bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmental Changes in Peripherin-eGFP Expression in Spiral Ganglion Neurons
Authors: Elliott Karen L. , Kersigo Jennifer , Lee Jeong Han , Jahan Israt , Pavlinkova Gabriela , Fritzsch Bernd , Yamoah Ebenezer N.
Published: June 2021

The two types of spiral ganglion neurons (SGNs), types I and II, innervate inner hair cells and outer hair cells, respectively, within the mammalian cochlea and send another process back to cochlear nuclei in the hindbrain. Studying these two neuronal types has been made easier with the identification of unique molecular markers. One of these markers, peripherin, was shown using antibodies to be present in all SGNs initially but becomes specific to type II SGNs during maturation. We used mice with fluorescently labeled peripherin (Prph-eGFP) to examine peripherin expression in SGNs during development and in aged mice. Using these mice, we confirm the initial expression of Prph-eGFP in both types I and II neurons and eventual restriction to only type II perikarya shortly after birth. However, while Prph-eGFP is uniquely expressed within type II cell bodies by P8, both types I and II peripheral and central processes continue to express Prph-eGFP for some time before becoming downregulated. Only at P30 was there selective type II Prph-eGFP expression in central but not peripheral processes. By 9 months, only the type II cell bodies and more distal central processes retain Prph-eGFP expression. Our results show that Prph-eGFP is a reliable marker for type II SGN cell bodies beyond P8; however, it is not generally a suitable marker for type II processes, except for central processes beyond P30. How the changes in Prph-eGFP expression relate to subsequent protein expression remains to be explored.
Huntingtin and the Synapse
Authors: Barron Jessica C. , Hurley Emily P. , Parsons Matthew P.
Published: June 2021

Huntington disease (HD) is a monogenic disease that results in a combination of motor, psychiatric and cognitive symptoms. HD is caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which results in the production of a pathogenic mutant HTT protein (mHTT). Although there is no cure at present for HD, a number of RNA-targeting therapies have recently entered clinical trials which aim to lower mHTT production through the use of antisense oligonucleotides (ASOs) and RNAi. However, many of these treatment strategies are non-selective in that they cannot differentiate between non-pathogenic wild type HTT (wtHTT) and the mHTT variant. As HD patients are already born with decreased levels of wtHTT, these genetic therapies may result in critically low levels of wtHTT. The consequence of wtHTT reduction in the adult brain is currently under debate, and here we argue that wtHTT loss is not well-tolerated at the synaptic level. Synaptic dysfunction is an extremely sensitive measure of subsequent cell death, and is known to precede neurodegeneration in numerous brain diseases including HD. The present review focuses on the prominent role of wtHTT at the synapse and considers the consequences of wtHTT loss on both pre- and postsynaptic function. We discuss how wtHTT is implicated in virtually all major facets of synaptic neurotransmission including anterograde and retrograde transport of proteins to/from terminal buttons and dendrites, neurotransmitter release, endocytic vesicle recycling, and postsynaptic receptor localization and recycling. We conclude that wtHTT presence is essential for proper synaptic function.
Mechanism and Prevention of Ototoxicity Induced by Aminoglycosides
Authors: Fu Xiaolong , Wan Peifeng , Li Peipei , Wang Jinpeng , Guo Siwei , Zhang Yuan , An Yachun , Ye Chao , Liu Ziyi , Gao Jiangang , Yang Jianming , Fan Jiangang , Chai Renjie
Published: June 2021

Aminoglycosides, a class of clinically important drugs, are widely used worldwide against gram-negative bacterial infections. However, there is growing evidence that aminoglycosides can cause hearing loss or balance problems. In this article, we mainly introduce the main mechanism of ototoxicity induced by aminoglycosides. Genetic analysis showed that the susceptibility of aminoglycosides was attributable to mutations in mtDNA, especially A1555G and C1494T mutations in 12S rRNA. In addition, the overexpression of NMDA receptors and the formation of free radicals also play an important role. Understanding the mechanism of ototoxicity induced by aminoglycosides is helpful to develop new therapeutic methods to protect hearing. In this article, the prevention methods of ototoxicity induced by aminoglycosides were introduced from the upstream and downstream aspects.
Movement-Related Cortical Potentials in Embodied Virtual Mirror Visual Feedback
Authors: Garipelli Gangadhar , Rossy Tamara , Perez-Marcos Daniel , Jöhr Jane , Diserens Karin
Published: June 2021

Background:Mirror therapy is thought to drive interhemispheric communication, resulting in a balanced activation. We hypothesized that embodied virtual mirror visual feedback (VR-MVF) presented on a computer screen may produce a similar activation. In this proof-of-concept study, we investigated differences in movement-related cortical potentials (MRCPs) in the electroencephalogram (EEG) from different visual feedback of user movements in 1 stroke patient and 13 age-matched adults.

Methods:A 60-year-old right-handed (Edinburgh score >95) male ischemic stroke [left paramedian pontine, National Institutes of Health Stroke Scale (NIHSS) = 6] patient and 13 age-matched right-handed (Edinburgh score >80) healthy adults (58 ± 9 years; six female) participated in the study. We recorded 16-electrode electroencephalogram (EEG), while participants performed planar center-out movements in two embodied visual feedback conditions: (i) direct (movements translated to the avatar's ipsilateral side) and (ii) mirror (movements translated to the avatar's contralateral side) with left (direct left/mirror left) or right (direct right/mirror right) arms.

