal species. However, they have not canvassed microbial population dynamics across flooding, evapo-concentration and desiccation stages. In this study, we used amplicon sequencing and potential function prediction on sediment and salt mat samples. We observed that the bacterial and fungal diversity in Lake Magic is strongly driven by carbon, temperature, pH and salt concentrations at the different stages of the lake. We also saw that the fungal diversity decreased as the environmental conditions became more extreme. However, prokaryotic diversity was very dynamic and bacteria dominated archaeal species, both in abundance and diversity, perhaps because bacteria better tolerate the extreme variation in conditions. Bacterial species diversity was the highest during early flooding stage and decreased during more stressful conditions. We observed an increase in acid tolerant and halotolerant species in the sediment, involved in functions such as sulfur and iron metabolism, i.e., species involved in buffering the external environment. Thus, due to activity within the microbial community, the environmental conditions in the sediment do not change to the same degree as conditions in the salt mat, resulting in the sediment becoming a safe haven for microbes, which are able to thrive during the extreme conditions of the evapo-concentration and desiccation stages.
RNA Virus-Encoded miRNAs: Current Insights and Future Challenges
Authors: Nanbo Asuka , Furuyama Wakako , Lin Zhen
Published: June 2021

MicroRNAs are small non-coding RNAs that regulate eukaryotic gene expression at the post-transcriptional level and affect a wide range of biological processes. Over the past two decades, numerous virus-encoded miRNAs have been identified. Some of them are crucial for viral replication, whereas others can help immune evasion. Recent sequencing-based bioinformatics methods have helped identify many novel miRNAs, which are encoded by RNA viruses. Unlike the well-characterized DNA virus-encoded miRNAs, the role of RNA virus-encoded miRNAs remains controversial. In this review, we first describe the current knowledge of miRNAs encoded by various RNA viruses, including newly emerging viruses. Next, we discuss how RNA virus-encoded miRNAs might facilitate viral replication, immunoevasion, and persistence in their hosts. Last, we briefly discuss the challenges in the experimental methodologies and potential applications of miRNAs for diagnosis and therapeutics.
Thermonucleases Contribute to Staphylococcus aureus Biofilm Formation in Implant-Associated Infections–A Redundant and Complementary Story
Authors: Yu Jinlong , Jiang Feng , Zhang Feiyang , Hamushan Musha , Du Jiafei , Mao Yanjie , Wang Qiaojie , Han Pei , Tang Jin , Shen Hao
Published: June 2021

Biofilms formed by Staphylococcus aureus are one of the predominant causes of implant-associated infections (IAIs). Previous studies have found that S. aureus nucleases nuc1 and nuc2 modulate biofilm formation. In this study, we found low nuc1/nuc2 expression and high biofilm-forming ability among IAI isolates. Furthermore, in a mouse model of exogenous IAIs, Δnuc1/2 exhibited higher bacterial load on the surface of the implant than that exhibited by the other groups (WT, Δnuc1, and Δnuc2). Survival analysis of the hematogenous IAI mouse model indicated that nuc1 is a virulence factor related to mortality. We then detected the influence of nuc1 and nuc2 on biofilm formation and immune evasion in vitro. Observation of in vitro biofilm structures with scanning electron microscopy and evaluation of bacterial aggregation with flow cytometry revealed that both nuc1 and nuc2 are involved in biofilm structuring and bacterial aggregation. Unlike nuc1, which is reported to participate in immune evasion, nuc2 cannot degrade neutrophil extracellular traps. Moreover, we found that nuc1/nuc2 transcription is negatively correlated during S. aureus growth, and a possible complementary relationship has been proposed. In conclusion, nuc1/nuc2 are complementary genes involved in biofilm formation in exogenous IAIs. However, nuc2 contributes less to virulence and is not involved in immune evasion.
The Effects of Environmental Adversities on Human Neocortical Neurogenesis Modeled in Brain Organoids
Authors: Sarieva Kseniia , Mayer Simone
Published: June 2021

Over the past decades, a growing body of evidence has demonstrated the impact of prenatal environmental adversity on the development of the human embryonic and fetal brain. Prenatal environmental adversity includes infectious agents, medication, and substances of use as well as inherently maternal factors, such as diabetes and stress. These adversities may cause long-lasting effects if occurring in sensitive time windows and, therefore, have high clinical relevance. However, our knowledge of their influence on specific cellular and molecular processes ofin uterobrain development remains scarce. This gap of knowledge can be partially explained by the restricted experimental access to the human embryonic and fetal brain and limited recapitulation of human-specific neurodevelopmental events in model organisms. In the past years, novel 3D human stem cell-basedin vitromodeling systems, so-called brain organoids, have proven their applicability for modeling early events of human brain development in health and disease. Since their emergence, brain organoids have been successfully employed to study molecular mechanisms of Zika and Herpes simplex virus-associated microcephaly, as well as more subtle events happening upon maternal alcohol and nicotine consumption. These studies converge on pathological mechanisms targeting neural stem cells. In this review, we discuss how brain organoids have recently revealed commonalities and differences in the effects of environmental adversities on human neurogenesis. We highlight both the breakthroughs in understanding the molecular consequences of environmental exposures achieved using organoids as well as the on-going challenges in the field related to variability in protocols and a lack of benchmarking, which make cross-study comparisons difficult.
Case Report: Subtotal Hemispherotomy Modulates the Epileptic Spasms in Aicardi Syndrome
Authors: Iimura Yasushi , Sugano Hidenori , Mitsuhashi Takumi , Ueda Tetsuya , Karagiozov Kostadin , Abe Shimpei , Otsubo Hiroshi
Published: June 2021

