bluuebunny/crossref_metadata_2025 huggingface dataset:
CD19 CAR-T Cells With Membrane-Bound IL-15 for B-Cell Acute Lymphoblastic Leukemia After Failure of CD19 and CD22 CAR-T Cells: Case Report
Authors: Sun Yao , Su Yongfeng , Wang Yizhi , Liu Na , Li Yuhang , Chen Jianlin , Qiao Zhuoqing , Niu Jingwen , Hu Jiangwei , Zhang Bin , Ning Hongmei , Hu Liangding
Published: October 2021

Objectives

At present, reinfusions of chimeric antigen receptor (CAR)-T cell have exhibited limited efficacy, while their efficacy on extramedullary relapse remains to be further elucidated in B-cell acute lymphoblastic leukemia (B-ALL). Although combination with IL-15 demonstrated the potential to enhance antitumor activity of CAR-T, the efficacy of this approach remains to be validated clinically.

Methods

We reported a patient with B-ALL with extramedullary relapse after allogeneic stem cell transplantation and who was resistant to chemotherapy and radiotherapy. In total, he received four treatments with CAR-T cells repeatedly under the status of disease progression.

Results

First, the patient received autologous murine CAR19-CD28-CD3ζ-T cells and achieved full resolution of extramedullary leukemia lasting 8 months. After systemic disease relapse, he received autologous humanized CAR22-41BB-CD3ζ-tEGFR-T cells and achieved complete remission (CR) with incomplete blood count recovery (CRi) with minimal residual disease (MRD) negativity in the bone marrow and shrinkage of extramedullary leukemia. Over 2 months later, he experienced a relapse of the systemic disease and he received autologous murine CAR19-41BB-CD3ζ-mIL15-T cells and achieved CRiMRD- lasting 5 months with the strongest expansion and persistence of CAR. Finally, on relapse of CD19− medullary disease, he received allogeneic humanized CAR22-41BB-CD3ζ-tEGFR-T cells but only achieved a transient decrease in the number of blasts. No CAR-T-cell-related encephalopathy syndrome was observed, and all side effects were manageable.

Conclusion

Our report hints the feasibility and safety of CD19 CAR-T cell expressing membrane-bound IL-15 for patient with B-ALL even if relapsed after multiple CAR-T-cell therapies.
Anti-Carbamylated Fibrinogen Antibodies Might Be Associated With a Specific Rheumatoid Phenotype and Include a Subset Recognizing In Vivo Epitopes of Its γ Chain One of Which Is Not Cross Reactive With Anti-Citrullinated Protein Antibodies
Authors: Brevet Pauline , Lattard Claire , Guillou Clément , Rottenberg Pascal , Fardellone Patrice , Le-Loët Xavier , Lequerré Thierry , Cosette Pascal , Boyer Olivier , Fréret Manuel , Vittecoq Olivier
Published: October 2021

To identify the targets recognized by anti-carbamylated protein antibodies (anti-CarP) in patients with early Rheumatoid Arthritis (RA), to study the cross-reactivity between anti-CarP and anti-citrullinated protein antibodies (ACPA) and to evaluate their prognostic value. 331 patients (184 RA and 147 other rheumatisms) from the Very Early Arthritis (VErA) French cohort were analyzed. We performed mass spectrometry analysis of RA sera displaying anti-CarP activity and epitope mapping of the carbamylated fibrinogen γ chain to identify immunodominant peptides. The specificity of these targets was studied using competition assays with the major antigens recognized by ACPA. The prognostic value of anti-carbamylated fibrinogen IgG antibodies (ACa-Fib IgG) was compared to that of anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-CarP using an in-house ELISA. Besides the α chain, the γ chain of fibrinogen, particularly one immunodominant epitope that has a specific reactivity, was identified as a circulating carbamylated target in sera. The prevalence of ACa-Fib was 37% at baseline and 10.9% for anti-CCP-negative RA. In anti-CCP-negative patients, ACa-Fib positivity was associated with a more inflammatory and erosive disease at baseline but not with rapid radiological progression, which remains strongly related to anti-CCP antibodies. Fibrinogen seems to be one of the antigens recognized in vivo by the anti-CarP response, particularly 2 epitopes of the γ chain, one of which is not cross reactive with ACPA. This specificity might be associated with a distinct clinical phenotype since ACa-Fib IgG were shown to be linked to systemic inflammation in very early RA but not to rapid radiological progression.
314 mm2 Hexagonal Double-Sided Spiral Silicon Drift Detector for Soft X-Ray Detection Based on Ultra-Pure High Resistance Silicon
Authors: Liu Manwen , Li Zheng , Deng Zhi , He Li , Xiong Bo , Li Yuyun , Feng Mingfu , Tang Lipeng , Cheng Min
Published: October 2021