Results:As hypothesized, we observed more balanced MRCP hemispheric negativity in themirror rightcompared to thedirect rightcondition [statistically significant at the FC4 electrode; 99.9% CI, (0.81, 13)]. MRCPs in the stroke participant showed reduced lateralized negativity in thedirect left(non-paretic) situation compared to healthy participants. Interestingly, the potentials were stronger in themirror left(non-paretic) compared todirect leftcase, with significantly more bilateral negativity at FC3 [95% CI (0.758 13.2)] and C2 [95% CI (0.04 9.52)].

Conclusions:Embodied mirror visual feedback is likely to influence bilateral sensorimotor cortical subthreshold activity during movement preparation and execution observed in MRCPs in both healthy participants and a stroke patient.
A Homozygous Deep Intronic Mutation Alters the Splicing of Nebulin Gene in a Patient With Nemaline Myopathy
Authors: Laflamme Nathalie , Lace Baiba , Thonta Setty Samarth , Rioux Nadie , Labrie Yvan , Droit Arnaud , Chrestian Nicolas , Rivest Serge
Published: June 2021

Nemaline myopathy is a rare disorder affecting the muscle sarcomere. Mutations in nebulin gene (NEB) are known to be responsible for about 50% of nemaline myopathy cases. Nebulin is a giant protein which is formed integrally with the sarcomeric thin filament. This complex gene is under extensive alternative splicing giving rise to multiple isoforms. In this study, we report a 6-year-old boy presenting with general muscular weaknesses. Identification of rod-shaped structures in the patient' biopsy raised doubt about the presence of a nemaline myopathy. Next-generation sequencing was used to identify a causative mutation for the patient syndrome. A homozygous deep intronic substitution was found in the intron 144 of the NEB. The variant was predicted by in silico tools to create a new donor splice site. Molecular analysis has shown that the mutation could alter splicing events of the nebulin gene leading to a significant decrease of isoforms level. This change in the expression level of nebulin could give rise to functional consequences in the sarcomere. These results are consistent with the phenotypes observed in the patient. Such a discovery of variants in this gene will allow a better understanding of the involvement of nebulin in neuromuscular diseases and help find new treatments for the nemaline myopathy.
Fixed-Life or Rechargeable Battery for Deep Brain Stimulation: Preference and Satisfaction in Chinese Patients With Parkinson's Disease
Authors: Qiu Xian , Peng Tingting , Lin Zhengyu , Zhu Kaiwen , Wang Yuhan , Sun Bomin , Ashkan Keyoumars , Zhang Chencheng , Li Dianyou
Published: June 2021

Introduction: DBS is a widely used therapy for PD. There is now a choice between fixed-life implantable pulse generators (IPGs) and rechargeable IPGs, each having advantages and disadvantages. This study aimed to evaluate the preference and satisfaction of Chinese patients with Parkinson's disease (PD) who were treated with deep brain stimulation (DBS).

Materials and Methods: Two hundred and twenty PD patients were treated with DBS and completed a self-reported questionnaire to assess their long-term satisfaction and experience with the type of battery they had chosen and the key factors affecting these choices. The survey was performed online and double-checked for completeness and accuracy.

Results: The median value of the postoperative duration was 18 months. The most popular way for patients to learn about DBS surgery was through media (79/220, 35.9%) including the Internet and television programs. In total, 87.3% of the DBS used rechargeable IPGs (r-IPG). The choice between rechargeable and non-rechargeable IPGs was significantly associated with affordability (χ(1)2 = 19.13, p < 0.001). Interestingly, the feature of remote programming significantly affected patients' choices between domestic and imported brands (χ(1)2 = 16.81, p < 0.001). 87.7% of the patients were satisfied with the stimulating effects as well as the implanted device itself. 40.6% of the patients with r-IPGs felt confident handling devices within 1 week after discharge. More than half of the patients checked their batteries every week. The mean interval for battery recharge was 4.3 days. 57.8% of the patients spent around 1 h recharging, and 71.4% of them recharged the battery independently.

Conclusions: Most patients were satisfied with their choice of IPGs. The patients' economic status and the remote programming function of the device were the two most critical factors in their decision. The skill of recharging the IPG was easy to master for most patients.
Narrowband Resting-State fNIRS Functional Connectivity in Autism Spectrum Disorder
Authors: Sun Weiting , Wu Xiaoyin , Zhang Tingzhen , Lin Fang , Sun Huiwen , Li Jun
Published: June 2021

Hemispheric asymmetry in the power spectrum of low-frequency spontaneous hemodynamic fluctuations has been previously observed in autism spectrum disorder (ASD). This observation may imply a specific narrow-frequency band in which individuals with ASD could show more significant alteration in resting-state functional connectivity (RSFC). To test this assumption, we evaluated narrowband RSFC at several frequencies for functional near-infrared spectroscopy signals recorded from the bilateral temporal lobes on 25 children with ASD and 22 typically developing (TD) children. In several narrow-frequency bands, we observed altered interhemispheric RSFC in ASD. However, in the band of 0.01–0.02 Hz, more mirrored channel pairs (or cortical sites) showed significantly weaker RSFC in the ASD group. Receiver operating characteristic analysis further demonstrated that RSFC in the narrowband of 0.01–0.02 Hz might have better differentiation ability between the ASD and TD groups. This may indicate that the narrowband RSFC could serve as a characteristic for the prediction of ASD.
Design Considerations for Long Term Non-invasive Brain Computer Interface Training With Tetraplegic CYBATHLON Pilot
Authors: Robinson Neethu , Chouhan Tushar , Mihelj Ernest , Kratka Paulina , Debraine Frédéric , Wenderoth Nicole , Guan Cuntai , Lehner Rea
Published: June 2021