The mechanism of epileptic spasms (ES) in Aicardi syndrome (AS) remains obscure. We compared intraoperative high-frequency oscillations (HFOs) and phase-amplitude coupling (PAC) before and after subtotal hemispherotomy in a 3-month-old girl with drug-resistant ES secondary to AS. Fetal ultrasonography showing corpus callosum agenesis, bilateral ventricular dilatation, and a large choroid plexus cyst confirmed AS diagnosis. Her ES started when she was 1 month old and had ten series of clustered ES per day despite phenobarbital and vitamin B6 treatment. After subtotal hemispherotomy, her ES dramatically improved. We analyzed two intraoperative electrocorticography modalities: (1), occurrence rate (OR) of HFOs; (2), PAC of HFOs and slow wave bands in the frontal, central, and parietal areas. We hypothesized that HFOs and PAC could be the biomarkers for efficacy of subtotal hemispherotomy in AS with ES. PAC in all three areas and OR of HFOs in the frontal and parietal areas significantly decreased, while OR of HFOs in the central area remained unchanged after subtotal hemispherotomy. We have demonstrated the usefulness of evaluating intraoperative HFOs and PAC to assess subtotal hemispherotomy effectiveness in AS patients with ES. Disconnecting the thalamocortical and subcortical pathways in the epileptic network plays a role in controlling ES generation.
An Investigation of a Frontal Negative Slow Wave in a Virtual Hedonic Purchase Task
Authors: Mei Yupeng , Jing Kunpeng , Chen Lele , Shi Rui , Song Zhijie
Published: June 2021

There is a connection between the frontal negative slow wave (FNSW) and the arousal inhibition in the hedonic purchase context. To calculate the FNSW (400–800 ms), event-related potentials (ERPs) method was applied to depict the neural substrates on prudent and impulsive consumers’ behaviors within various states of promotion. Promotion types include the pure price promotion and the mixed promotion (a mixture of a charitable donation and a discount). Behaviorally, consumers response more quickly in the pure price promotion condition and they express a preference for the mixed promotion. More importantly, a larger FNSW emerged in the impulsive consumers than the prudent, suggesting that the former might tend to control their eagerness to consume hedonic items. Compared with the price promotion as the worse option, the mixed promotion as the better option caused more perceptual conflict, leading to an increase in N2 amplitude. It suggests that consumers incline to reject the worse offers. These results also reveal that people primarily have to search negative promotion information by their insight and subsequently impulsive consumers inhibit the responses to the promotion information. The method of ERPs and FNSW should be helpful for marketing researchers and professionals on hedonic consumption and sales promotion.
DarkASDNet: Classification of ASD on Functional MRI Using Deep Neural Network
Authors: Ahammed Md Shale , Niu Sijie , Ahmed Md Rishad , Dong Jiwen , Gao Xizhan , Chen Yuehui
Published: June 2021

Non-invasive whole-brain scans aid the diagnosis of neuropsychiatric disorder diseases such as autism, dementia, and brain cancer. The assessable analysis for autism spectrum disorders (ASD) is rationally challenging due to the limitations of publicly available datasets. For diagnostic or prognostic tools, functional Magnetic Resonance Imaging (fMRI) exposed affirmation to the biomarkers in neuroimaging research because of fMRI pickup inherent connectivity between the brain and regions. There are profound studies in ASD with introducing machine learning or deep learning methods that have manifested advanced steps for ASD predictions based on fMRI data. However, utmost antecedent models have an inadequacy in their capacity to manipulate performance metrics such as accuracy, precision, recall, and F1-score. To overcome these problems, we proposed an avant-garde DarkASDNet, which has the competence to extract features from a lower level to a higher level and bring out promising results. In this work, we considered 3D fMRI data to predict binary classification between ASD and typical control (TC). Firstly, we pre-processed the 3D fMRI data by adopting proper slice time correction and normalization. Then, we introduced a novel DarkASDNet which surpassed the benchmark accuracy for the classification of ASD. Our model's outcomes unveil that our proposed method established state-of-the-art accuracy of 94.70% to classify ASD vs. TC in ABIDE-I, NYU dataset. Finally, we contemplated our model by performing evaluation metrics including precision, recall, F1-score, ROC curve, and AUC score, and legitimize by distinguishing with recent literature descriptions to vindicate our outcomes. The proposed DarkASDNet architecture provides a novel benchmark approach for ASD classification using fMRI processed data.
Exosomal circRNA in Digestive System Tumors: The Main Player or Coadjuvants?
Authors: Wang Haoying , Zeng Xi , Zheng Ya , Wang Yuping , Zhou Yongning
Published: June 2021