An X-ray pulsar is a remnant of massive star evolution, collapse, and supernova explosions. It has an extremely stable spin cycle and is known as the most accurate astronomical clock in the natural world. It presents high-precision navigational information, such as the location, speed, time, and attitude, which are used in deep space exploration and interstellar flight, such as the X-ray pulsar navigation (XPNAV). However, the energy of the X-ray from the pulsar is very low and its signal is very weak; this X-ray is known as the soft X-ray. In the low and medium energy radiation spectroscopy, the semiconductor detectors, especially the silicon drift detectors (SDD), achieve the best energy resolution. In this study, a 314 mm2 and a 600 mm2 double-sided spiral hexagonal silicon drift detector (DSSH-SDD) single cell for the pulsar soft X-ray detection is analyzed based on ultra-pure high-resistance silicon. The DSSH-SDD device is fabricated using ultra-pure high-resistivity silicon substrates patterned with ion-implanted electrodes. This study proposes a model capable of reaching a large area of 314 mm2 or 600 mm2 single cell and maintaining an optimal drift electric field. The design, modeling, 3D simulation, and the fabrication of the model are performed to analyze the physical performance of the DSSH-SDD. The electrical characteristics of the as-processed SDD chips, including leakage current, anode capacitance, and the spiral resistor current under the positive and negative biases are measured, and the energy resolution test is performed at the Tsinghua University. The energy resolution is an important indicator of the detector and is often expressed by full width at half maximum (FWHM). The results obtained in this study can be applied in the future for novel, flexible, large-area, high-resolution ionizing radiation detection systems capable of providing quantitative and real-time information of the relative position of spacecraft and pulsars through the pulsar X-ray radiation.
Health Related Quality of Life in Interstitial Lung Disease: Can We Use the Same Concepts Around the World?
Authors: Aronson Kerri I. , Suzuki Atsushi
Published: October 2021

Health-Related Quality of Life (HRQOL) is increasingly viewed as an important patient-centered outcome by leading health organizations, clinicians, and patients alike. This is especially true in the interstitial lung disease community where patients often struggle with progressive and debilitating disease with few therapeutic options. In order to test the effectiveness of new pharmacologic therapies and non-pharmacologic interventions globally in ILD, this will require expansion of clinical research studies to a multinational level and HRQOL will be an important endpoint to many. In order to successfully expand trials across multiple nations and compare the results of studies between different communities we must recognize that there are differences in the concepts of HRQOL across the world and have strategies to address these differences. In this review, we will describe the different global influences on HRQOL both generally and in the context of ILD, discuss the processes of linguistic translation and cross-cultural adaptation of HRQOL Patient Reported Outcome Measures (PROMs), and highlight the gaps and opportunities for improving HRQOL measurement in ILD across the world.
Ammonia- and Nitrite-Oxidizing Bacteria are Dominant in Nitrification of Maize Rhizosphere Soil Following Combined Application of Biochar and Chemical Fertilizer
Authors: Sun Ping , Zhao Ziting , Fan Pingshan , Chen Wei , Ruan Yunze , Wang Qing
Published: October 2021

Autotrophic nitrification is regulated by canonical ammonia-oxidizing archaea (AOA) and bacteria (AOB) and nitrite-oxidizing bacteria (NOB). To date, most studies have focused on the role of canonical ammonia oxidizers in nitrification while neglecting the NOB. In order to understand the impacts of combined biochar and chemical fertilizer addition on nitrification and associated nitrifiers in plant rhizosphere soil, we collected rhizosphere soil from a maize field under four different treatments: no fertilization (CK), biochar (B), chemical nitrogen (N) + phosphorus (P) + potassium (K) fertilizers (NPK), and biochar + NPK fertilizers (B + NPK). The potential nitrification rate (PNR), community abundances, and structures of AOA, AOB, complete ammonia-oxidizing bacteria (Comammox Nitrospira clade A), and Nitrobacter- and Nitrospira-like NOB were measured. Biochar and/or NPK additions increased soil pH and nutrient contents in rhizosphere soil. B, NPK, and B + NPK treatments significantly stimulated PNR and abundances of AOB, Comammox, and Nitrobacter- and Nitrospira-like NOB, with the highest values observed in the B + NPK treatment. Pearson correlation and random forest analyses predicted more importance of AOB, Comammox Nitrospira clade A, and Nitrobacter- and Nitrospira-like NOB abundances over AOA on PNR. Biochar and/or NPK additions strongly altered whole nitrifying community structures. Redundancy analysis (RDA) showed that nitrifying community structures were significantly affected by pH and nutrient contents. This research shows that combined application of biochar and NPK fertilizer has a positive effect on improving soil nitrification by affecting communities of AOB and NOB in rhizosphere soil. These new revelations, especially as they related to understudied NOB, can be used to increase efficiency of agricultural land and resource management.
Effects of Supplementing Intestinal Autochthonous Bacteria in Plant-Based Diets on Growth, Nutrient Digestibility, and Gut Health of Bullfrogs (Lithobates catesbeianus)
Authors: Wang Zhe , Zhang Chunxiao , Lu Kangle , Song Kai , Li Xueshan , Wang Ling , Rahimnejad Samad
Published: October 2021