Several studies in the recent past have demonstrated how Brain Computer Interface (BCI) technology can uncover the neural mechanisms underlying various tasks and translate them into control commands. While a multitude of studies have demonstrated the theoretic potential of BCI, a point of concern is that the studies are still confined to lab settings and mostly limited to healthy, able-bodied subjects. The CYBATHLON 2020 BCI race represents an opportunity to further develop BCI design strategies for use in real-time applications with a tetraplegic end user. In this study, as part of the preparation to participate in CYBATHLON 2020 BCI race, we investigate the design aspects of BCI in relation to the choice of its components, in particular, the type of calibration paradigm and its relevance for long-term use. The end goal was to develop a user-friendly and engaging interface suited for long-term use, especially for a spinal-cord injured (SCI) patient. We compared the efficacy of conventional open-loop calibration paradigms with real-time closed-loop paradigms, using pre-trained BCI decoders. Various indicators of performance were analyzed for this study, including the resulting classification performance, game completion time, brain activation maps, and also subjective feedback from the pilot. Our results show that the closed-loop calibration paradigms with real-time feedback is more engaging for the pilot. They also show an indication of achieving better online median classification performance as compared to conventional calibration paradigms (p = 0.0008). We also observe that stronger and more localized brain activation patterns are elicited in the closed-loop paradigm in which the experiment interface closely resembled the end application. Thus, based on this longitudinal evaluation of single-subject data, we demonstrate that BCI-based calibration paradigms with active user-engagement, such as with real-time feedback, could help in achieving better user acceptability and performance.
Auditory Discrimination in Autism Spectrum Disorder
Authors: Rotschafer Sarah Elizabeth
Published: June 2021

Autism spectrum disorder (ASD) is increasingly common with 1 in 59 children in the United States currently meeting the diagnostic criteria. Altered sensory processing is typical in ASD, with auditory sensitivities being especially common; in particular, people with ASD frequently show heightened sensitivity to environmental sounds and a poor ability to tolerate loud sounds. These sensitivities may contribute to impairments in language comprehension and to a worsened ability to distinguish relevant sounds from background noise. Event-related potential tests have found that individuals with ASD show altered cortical activity to both simple and speech-like sounds, which likely contribute to the observed processing impairments. Our goal in this review is to provide a description of ASD-related changes to the auditory system and how those changes contribute to the impairments seen in sound discrimination, sound-in-noise performance, and language processing. In particular, we emphasize how differences in the degree of cortical activation and in temporal processing may contribute to errors in sound discrimination.
Self-Reset Image Sensor With a Signal-to-Noise Ratio Over 70 dB and Its Application to Brain Surface Imaging
Authors: Pakpuwadon Thanet , Sasagawa Kiyotaka , Guinto Mark Christian , Ohta Yasumi , Haruta Makito , Takehara Hironari , Tashiro Hiroyuki , Ohta Jun
Published: June 2021

In this study, we propose a complementary-metal-oxide-semiconductor (CMOS) image sensor with a self-resetting system demonstrating a high signal-to-noise ratio (SNR) to detect small intrinsic signals such as a hemodynamic reaction or neural activity in a mouse brain. The photodiode structure was modified from N-well/P-sub to P+/N-well/P-sub to increase the photodiode capacitance to reduce the number of self-resets required to decrease the unstable stage. Moreover, our new relay board was used for the first time. As a result, an effective SNR of over 70 dB was achieved within the same pixel size and fill factor. The unstable state was drastically reduced. Thus, we will be able to detect neural activity. With its compact size, this device has significant potential to become an intrinsic signal detector in freely moving animals. We also demonstrated in vivo imaging with image processing by removing additional noise from the self-reset operation.
[18F]FDG PET/CT Studies in Transgenic Hualpha-Syn (A53T) Parkinson’s Disease Mouse Model of α-Synucleinopathy
Authors: Mondal Rommani , Campoy Anthony-David Tawatao , Liang Christopher , Mukherjee Jogeshwar
Published: June 2021

Transgenic mice line M83 that express the A53T mutant α–synuclein protein at six times the level of endogenous mice α–synuclein are a model of α-synucleinopathy found in Parkinson’s disease (PD). This Hualpha-Syn (A53T) PD model is useful in assessing non-motor deficits at earlier stages of onset of PD. We report findings on metabolic changes using [18F]FDG PET/CT in the Hualpha-Syn (A53T) PD mouse model in comparison to non-carrier mice. Whole-body PET/CT imaging of male and female mice were carried out 2 h after [18F]FDG ip administration under 3% isoflurane anesthesia. Brain images were analyzed with PET images coregistered to a mouse brain MRI template. Hualpha-Syn (A53T) mice had significantly lower [18F]FDG uptake in several brain regions compared to the no-carrier mice. Significant hind limb muscle and lower spinal cord [18F]FDG hypometabolism at 9 months of age in A53T PD mice was also indicative of neurodegenerative disease, with a progressive motoric dysfunction leading to death. Significant decrease (up to 30%) in [18F]FDG uptake were observed in 9-month old male and female Hualpha-Syn (A53) mice. This is consistent with the cortical hypometabolism in PD patients. Hualpha-Syn (A53) mice may thus be a suitable model for studies related to PD α-synucleinopathy for the discovery of new biomarkers.
Central Nervous System-Endogenous TLR7 and TLR9 Induce Different Immune Responses and Effects on Experimental Autoimmune Encephalomyelitis
Authors: Dieu Ruthe Storgaard , Wais Vian , Sørensen Michael Zaucha , Marczynska Joanna , Dubik Magdalena , Kavan Stephanie , Thomassen Mads , Burton Mark , Kruse Torben , Khorooshi Reza , Owens Trevor
Published: June 2021