Exosomes are a type of extracellular microvesicles with a diameter of 40–160 nm. Circular RNA (circRNA) is a type of closed circular RNA molecule that is highly conserved in evolution. Exosomal circRNA plays a vital role in the proliferation, invasion, migration, and drug resistance of digestive system tumors. In this study, we used The Cancer Genome Atlas (TCGA) database, UALCAN, Python crawler, miRTargetLink Human, Database for Annotation, Visualization, and Integrated Discovery (DAVID), micBioinformatic online tool, and Cytoscape software (3.7.1). The results showed that circ-RanGAP1 in gastric cancer, circUHRF1 in hepatocellular carcinoma, and circFMN2 in colorectal cancer regulate the malignant behavior of tumors and affect the expression of their host gene through sponging miR-877-3p, miR-449c-5p, and miR-1182, respectively. Twenty exosomal circRNAs regulate 6,570 target genes through sponging 23 miRNAs. Firstly, 270 of those target genes are regulated by two or more miRNAs, which are highly correlated with 83 tumor-related pathways and six Kyoto Encyclopedia of Genes and Genomes pathways. Secondly, 1,146 target genes were significantly differentially expressed in corresponding digestive system tumors, and functional enrichment analysis revealed that 78 of those were involved in 20 cancer-related pathways. In short, the bioinformatics analysis showed that these exosomal circRNAs are stably expressed in body fluids, and regulate the occurrence and development of gastric cancer, hepatocellular carcinoma, colorectal cancer, and other digestive system tumors through sponging miRNAs. Exosomal circRNAs may be used as biomarkers for the diagnosis of disease and identification of effective therapeutic targets in the future, as well as improve the prognosis of patients with digestive system tumors.
Superb Microvascular Imaging Technology Can Improve the Diagnostic Efficiency of the BI-RADS System
Authors: Cai Siman , Wang Hongyan , Zhang Xiaoyan , Zhang Li , Zhu Qingli , Sun Qiang , Li Jianchu , Jiang Yuxin
Published: June 2021

Background

To explore whether superb microvascular imaging (SMI)SMI can improve the diagnostic efficiency by evaluating the vascular index (VI) and vascular architecture (VA) in breast lesions.

Methods

This is a retrospective study of data collected prospectively for research use. Taking 225 consecutive cases of breast lesions from November 2016 to December 2017 as a training set, the VI values and VA types of benign and malignant lesions were calculated based on the pathological results. Taking 238 consecutive cases of breast lesions from January 2018 to October 2018 as the verification set, the diagnostic sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated to compare the diagnostic efficacy.

Results

The training set included 225 breast lesions and the validation set 238 breast lesions. The VI value in the malignant group (10.3 ± 8.0) was significantly higher than that in the benign group (4.3 ± 5.0)(P<0.001). A VI value of 4.05 was used as the diagnostic threshold for differentiating benign from malignant lesions, with a sensitivity of 80.5%, a specificity of 61.9%, an accuracy of 71.1%, a PPV of 62.9%, a NPV of 76.9%, and an area under the curve of 0.758 (0.696-0.819). There was a significant difference in the types of benign and malignant VA (P < 0.001), and the PPV of the root hair-like and crab claw-like VAs were 93.9% and 100.0%, respectively. The diagnostic sensitivity, specificity, accuracy, PPV, NPV and area under the AUC curve were 58.0%, 98.2%, 97.0%, 70.3% and 0.781, respectively (95%CI: 0.719-0.844). SMI combined with conventional ultrasound improved the diagnostic specificity (70.0% vs. 90.0%), accuracy (87.4% vs. 96.6%), and PPV (82.5% vs. 93.2%) without decreasing the diagnostic sensitivity (99.3%), yielded higher diagnostic performance with the area under the ROC curve was 0.941 (95%CI: 0904-0.979) compared with conventional US alone (P < 0.001).

Conclusion

A VI value 4.05 is a cut-off value with good diagnostic efficacy. The residual root-like and crab claw-like VAs are the characteristic VAs of malignant lesions. Conventional ultrasound combined with the VI and VA can improve the diagnostic specificity, accuracy and PPV without reducing the diagnostic sensitivity.
Case Report: Re-Sensitization to Gefitinib in Lung Adenocarcinoma Harboring EGFR Mutation and High PD-L1 Expression After Immunotherapy Resistance, Which Finally Transform Into Small Cell Carcinoma
Authors: Zhai Xiaoqian , Liu Jiewei , Liang Zuoyu , Li Zhixi , Liu Yanyang , Huang Lin , Wang Weiya , Luo Feng
Published: June 2021