Innate receptors, including Toll like receptors (TLRs), are implicated in pathogenesis of CNS inflammatory diseases such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). TLR response to pathogens or endogenous signals includes production of immunoregulatory mediators. One of these, interferon (IFN)β, a Type I IFN, plays a protective role in MS and EAE. We have previously shown that intrathecal administration of selected TLR ligands induced IFNβ and infiltration of blood-derived myeloid cells into the central nervous system (CNS), and suppressed EAE in mice. We have now extended these studies to evaluate a potential therapeutic role for CNS-endogenous TLR7 and TLR9. Intrathecal application of Imiquimod (TLR7 ligand) or CpG oligonucleotide (TLR9 ligand) into CNS of otherwise unmanipulated mice induced IFNβ expression, with greater magnitude in response to CpG. CD45+ cells in the meninges were identified as source of IFNβ. Intrathecal CpG induced infiltration of monocytes, neutrophils, CD4+ T cells and NK cells whereas Imiquimod did not recruit blood-derived CD45+ cells. CpG, but not Imiquimod, had a beneficial effect on EAE, when given at time of disease onset. This therapeutic effect of CpG on EAE was not seen in mice lacking the Type I IFN receptor. In mice with EAE treated with CpG, the proportion of monocytes was significantly increased in the CNS. Infiltrating cells were predominantly localized to spinal cord meninges and demyelination was significantly reduced compared to non-treated mice with EAE. Our findings show that TLR7 and TLR9 signaling induce distinct inflammatory responses in the CNS with different outcome in EAE and point to recruitment of blood-derived cells and IFNβ induction as possible mechanistic links between TLR9 stimulation and amelioration of EAE. The protective role of TLR9 signaling in the CNS may have application in treatment of diseases such as MS.
Roles and Transcriptional Responses of Inhibitory Neurons in Learning and Memory
Authors: Giorgi Corinna , Marinelli Silvia
Published: June 2021

Increasing evidence supports a model whereby memories are encoded by sparse ensembles of neurons called engrams, activated during memory encoding and reactivated upon recall. An engram consists of a network of cells that undergo long-lasting modifications of their transcriptional programs and connectivity. Ground-breaking advancements in this field have been made possible by the creative exploitation of the characteristic transcriptional responses of neurons to activity, allowing both engram labeling and manipulation. Nevertheless, numerous aspects of engram cell-type composition and function remain to be addressed. As recent transcriptomic studies have revealed, memory encoding induces persistent transcriptional and functional changes in a plethora of neuronal subtypes and non-neuronal cells, including glutamatergic excitatory neurons, GABAergic inhibitory neurons, and glia cells. Dissecting the contribution of these different cellular classes to memory engram formation and activity is quite a challenging yet essential endeavor. In this review, we focus on the role played by the GABAergic inhibitory component of the engram through two complementary lenses. On one hand, we report on available physiological evidence addressing the involvement of inhibitory neurons to different stages of memory formation, consolidation, storage and recall. On the other, we capitalize on a growing number of transcriptomic studies that profile the transcriptional response of inhibitory neurons to activity, revealing important clues on their potential involvement in learning and memory processes. The picture that emerges suggests that inhibitory neurons are an essential component of the engram, likely involved in engram allocation, in tuning engram excitation and in storing the memory trace.
An EBC/Plasma miRNA Signature Discriminates Lung Adenocarcinomas From Pleural Mesothelioma and Healthy Controls
Authors: Faversani Alice , Favero Chiara , Dioni Laura , Pesatori Angela Cecilia , Bollati Valentina , Montoli Matteo , Musso Valeria , Terrasi Andrea , Fusco Nicola , Nosotti Mario , Vaira Valentina , Palleschi Alessandro
Published: June 2021

Background

Despite significant improvement in screening programs for cancers of the respiratory district, especially in at-risk subjects, early disease detection is still a major issue. In this scenario, new molecular and non-invasive biomarkers are needed to improve early disease diagnosis.

Methods

We profiled the miRNome in exhaled breath condensate (EBC) and plasma samples from fourteen patients affected by lung AdCa, nine healthy subjects. miRNA signatures were then analyzed in another neoplasia of the respiratory district, i.e. pleural mesothelioma (n = 23) and subjects previously exposed to asbestos were used as controls for this cohort (n = 19). Selected miRNAs were analyzed in purified pulmonary neoplastic or normal epithelial and stromal cell subpopulation from AdCa patients. Finally, the plasmatic miRNA signature was analyzed in a publicly available cohort of NSCLC patients for data validation and in silico analysis was performed with predicted miRNA targets using the multiMiR tool and STRING database.

Results

miR-597-5p and miR-1260a are significantly over-expressed in EBC from lung AdCa and are associated with AdCa. Similarly, miR-1260a is also up-regulated in the plasma of AdCa patients together with miR-518f-3p and correlates with presence of lung cancer, whereas let-7f-5p is under-expressed. Analysis of these circulating miRNAs in pleural mesothelioma cases confirmed that up-regulation of miR-518f-3p, -597-5p and -1260a, is specific for lung AdCa. Lastly, quantification of the miRNAs in laser-assisted microdissected lung tissues revealed that miR-518f-3p, 597-5p and miR-1260a are predominantly expressed in tumor epithelial cells. Validation analysis confirmed miR-518f-3p as a possible circulating biomarker of NSCLC. In silico analysis of the potentially modulated biological processes by these three miRNAs, shows that tumor bioenergetics are the most affected pathways.

Conclusions

Overall, our data suggest a 3-miRNAs signature as a non-invasive and accurate biomarker of lung AdCa. This approach could supplement the current screening approaches for early lung cancer diagnosis.
Machine Learning for Early Warning of Septic Shock in Children With Hematological Malignancies Accompanied by Fever or Neutropenia: A Single Center Retrospective Study
Authors: Xiang Long , Wang Hansong , Fan Shujun , Zhang Wenlan , Lu Hua , Dong Bin , Liu Shijian , Chen Yiwei , Wang Ying , Zhao Liebin , Fu Lijun
Published: June 2021

Objectives

The purpose of this article was to establish and validate clinically applicable septic shock early warning model (SSEW model) that can identify septic shock in hospitalized children with onco-hematological malignancies accompanied with fever or neutropenia.

Methods

Data from EMRs were collected from hospitalized pediatric patients with hematological and oncological disease at Shanghai Children’s Medical Center. Medical records of patients (>30 days and <19 years old) with fever (≥38°C) or absolute neutrophil count (ANC) below 1.0 × 109/L hospitalized with hematological or oncological disease between January 1, 2017 and August 1, 2019 were considered. Patients in whom septic shock was diagnosed during the observation period formed the septic shock group, whereas non-septic-shock group was the control group. In the septic shock group, the time points at 4, 8, 12, and 24 hours prior to septic shock were taken as observation points, and corresponding observation points were obtained in the control group after matching. We employed machine learning artificial intelligence (AI) to filter features and used XGBoost algorithm to build SSEW model. Area under the ROC curve (AU-ROC) was used to compare the effectiveness among the SSEW Model, logistic regression model, and pediatric sequential organ failure score (pSOFA) for early warning of septic shock.

Main Results

A total of 64 observation periods in the septic shock group and 2191 in the control group were included. AU-ROC of the SSEW model had higher predictive value for septic shock compared with the pSOFA score (0.93 vs. 0.76, Z = −2.73, P = 0.006). Further analysis showed that the AU-ROC of the SSEW model was superior to the pSOFA score at the observation points 4, 8, 12, and 24 h before septic shock. At the 24 h observation point, the SSEW model incorporated 14 module root features and 23 derived features.

Conclusion

The SSEW model for hematological or oncological pediatric patients could help clinicians to predict the risk of septic shock in patients with fever or neutropenia 24 h in advance. Further prospective studies on clinical application scenarios are needed to determine the clinical utility of this AI model.
CD38 Multi-Functionality in Oral Squamous Cell Carcinoma: Prognostic Implications, Immune Balance, and Immune Checkpoint
Authors: Ding Zhuang , He Yijia , Fu Yong , Zhu Nisha , Zhao Mengxiang , Song Yuxian , Huang Xiaofeng , Chen Sheng , Yang Yan , Zhang Caihong , Hu Qingang , Ni Yanhong , Ding Liang
Published: June 2021

Background

CD38 belongs to the ribosyl cyclase family and is expressed on various hematological cells and involved in immunosuppression and tumor promotion. Although targeting CD38 antibodies has been approved for treatment of multiple myeloma, the function of CD38 in solid tumor, oral squamous cell carcinoma (OSCC)etc., has not been investigated.

Methods

This retrospective study included 92 OSCC samples and analyzed the spatial distribution of CD38 by immunohistochemistry (IHC). The values of diagnosis and prognosis of CD38 were evaluated. Additionally, 53 OSCC preoperative peripheral blood samples were used to be analyzed by flow cytometry. Tumor Immune Estimation Resource (TIMER) and cBioPortal databases were used to study CD38 level in various tumors and its correlation with tumor immune microenvironment in head and neck squamous cell carcinoma (HNSCC).

Results

CD38 ubiquitously presented in tumor cells (TCs), fibroblast-like cells (FLCs), and tumor-infiltrating lymphocytes (TILs). Patients with highly expressed CD38 in TCs (CD38TCs) had higher TNM stage and risk of lymph node metastasis. Upregulation of CD38 in FLCs (CD38FLCs) was significantly associated with poor WPOI. Escalated CD38 in TILs (CD38TILs) led to higher Ki-67 level of tumor cells. Moreover, patients with enhanced CD38TCswere susceptible to postoperative metastasis occurrence, and those with highly expressed CD38TILsindependently predicted shorter overall and disease-free survival. Strikingly, patients with highly expressed CD38TILs, but not CD38TCsand CD38FLCs, had significantly lower CD3+CD4+T cells and higher ratio of CD3−CD16+CD56+NK cells. The imbalance of immune system is attributed to dysregulated immune checkpoint molecules (VISTA, PD-1, LAG-3, CTLA-4, TIGIT, GITR) as well as particular immune cell subsets, which were positively correlated with CD38 expression in HNSCC.

Conclusion

CD38 is a poor prognostic biomarker for OSCC patients and plays a vital role in governing immune microenvironment and circulating lymphocyte homeostasis. Co-expression between CD38 and immune checkpoint molecules provides new insight into immune checkpoint therapy.
Association of Breast Cancer Screening Behaviors With Stage at Breast Cancer Diagnosis and Potential for Additive Multi-Cancer Detection via Liquid Biopsy Screening: A Claims-Based Study
Authors: Hathaway Christine , Paetsch Peter , Li Yali , Wu Jincao , Asgarian Sam , Parker Alex , Welsh Alley , Deverka Patricia , Cohain Ariella
Published: June 2021

Purpose

To evaluate mammography uptake and subsequent breast cancer diagnoses, as well as the prospect of additive cancer detection via a liquid biopsy multi-cancer early detection (MCED) screening test during a routine preventive care exam (PCE).