The treatment sequence of immunotherapy (IO) and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is of great importance for the survival of non-small cell lung cancer (NSCLC) patients with EGFR sensitive mutation. Here, we reported an advanced lung adenocarcinoma case concurrent with EGFR sensitive mutation and high PD-L1 expression (>50%) that was administrated with gefitinib firstly, and then became resistant to EGFR-TKI. He received the strategy of immunity-combined chemo-radiotherapy and responded significantly. However, the disease re-progressed after 10 months. Surprisingly, the tumor re-sensitized to gefitinib for 13 months. At final, following the treatment pressure of TKI-IO combination therapy-TKI strategy, tumor clone eventually transformed into small cell lung carcinoma (SCLC). For one thing, our study provided novel approach and extended the treatment spectra of overcoming immunotherapy resistance after EGFR resistance in driver oncogene-mutated NSCLC. For another thing, our case is the first time to report that SCLC transformation can be achieved after gefitinib–pembrolizumab–gefitinib resistance in EGFR sensitive mutation NSCLC, providing a new condition for SCLC transformation.
Epigenetics in the Pathogenesis and Treatment of Cutaneous T-Cell Lymphoma
Authors: Zhang Ping , Zhang Mingzhi
Published: June 2021

Cutaneous T-cell lymphomas (CTCLs) comprise a group of heterogeneous diseases involving malignant T cells. The pathogenesis and etiology of CTCL are still unclear, although a large number of genetic and epidemiological studies on CTCL have been conducted. Most CTCLs have an indolent course, making early diagnosis difficult. Once large-cell transformation occurs, CTCL progresses to more aggressive types, resulting in an overall survival of less than five years. Epigenetic drugs, which have shown certain curative effects, have been selected as third-line drugs in patients with relapsing and refractory CTCL. Many studies have also identified epigenetic biomarkers from tissues and peripheral blood of patients with CTCL and suggested that epigenetic changes play a role in malignant transformation and histone deacetylase inhibitor (HDACi) resistance in CTCL. Single-cell sequencing has been applied in CTCL studies, revealing heterogeneity in CTCL malignant T cells. The mechanisms of HDACi resistance have also been described, further facilitating the discovery of novel HDACi targets. Despite the heterogeneity of CTCL disease and its obscure pathogenesis, more epigenetic abnormalities have been gradually discovered recently, which not only enables us to understand CTCL disease further but also improves our understanding of the specific role of epigenetics in the pathogenesis and treatment. In this review, we discuss the recent discoveries concerning the pathological roles of epigenetics and epigenetic therapy in CTCL.
Small-Molecule Inhibitor Targeting Protein Kinase D: A Potential Therapeutic Strategy
Authors: Lv Die , Chen Hongli , Feng Yun , Cui Bomiao , Kang Yingzhu , Zhang Ping , Luo Min , Chen Jiao
Published: June 2021

The protein kinase D (PKD) family is a family of serine-threonine kinases that are members of the calcium/calmodulin-dependent kinase (CaMK) superfamily. PKDs have been increasingly implicated in multiple pivotal cellular processes and pathological conditions. PKD dysregulation is associated with several diseases, including cancer, inflammation, and obesity. Over the past few years, small-molecule inhibitors have emerged as alternative targeted therapy with fewer adverse side effects than currently available chemotherapy, and these specifically targeted inhibitors limit non-specific toxicities. The successful development of PKD inhibitors would significantly suppress the growth and proliferation of various cancers and inhibit the progression of other diseases. Various PKD inhibitors have been studied in the preclinical setting. In this context, we summarize the PKD inhibitors under investigation and their application for different kinds of diseases.
Case Report: Long-Term Survival With Anlotinib in a Patient With Advanced Undifferentiated Large-Cell Lung Cancer and Rare Tonsillar Metastasis
Authors: Xu Tianwei , Wei Chenchen , Zou Xiaoteng , Lu Binbin , Wang Zhaoxia
Published: June 2021

Undifferentiated large-cell lung cancer is a rare type of non-small cell lung cancer (NSCLC) with a poor prognosis. It is insensitive to chemotherapy and easily develops drug resistance. Analysis of the Surveillance, Epidemiology, and End Results (SEER) database showed that patients with stage IV undifferentiated large-cell lung cancer had a median overall survival (OS) of only 4 months and that those who received chemotherapy had a median OS of only 5 months longer than those who did not. For the first time, we report a case of advanced large-cell undifferentiated lung cancer with rare tonsil metastasis. The patient developed resistance after 3 months of platinum-based systemic chemotherapy and local treatment. Antiangiogenic therapy has been continuously progressing and has shown certain efficacy in treating many malignant tumors, such as lung cancer. However, there are no relevant studies or case reports on antiangiogenic therapy in the treatment of undifferentiated large-cell lung cancer. Anlotinib, an orally delivered small-molecule antiangiogenic tyrosine kinase inhibitor (TKI), was administered to this patient after chemotherapy resistance occurred, and the outcome was assessed as continued stable disease (SD). As of the last follow-up evaluation, the progression-free survival (PFS) of the patient was 21.5 months, and the OS was 27.5 months. Retrospective immunohistochemical analysis showed that the patient was positive for one of the targets of anlotinib (PDGFR). In general, the findings in this case suggest that anlotinib may be an option with good efficacy for patients with large-cell undifferentiated lung cancer after chemotherapy resistance that may have good efficacy and also suggest that PDGFR may be the target underlying this effect.
Prospective Observational Study of Bisphosphonate-Related Osteonecrosis of the Jaw in Multiple Myeloma: Microbiota Profiling and Cytokine Expression
Authors: Badros Ashraf Z. , Meddeb Mariam , Weikel Dianna , Philip Sunita , Milliron Todd , Lapidus Rena , Hester Lisa , Goloubeva Olga , Meiller Timothy F. , Mongodin Emmanuel F.
Published: June 2021

Purpose

Define incidence and risk factors of osteonecrosis of the jaw (ONJ) and explore oral microbial signatures and host immune response as reflected by cytokine changes in saliva and serum in multiple myeloma (MM) patients on bisphosphate (BP) therapy.