Methods

Patients with incident breast cancer were identified from five years of longitudinal Blue Health Intelligence® (BHI®) claims data (2014-19) and their screening mammogram and PCE utilization were characterized. Ordinal logistic regression analyses were performed to identify the association of a biennial screening mammogram with stage at diagnosis. Additional screening opportunities for breast cancer during a PCE within two years before diagnosis were identified, and the method extrapolated to all cancers, including those without recommended screening modalities.

Results

Claims for biennial screening mammograms and the time from screening to diagnosis were found to be predictors of breast cancer stage at diagnosis. When compared to women who received a screening mammogram proximal to their breast cancer diagnosis (0-4 months), women who were adherent to guidelines but had a longer time window from their screening mammogram to diagnosis (4-24 months) had a 87% increased odds of a later-stage (stages III or IV) breast cancer diagnosis (p-value <0.001), while women with no biennial screening mammogram had a 155% increased odds of a later-stage breast cancer diagnosis (p-value <0.001). This highlights the importance of screening in the earlier detection of breast cancer. Of incident breast cancer cases, 23% had no evidence of a screening mammogram in the two years before diagnosis. However, 49% of these women had a PCE within that time. Thus, an additional 11% of breast cancer cases could have been screened if a MCED test had been available during a PCE. Additionally, MCED tests have the potential to target up to 58% of the top 5 cancers that are the leading causes of cancer death currently without a USPSTF recommended screening modality (prostate, pancreatic, liver, lymphoma, and ovarian cancer).

Conclusion

The study used claims data to demonstrate the association of cancer screening with cancer stage at diagnosis and demonstrates the unmet potential for a MCED screening test which could be ordered during a PCE.
ATP and Adenosine in the Retina and Retinal Diseases
Authors: Ye Shan-Shan , Tang Yong , Song Jian-Tao
Published: June 2021

Extracellular ATP and its ultimate degradation product adenosine are potent extracellular signaling molecules that elicit a variety of pathophysiological pathways in retina through the activation of P2 and P1 purinoceptors, respectively. Excessive build-up of extracellular ATP accelerates pathologic responses in retinal diseases, whereas accumulation of adenosine protects retinal cells against degeneration or inflammation. This mini-review focuses on the roles of ATP and adenosine in three types of blinding diseases including age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR). Several agonists and antagonists of ATP receptors and adenosine receptors (ARs) have been developed for the potential treatment of glaucoma, DR and AMD: antagonists of P2X7 receptor (P2X7R) (BBG, MRS2540) prevent ATP-induced neuronal apoptosis in glaucoma, DR, and AMD; A1 receptor (A1R) agonists (INO-8875) lower intraocular pressure in glaucoma; A2A receptor (A2AR) agonists (CGS21680) or antagonists (SCH58261, ZM241385) reduce neuroinflammation in glaucoma, DR, and AMD; A3 receptor (A3R) agonists (2-Cl-lB-MECA, MRS3558) protect retinal ganglion cells (RGCs) from apoptosis in glaucoma.
The Protective Effects of a Combination of an Arginine Silicate Complex and Magnesium Biotinate Against UV-Induced Skin Damage in Rats
Authors: Cicek Demet , Demir Betul , Orhan Cemal , Tuzcu Mehmet , Ozercan Ibrahim Hanifi , Sahin Nurhan , Komorowski James , Ojalvo Sara Perez , Sylla Sarah , Sahin Kazim
Published: June 2021

The purpose of this study was to observe the effects of a novel combination of inositol-stabilized arginine silicate complex (ASI) and magnesium biotinate (MgB) on the prevention of skin damage after UVB exposure in rats. Forty-nine Sprague-Dawley rats were randomized into one of the following groups: (1) NC, normal control, (2) SC, shaved control, (3) UVB (exposed to UVB radiation), (4) ASI+MgB-L (Low Dose), (5) ASI+MgB-H (High Dose), (6) ASI+MgB-L+MgB cream, (7) ASI+MgB-H+MgB cream. The results showed that ASI+MgB treatment alleviated the macroscopic and histopathological damages in the skin of rats caused by UVB exposure. Skin elasticity evaluation showed a similar trend. ASI+MgB increased serum Mg, Fe, Zn, Cu, Si, biotin, and arginine concentrations and skin hydroxyproline and biotinidase levels while decreasing skin elastase activity (p < 0.05) and malondialdehyde (MDA) concentration (p < 0.001). Moreover, ASI+MgB treatment increased skin levels of biotin-dependent carboxylases (ACC1, ACC2, PC, PCC, MCC) and decreased mammalian target of rapamycin (mTOR) pathways and matrix metalloproteinase protein levels by the regulation of the activator protein 1 (AP-1), and mitogen activated protein kinases (MAPKs) signaling pathways. In addition, ASI+MgB caused lower levels of inflammatory factors, including TNF-α, NFκB, IL-6, IL-8, and COX-2 in the skin samples (p < 0.05). The levels of Bax and caspase-3 were increased, while anti-apoptotic protein Bcl-2 was decreased by UVB exposure, which was reversed by ASI+MgB treatment. These results show that treatment with ASI and MgB protects against skin damage by improving skin appearance, elasticity, inflammation, apoptosis, and overall health.
Blood-Glucose-Lowering Effect of Coptidis Rhizoma Extracts From Different Origins via Gut Microbiota Modulation in db/db Mice
Authors: Lyu Yuanfeng , Lin Lin , Xie Yuning , Li Dan , Xiao Min , Zhang Yufeng , Cheung Stanley Chun Kai , Shaw Pang Chui , Yang Xiao , Chan Paul Kay Sheung , Kong Alice Pik Shan , Zuo Zhong
Published: June 2021

Background:Coptidis rhizoma extracts (CREs) have been used widely for their anti-diabetic and anti-microbial activities, and berberine/jatrorrhizine/coptisine/palmatine are the primary bioactive components. Although guidelines have adopted content analyses of these components as a quality control method for CREs, it is difficult to differentiate the CREs from different sources using this method because of the lack of indications for their related pharmacological activities.

Purpose: To explore the effect of CREs (CREA/CREB/CREC) with different compositions of major components on the gut microbiota and blood glucose levels in db/db mice.

Methods: Degradation of berberine/jatrorrhizine/coptisine/palmatine from CREA/CREB/CREC in rat/mouse intestinal contents and their impact on nine common gastrointestinal bacteria were investigated. In addition, the effects of oral administration of CREA/CREB/CREC for 2 weeks on the gut microbiota and blood glucose levels in db/db mice were monitored via insulin/glucose tolerance test (ITT/GTT), insulin concentration, homeostatic model assessment of insulin resistance and fecal 16S rRNA sequencing.

Results and Conclusion: The total amount of berberine/jatrorrhizine/coptisine/palmatine was highest in CREA. Clostridium perfringens was strongly inhibited by all three CREs, with CREA demonstrating the most significant inhibitory effects on minimum inhibitory concentration, time-kill kinetics, and ATP production. In db/db mice, CREA resulted in the most significant decrease in ITT/GTT and depicted different changes in the microbiota from CREB/CREC. Thus, CREs with different compositions of berberine/jatrorrhizine/coptisine/palmatine differed in terms of time-kill kinetics and ATP production assays on C. perfringens. CREA revealed the potent bacterial inhibitory effects and glucose-lowering activity.
Dipole-Fed Rectangular Dielectric Resonator Antennas for Magnetic Resonance Imaging at 7 T: The Impact of Quasi-Transverse Electric Modes on Transmit Field Distribution
Authors: Wenz Daniel , Gruetter Rolf
Published: June 2021

Shortened dipole antennas based on rectangular dielectric blocks play an important role in ultrahigh field magnetic resonance imaging (UHF-MRI) radio frequency (RF) coil design. However, the generally assumed direct contact with the subject is difficult to maintain in typical in vivo settings. We have previously observed that certain dielectrically shortened dipole antennas can produce a substantially altered transmit field distribution with a very low transmit efficiency when the block and the sample are physically separated. Therefore, the aim of this study was to determine a) why certain designs of dielectrically shortened dipole antennas can produce an inefficient transmit field when the block and the sample are physically separated and b) how this depends on key parameters such as rectangular block geometry, dielectric constant, loading geometry, and RF feeding. In this work, two main types of quasi-transverse dielectric modes were found in different rectangular block geometries and interpreted as TE11δz (MR efficient) and TE1δδy (MR inefficient), and their impact on in vivo MRI experiments involving the human head, calf, and wrist was explored. This study shows, for the first time, why certain antennas preserve their transmit field efficiency despite physical separation from the sample. We conclude that the proposed approach has the potential to provide new insights into dipole antenna design for UHF-MRI.
Transcriptomic Analysis of Changes in Gene Expression During Flowering Induction in Sugarcane Under Controlled Photoperiodic Conditions
Authors: Manechini João Ricardo Vieira , Santos Paulo Henrique da Silva , Romanel Elisson , Brito Michael dos Santos , Scarpari Maximiliano Salles , Jackson Stephen , Pinto Luciana Rossini , Vicentini Renato
Published: June 2021

Flowering is of utmost relevance for the agricultural productivity of the sugarcane bioeconomy, but data and knowledge of the genetic mechanisms underlying its photoperiodic induction are still scarce. An understanding of the molecular mechanisms that regulate the transition from vegetative to reproductive growth in sugarcane could provide better control of flowering for breeding. This study aimed to investigate the transcriptome of +1 mature leaves of a sugarcane cultivar subjected to florally inductive and non-inductive photoperiodic treatments to identify gene expression patterns and molecular regulatory modules. We identified 7,083 differentially expressed (DE) genes, of which 5,623 showed significant identity to other plant genes. Functional group analysis showed differential regulation of important metabolic pathways involved in plant development, such as plant hormones (i.e., cytokinin, gibberellin, and abscisic acid), light reactions, and photorespiration. Gene ontology enrichment analysis revealed evidence of upregulated processes and functions related to the response to abiotic stress, photoprotection, photosynthesis, light harvesting, and pigment biosynthesis, whereas important categories related to growth and vegetative development of plants, such as plant organ morphogenesis, shoot system development, macromolecule metabolic process, and lignin biosynthesis, were downregulated. Also, out of 76 sugarcane transcripts considered putative orthologs to flowering genes from other plants (such as Arabidopsis thaliana, Oryza sativa, and Sorghum bicolor), 21 transcripts were DE. Nine DE genes related to flowering and response to photoperiod were analyzed either at mature or spindle leaves at two development stages corresponding to the early stage of induction and inflorescence primordia formation. Finally, we report a set of flowering-induced long non-coding RNAs and describe their level of conservation to other crops, many of which showed expression patterns correlated against those in the functionally grouped gene network.
Overexpression of BnPCS1, a Novel Phytochelatin Synthase Gene From Ramie (Boehmeria nivea), Enhanced Cd Tolerance, Accumulation, and Translocation in Arabidopsis thaliana
Authors: Zhu Shoujing , Shi Wenjuan , Jie Yucheng
Published: June 2021