Patients and Methods

A single center observational prospective study of MM patients (n = 110) on >2 years of BP, none had ONJ at enrollment. Patients were followed every 3 months for 18 months with clinical/dental examination and serial measurements of inflammatory cytokines, bone turnover markers, and angiogenic growth factors. Oral microbiota was characterized by sequencing of 16S rRNA gene from saliva.

Results

Over the study period 14 patients (13%) developed BRONJ, at a median of 5.7 years (95% CI: 1.9–12.0) from MM diagnosis. Chronic periodontal disease was the main clinically observed risk factor. Oral microbial profiling revealed lower bacterial richness/diversity in BRONJ. Streptococcus intermedius, S. mutans, and S. perioris were abundant in controls; S. sonstellatus and S anginosus were prevalent in BRONJ. In the saliva, at baseline patients who developed BRONJ had higher levels of MIP-1β; TNF-α and IL-6 compared to those without BRONJ, cytokine profile consistent with M-1 macrophage activation. In the serum, patients with BRONJ have significantly lower levels of TGF beta and VEGF over the study period.

Conclusion

Periodontal disease associated with low microbial diversity and predominance of invasive species with a proinflammatory cytokine profile leading to tissue damage and alteration of immunity seems to be the main culprit in pathogenesis of BRONJ.
The Non-Steroidal Mineralocorticoid Receptor Antagonist KBP-5074 Limits Albuminuria and has Improved Therapeutic Index Compared With Eplerenone in a Rat Model With Mineralocorticoid-Induced Renal Injury
Authors: Jaisser Frédéric , Tan Xiaojuan , Chi Shuangshuang , Liu Jinrong , Wang Ping , Bush Mark , Benn Vincent , Yang Y. Fred , Zhang Jay
Published: June 2021

The therapeutic indices (TIs) and efficacy of the non-steroidal mineralocorticoid receptor antagonist (MRA) KBP-5074 and steroidal MRA eplerenone were evaluated in a uninephrectomized Sprague Dawley rat model of aldosterone-mediated renal disease. In two parallel studies, rats were placed on a high-salt diet and received aldosterone by osmotic mini-pump infusion over the course of 27 days. The urinary albumin-to-creatinine ratio (UACR) was evaluated after 7, 14, and 26 days of treatment. Serum K+ was evaluated after 14 and 27 days of treatment. Urinary Na+, urinary K+, and urinary Na+/K+ ratio were evaluated after 7, 14, and 26 days of treatment. The TI was calculated for each drug as the ratio of the concentration of drug producing 50% of maximum effect (EC50) for increasing serum K+ to the EC50 for lowering UACR. The TIs were 24.5 for KBP-5074 and 0.620 for eplerenone, resulting in a 39-fold improved TI for KBP-5074 compared with eplerenone. Aldosterone treatment increased UACR, decreased serum K+, and decreased urinary Na+ relative to sham-operated controls that did not receive aldosterone infusion in both studies, validating the aldosterone/salt renal injury model. KBP-5074 prevented the increase in UACR at 0.5, 1.5, and 5 mg/kg BID while eplerenone did so only at the two highest doses of 50 and 450 mg/kg BID. Both KBP-5074 and eplerenone blunted the reduction in serum K+ seen in the aldosterone treatment group, with significant increases in serum K+ at the high doses only (5 mg/kg and 450 mg/kg BID, respectively). Additionally, the urinary Na+ and Na+/K+ ratio significantly increased at the middle and high doses of KBP-5074, but only at the highest dose of eplerenone. These results showed increased TI and efficacy for KBP-5074 compared with eplerenone over a wider therapeutic window.
Clinical Analysis of Intravenous and Oral Sequential Treatment With Voriconazole for Candida Central Nervous System Infection in Six Premature Infants
Authors: Zhu Yingying , Gong Xiaohui , Li Zhiling , Wang Danni , Yan Chongbing
Published: June 2021

Objective: The aim of the study was to observe the clinical efficacy and safety of intravenous and oral sequential treatment with voriconazole for Candida central nervous system (CNS) infection in premature infants.

Methods: The study included retrospective analysis of the clinical data of six premature infants with Candida CNS infection admitted to the neonatology department in Shanghai Children’s Hospital between November 2016 and November 2019. By reviewing the characteristics of voriconazole based on the literature, it showed that infants without gastrointestinal dysfunction could be effectively treated by intravenous and oral sequential therapy with voriconazole (both 7 mg/kg/dose, every 12 h). Clinical manifestations, the time required for the cerebrospinal fluid (CSF), blood culture, nonspecific infection markers such as platelets and C-reactive protein (CRP) to turn normal, and drug-related side effects were observed and recorded in the process of treatment. All data were statistically analyzed by T test and Mann–Whitney U test.

Results: A total of six premature infants were diagnosed with Candida CNS infection, two cases were diagnosed by a positive CSF culture and four cases were clinically diagnosed. Blood culture was positive for Candida in five cases. Among the 6 patients, 4 cases were Candida albicans and 2 cases were Candida parapsilosis. All the six cases were cured. After 3–5 days of treatment, symptoms such as lethargy, apnea, and feeding intolerance were improved and disappeared; a repeated blood culture turned negative in 3–7 days; CSF returned to normal in 15 ± 9 days on an average. Brain abscess, meningeal inflammation, and other infectious lesions were cleared on cranial magnetic resonance imaging (MRI) after treatment. The average total course of voriconazole was 61 ± 29 days, and the average oral treatment was 28 ± 15 days. No Candida recurrence was found during the treatment, and no drug-related side effects such as skin rash, liver and kidney function impairment, or visual abnormalities were found. The white blood cells, CSF glucose/plasma glucose ratio, and protein in CSF were significantly improved after the treatment (p < 0.05). No statistically significant difference was identified in the liver and kidney function indexes (p > 0.05).

Conclusion: Voriconazole is a relatively safe and effective alternative treatment for Candida CNS infection in preterm infants. No severe drug-related side effects were detected.
Identification of Koumine as a Translocator Protein 18 kDa Positive Allosteric Modulator for the Treatment of Inflammatory and Neuropathic Pain
Authors: Xiong Bojun , Jin Guilin , Xu Ying , You Wenbing , Luo Yufei , Fang Menghan , Chen Bing , Huang Huihui , Yang Jian , Lin Xu , Yu Changxi
Published: June 2021

Koumine is an alkaloid that displays notable activity against inflammatory and neuropathic pain, but its therapeutic target and molecular mechanism still need further study. Translocator protein 18 kDa (TSPO) is a vital therapeutic target for pain treatment, and recent research implies that there may be allostery in TSPO. Our previous competitive binding assay hint that koumine may function as a TSPO positive allosteric modulator (PAM). Here, for the first time, we report the pharmacological characterization of koumine as a TSPO PAM. The results imply that koumine might be a high-affinity ligand of TSPO and that it likely acts as a PAM since it could delay the dissociation of 3H-PK11195 from TSPO. Importantly, the allostery was retained in vivo, as koumine augmented Ro5-4864-mediated analgesic and anti-inflammatory effects in several acute and chronic inflammatory and neuropathic pain models. Moreover, the positive allosteric modulatory effect of koumine on TSPO was further demonstrated in cell proliferation assays in T98G human glioblastoma cells. In summary, we have identified and characterized koumine as a TSPO PAM for the treatment of inflammatory and neuropathic pain. Our data lay a solid foundation for the use of the clinical candidate koumine to treat inflammatory and neuropathic pain, further demonstrate the allostery in TSPO, and provide the first proof of principle that TSPO PAM may be a novel avenue for the discovery of analgesics.
Towards Measuring the Maxwell–Boltzmann Distribution of a Single Heated Particle
Authors: Su Xiaoya , Fischer Alexander , Cichos Frank
Published: June 2021

The Maxwell–Boltzmann distribution is a hallmark of statistical physics in thermodynamic equilibrium linking the probability density of a particle’s kinetic energies to the temperature of the system that also determines its configurational fluctuations. This unique relation is lost for Hot Brownian Motion, e.g., when the Brownian particle is constantly heated to create an inhomogeneous temperature in the surrounding liquid. While the fluctuations of the particle in this case can be described with an effective temperature, it is not unique for all degrees of freedom and suggested to be different at different timescales. In this work, we report on our progress to measure the effective temperature of Hot Brownian Motion in the ballistic regime. We have constructed an optical setup to measure the displacement of a heated Brownian particle with a temporal resolution of 10 ns giving a corresponding spatial resolution of about 23 pm for a 0.92 μm PMMA particle in water. Using a gold-coated polystyrene (AuPS) particle of 2.15 μm diameter we determine the mean squared displacement of the particle over more than six orders of magnitude in time. Our data recovers the trends for the effective temperature at long timescales, yet shows also clear effects in the region of hydrodynamic long time tails.
Cardiomyocyte Deletion of Bmal1 Exacerbates QT- and RR-Interval Prolongation in Scn5a+/ΔKPQ Mice
Authors: Schroder Elizabeth A. , Wayland Jennifer L. , Samuels Kaitlyn M. , Shah Syed F. , Burgess Don E. , Seward Tanya , Elayi Claude S. , Esser Karyn A. , Delisle Brian P.
Published: June 2021