Phytochelatins (PCs) play important roles in the detoxification of and tolerance to heavy metals in plants. The synthesis of PCs is catalyzed by phytochelatin synthase (PCS), which is activated by heavy metal ions. In this study, we isolated a PCS gene, BnPCS1, from the bast fiber crop ramie (Boehmeria nivea) using the RACE (rapid amplification of cDNA ends) method. The full-length BnPCS1 cDNA is 1,949 bp in length with a 1,518 bp open reading frame (ORF) that encodes a 505 amino acid protein. The deduced BnPCS1 protein has a conserved N-terminus containing the catalytic triad Cys58, His164, Asp182, and a flexible C-terminal region containing a C371C372QETC376VKC379 motif. The BnPCS1 promoter region contains several cis-acting elements involved in phytohormone or abiotic stress responses. Subcellular localization analysis indicates that the BnPCS1-GFP protein localizes to the nucleus and the cytoplasm. Real-time PCR assays show that the expression of BnPCS1 is significantly induced by cadmium (Cd) and the plant hormone abscisic acid (ABA). Overexpression lines of BnPCS1 exhibited better root growth and fresh weight, lower level of MDA and H2O2, and higher Cd accumulation and translocation factor compared to the WT under Cd stress. Taken together, these results could provide new gene resources for phytoremediation of Cd-contaminated soils.
Bioluminescent Xanthomonas hortorum pv. gardneri as a Tool to Quantify Bacteria in Planta, Screen Germplasm, and Identify Infection Routes on Leaf Surfaces
Authors: Bernal Eduardo , Deblais Loïc , Rajashekara Gireesh , Francis David M.
Published: June 2021

Imaging technology can provide insight into biological processes governing plant-pathogen interactions. We created and used a bioluminescent strain ofXanthomonas hortorumpv.gardneri(Xgb) to quantify infection processes in plants using tomato as a model. AnX. hortorumpv.gardneriis one of the fourXanthomonasspecies that causes bacterial spots in tomatoes. We used Xgbto quantify bacterial growthin planta, to assess disease severity in resistant and susceptible tomato lines, and to observe infection routes in leaves. A positive and significant linear correlation r (67) = 0.57,p≤ 0.0001 was observed between bioluminescence signals emitted by Xgbin plantaand bacterial populations determined through dilution plating. Based on bioluminescence imaging, resistant and susceptible tomato lines had significantly different average radiances. In addition, there was a positive and significant correlation r = 0.45, p = 0.024 betweenX. hortorumpv.gardneri-inoculated tomato lines evaluated by bioluminescence imaging and tomatoes rated in the field using the Horsfall-Barrat Scale. Heritability was calculated to compare the genetic variance for disease severity using bioluminescence imaging and classical field ratings. The genetic variances were 25 and 63% for bioluminescence imaging and field ratings, respectively. The disadvantage of lower heritability attained by bioluminescence imaging may be offset by the ability to complete germplasm evaluation experiments within 30 days rather than 90–120 days in field trials. We further exploredX. hortorumpv.gardneriinfection routes on leaves using spray and dip inoculation techniques. Patterns of bioluminescence demonstrated that the inoculation technique affected the distribution of bacteria, an observation verified using scanning electron microscopy (SEM). We found significant non-random distributions ofX. hortorumpv.gardnerion leaf surfaces with the method of inoculation affecting bacterial distribution on leaf surfaces at 4 h postinoculation (hpi). At 18 hpi, regardless of inoculation method,X. hortorumpv.gardnerilocalized on leaf edges near hydathodes based on bioluminescence imaging and confirmed by electron microscopy. These findings demonstrated the utility of bioluminescentX. hortorumpv.gardnerito estimate bacterial populationsin planta, to select for resistant germplasm, and to detect likely points of infection.
Effects of Artificially Reproduced Fluctuations in Sunlight Spectral Distribution on the Net Photosynthetic Rate of Cucumber Leaves
Authors: Matsuda Ryo , Ito Hiroki , Fujiwara Kazuhiro
Published: June 2021

The effects of photosynthetic photon flux density (PPFD) fluctuations in sunlight have already been investigated; however, the spectral photon flux density distribution (SPD) has hardly been considered. Here, sunlight SPD fluctuations recorded for 200 min in October in Tokyo, Japan were artificially reproduced using an LED-artificial sunlight source system. The net photosynthetic rate (Pn) of cucumber leaves under reproduced sunlight was measured and compared with the Pn estimated from a steady-state PPFD–Pn curve for the same leaves. The measured and estimated Pn agreed except when the PPFD was low, where the measured Pn was lower than the estimated Pn. The ratio of measured Pn to estimated Pn was 0.94–0.95 for PPFD ranges of 300–700 μmol m–2 s–1, while the value was 0.98–0.99 for 900–1,300 μmol m–2 s–1, and the overall ratio was 0.97. This 3% reduction in the measured Pn compared with the Pn estimated from a steady-state PPFD–Pn curve was significantly smaller than the approximately 20–30% reduction reported in previous experimental and simulation studies. This result suggests that the loss of integral net photosynthetic gain under fluctuating sunlight can vary among days with different fluctuation patterns or may be non-significant when fluctuations in both PPFD and relative SPD of sunlight are taken into consideration.