Circadian rhythms are generated by cell autonomous circadian clocks that perform a ubiquitous cellular time-keeping function and cell type-specific functions important for normal physiology. Studies show inducing the deletion of the core circadian clock transcription factor Bmal1 in adult mouse cardiomyocytes disrupts cardiac circadian clock function, cardiac ion channel expression, slows heart rate, and prolongs the QT-interval at slow heart rates. This study determined how inducing the deletion of Bmal1 in adult cardiomyocytes impacted the in vivo electrophysiological phenotype of a knock-in mouse model for the arrhythmogenic long QT syndrome (Scn5a+/ΔKPQ). Electrocardiographic telemetry showed inducing the deletion of Bmal1 in the cardiomyocytes of mice with or without the ΔKPQ-Scn5a mutation increased the QT-interval at RR-intervals that were ≥130 ms. Inducing the deletion of Bmal1 in the cardiomyocytes of mice with or without the ΔKPQ-Scn5a mutation also increased the day/night rhythm-adjusted mean in the RR-interval, but it did not change the period, phase or amplitude. Compared to mice without the ΔKPQ-Scn5a mutation, mice with the ΔKPQ-Scn5a mutation had reduced heart rate variability (HRV) during the peak of the day/night rhythm in the RR-interval. Inducing the deletion of Bmal1 in cardiomyocytes did not affect HRV in mice without the ΔKPQ-Scn5a mutation, but it did increase HRV in mice with the ΔKPQ-Scn5a mutation. The data demonstrate that deleting Bmal1 in cardiomyocytes exacerbates QT- and RR-interval prolongation in mice with the ΔKPQ-Scn5a mutation.
The Comparison of Different Constitutive Laws and Fiber Architectures for the Aortic Valve on Fluid–Structure Interaction Simulation
Authors: Cai Li , Zhang Ruihang , Li Yiqiang , Zhu Guangyu , Ma Xingshuang , Wang Yongheng , Luo Xiaoyu , Gao Hao
Published: June 2021

Built on the hybrid immersed boundary/finite element (IB/FE) method, fluid–structure interaction (FSI) simulations of aortic valve (AV) dynamics are performed with three different constitutive laws and two different fiber architectures for the AV leaflets. An idealized AV model is used and mounted in a straight tube, and a three-element Windkessel model is further attached to the aorta. After obtaining ex vivo biaxial tensile testing of porcine AV leaflets, we first determine the constitutive parameters of the selected three constitutive laws by matching the analytical stretch–stress relations derived from constitutive laws to the experimentally measured data. Both the average error and relevant R-squared value reveal that the anisotropic non-linear constitutive law with exponential terms for both the fiber and cross-fiber directions could be more suitable for characterizing the mechanical behaviors of the AV leaflets. We then thoroughly compare the simulation results from both structural mechanics and hemodynamics. Compared to the other two constitutive laws, the anisotropic non-linear constitutive law with exponential terms for both the fiber and cross-fiber directions shows the larger leaflet displacements at the opened state, the largest forward jet flow, the smaller regurgitant flow. We further analyze hemodynamic parameters of the six different cases, including the regurgitant fraction, the mean transvalvular pressure gradient, the effective orifice area, and the energy loss of the left ventricle. We find that the fiber architecture with body-fitted orientation shows better dynamic behaviors in the leaflets, especially with the constitutive law using exponential terms for both the fiber and cross-fiber directions. In conclusion, both constitutive laws and fiber architectures can affect AV dynamics. Our results further suggest that the strain energy function with exponential terms for both the fiber and cross-fiber directions could be more suitable for describing the AV leaflet mechanical behaviors. Future experimental studies are needed to identify competent constitutive laws for the AV leaflets and their associated fiber orientations with controlled experiments. Although limitations exist in the present AV model, our results provide important information for selecting appropriate constitutive laws and fiber architectures when modeling AV dynamics.
Heat Stress-Dependent Association of Membrane Trafficking Proteins With mRNPs Is Selective
Authors: Wolff Heike , Jakoby Marc , Stephan Lisa , Koebke Eva , Hülskamp Martin
Published: June 2021

The Arabidopsis AAA ATPase SKD1 is essential for ESCRT-dependent endosomal sorting by mediating the disassembly of the ESCRTIII complex in an ATP-dependent manner. In this study, we show that SKD1 localizes to messenger ribonucleoprotein complexes upon heat stress. Consistent with this, the interactome of SKD1 revealed differential interactions under normal and stress conditions and included membrane transport proteins as well as proteins associated with RNA metabolism. Localization studies with selected interactome proteins revealed that not only RNA associated proteins but also several ESCRTIII and membrane trafficking proteins were recruited to messenger ribonucleoprotein granules after heat stress.
Genome-Wide Analysis of MYB Gene Family in Chinese Bayberry (Morella rubra) and Identification of Members Regulating Flavonoid Biosynthesis
Authors: Cao Yunlin , Jia Huimin , Xing Mengyun , Jin Rong , Grierson Donald , Gao Zhongshan , Sun Chongde , Chen Kunsong , Xu Changjie , Li Xian
Published: June 2021

Chinese bayberry (Morella rubra), the most economically important fruit tree in the Myricaceae family, is a rich source of natural flavonoids. Recently the Chinese bayberry genome has been sequenced, and this provides an opportunity to investigate the organization and evolutionary characteristics of MrMYB genes from a whole genome view. In the present study, we performed the genome-wide analysis of MYB genes in Chinese bayberry and identified 174 MrMYB transcription factors (TFs), including 122 R2R3-MYBs, 43 1R-MYBs, two 3R-MYBs, one 4R-MYB, and six atypical MYBs. Collinearity analysis indicated that both syntenic and tandem duplications contributed to expansion of the MrMYB gene family. Analysis of transcript levels revealed the distinct expression patterns of different MrMYB genes, and those which may play important roles in leaf and flower development. Through phylogenetic analysis and correlation analyses, nine MrMYB TFs were selected as candidates regulating flavonoid biosynthesis. By using dual-luciferase assays, MrMYB12 was shown to trans-activate the MrFLS1 promoter, and MrMYB39 and MrMYB58a trans-activated the MrLAR1 promoter. In addition, overexpression of 35S:MrMYB12 caused a significant increase in flavonol contents and induced the expression of NtCHS, NtF3H, and NtFLS in transgenic tobacco leaves and flowers and significantly reduced anthocyanin accumulation, resulting in pale-pink or pure white flowers. This indicates that MrMYB12 redirected the flux away from anthocyanin biosynthesis resulting in higher flavonol content. The present study provides valuable information for understanding the classification, gene and motif structure, evolution and predicted functions of the MrMYB gene family and identifies MYBs regulating different aspects of flavonoid biosynthesis in Chinese bayberry.
Salicylic Acid Is Involved in Rootstock–Scion Communication in Improving the Chilling Tolerance of Grafted Cucumber
Authors: Fu Xin , Feng Yi-Qing , Zhang Xiao-Wei , Zhang Yan-Yan , Bi Huan-Gai , Ai Xi-Zhen
Published: June 2021

Salicylic acid (SA) has been proven to be a multifunctional signaling molecule that participates in the response of plants to abiotic stresses. In this study, we used cold-sensitive cucumber and cold-tolerant pumpkin as experimental materials to examine the roles of SA in root–shoot communication responses to aerial or/and root-zone chilling stress in own-root and hetero-root grafted cucumber and pumpkin plants. The results showed that pumpkin (Cm) rootstock enhanced the chilling tolerance of grafted cucumber, as evidenced by the observed lower levels of electrolyte leakage (EL), malondialdehyde (MDA), and higher photosynthetic rate (Pn) and gene expression of Rubisco activase (RCA). However, cucumber (Cs) rootstock decreased the chilling tolerance of grafted pumpkins. Cs/Cm plants showed an increase in the mRNA expression of C-repeat-binding factor (CBF1), an inducer of CBF expression (ICE1), and cold-responsive (COR47) genes and CBF1 protein levels in leaves under 5/25 and 5/5°C stresses, or in roots under 25/5 and 5/5°C stresses, respectively, compared with the Cs/Cs. Chilling stress increased the endogenous SA content and the activity of phenylalanine ammonia-lyase (PAL), and the increase in SA content and activity of PAL in Cs/Cm plants was much higher than in Cs/Cs plants. Transcription profiling analysis revealed the key genes of SA biosynthesis, PAL, ICS, and SABP2 were upregulated, while SAMT, the key gene of SA degradation, was downregulated in Cs/Cm leaves, compared with Cs/Cs leaves under chilling stress. The accumulation of SA in the Cs/Cm leaves was mainly attributed to an increase in SA biosynthesis in leaves and that in transport from roots under aerial and root-zone chilling stress, respectively. In addition, exogenous SA significantly upregulated the expression level of cold-responsive (COR) genes, enhanced actual photochemical efficiency (ΦPSII), maximum photochemical efficiency (Fv/Fm), and Pn, while decreased EL, MDA, and CI in grafted cucumber. These results suggest that SA is involved in rootstock–scion communication and grafting-induced chilling tolerance by upregulating the expression of COR genes in cucumber plants under chilling stress.
A Fresh Look at the Unconscious Thought Effect: Using Mind-Wandering Measures to Investigate Thought Processes in Decision Problems With High Information Load
Authors: Steindorf Lena , Rummel Jan , Boywitt C. Dennis
Published: June 2021

Unconscious Thought Theory (Dijksterhuis, 2004) states that thinking about a complex problem unconsciously can result in better solutions than conscious deliberation. We take a fresh look at the cognitive processes underlying “unconscious” thought by analyzing data of 822 participants who worked on a complex apartment-evaluation task in three experiments. This task’s information-presentation and evaluation parts were separated by different kinds of filler-interval activities, which corresponded to standard conscious-thought and unconscious-thought manipulations. Employing experience-sampling methods, we obtained thought reports during and after filler-interval engagement. Evidence concerning the existence of the Unconscious Thought Effect was mixed, with such an effect being present in the first two experiments only. In these experiments, we further found less problem deliberation to be associated with better performance on the apartment task. Interestingly, this benefit disappeared when we probed participants’ thoughts during the filler interval. We suggested that explicit thought awareness diminishes the Unconscious Thought Effect.