Poor utilization efficiency of plant protein diets always leads to intestinal barrier dysfunction and growth inhibition in animals. Probiotics have shown promise in improving growth performance and gut health of the host. However, obtaining the host-beneficial probiotic from thousands of bacterial phylotypes is challenging. Here, four intestinal autochthonous bacteria were isolated from fast-growing bullfrog after a 60-day feeding on a soybean meal (SM)-based diet. Another feeding trial was conducted to evaluate the effects of supplementing these strains in an SM-based diet on growth, nutrient digestibility, immunity, and gut health of bullfrog. A high-SM basal diet was used as a non-supplemented control group (NC), and four other diets were prepared by supplementing the basal diet with 1 × 107 CFU/g of Bacillus siamensis, Bacillus tequilensis (BT), Bacillus velezensis, and Lactococcus lactis (LL). Results showed that weight gain, feed efficiency, nitrogen retention, and apparent digestibility coefficients of dry matter and protein were significantly higher in the LL group compared with the NC group (p < 0.05). Furthermore, compared with the NC group, both BT and LL groups showed markedly higher jejunal protease and amylase activities, serum complement 4 and immunoglobulin M levels, jejunal muscularis thickness (p < 0.05), and up-regulated expression of il-10 and zo-1 genes (p < 0.05). High-throughput sequencing revealed higher abundances of Bacillus and Cetobacterium in BT and LL groups, respectively, accompanied with decreased abundances of Enterobacter and Escherichia–Shigella. Besides, KEGG pathways related to metabolisms were significantly enhanced by the LL diet relative to the NC diet (p < 0.05). Overall, the beneficial effects of two frog-derived probiotics were determined: supplementation of L. lactis in SM-based diet promoted growth and nutrient digestibility; both B. tequilensis and L. lactis supplementation improved immune response and intestinal barrier function of bullfrogs.
Phylogenomics of Haloarchaea: The Controversy of the Genera Natrinema-Haloterrigena
Authors: de la Haba Rafael R. , Minegishi Hiroaki , Kamekura Masahiro , Shimane Yasuhiro , Ventosa Antonio
Published: October 2021

The haloarchaeal genera Natrinema and Haloterrigena were described almost simultaneously by two different research groups and some strains studied separately were described as different species of these genera. Furthermore, the description of additional species were assigned to either Natrinema or Haloterrigena, mainly on the basis of the phylogenetic comparative analysis of single genes (16S rRNA gene and more recently rpoB’ gene), but these species were not adequately separated or assigned to the corresponding genus. Some studies suggested that the species of these two genera should be unified into a single genus, while other studies indicated that the genera should remain but some of the species should be reassigned. In this study, we have sequenced or collected the genomes of the type strains of species of Natrinema and Haloterrigena and we have carried out a comparative genomic analysis in order to clarify the controversy related to these two genera. The phylogenomic analysis based on the comparison of 525 translated single-copy orthologous genes and the Overall Genome Relatedness Indexes (i.e., AAI, POCP, ANI, and dDDH) clearly indicate that the species Haloterrigena hispanica, Haloterrigena limicola, Haloterrigena longa, Haloterrigena mahii, Haloterrigena saccharevitans, Haloterrigena thermotolerans, and Halopiger salifodinae should be transferred to the genus Natrinema, as Natrinema hispanicum, Natrinema limicola, Natrinema longum, Natrinema mahii, Natrinema saccharevitans, Natrinema thermotolerans, and Natrinema salifodinae, respectively. On the contrary, the species Haloterrigena turkmenica, Haloterrigena salifodinae, and Haloterrigena salina will remain as the only representative species of the genus Haloterrigena. Besides, the species Haloterrigena daqingensis should be reclassified as a member of the genus Natronorubrum, as Natronorubrum daqingense. At the species level, Haloterrigena jeotgali and Natrinema ejinorense should be considered as a later heterotypic synonyms of the species Haloterrigena (Natrinema) thermotolerans and Haloterrigena (Natrinema) longa, respectively. Synteny analysis and phenotypic features also supported those proposals.
Toll-Like Receptor 2 is Involved in Abnormal Pregnancy in Mice Infected with Toxoplasma gondii During Late Pregnancy
Authors: Ikeda Rina , Ushio Nanako , Abdou Ahmed M. , Furuoka Hidefumi , Nishikawa Yoshifumi
Published: October 2021

Infection withToxoplasma gondiiduring pregnancy causes failure of pregnancy maintenance, resulting in fetal death, abortion, stillbirth, or premature birth, but the mechanism of disease onset remains unclear. Although Toll-like receptor 2 (TLR2) is expressed on antigen-presenting cells and trophoblasts, the role of TLR2 inT. gondiiinfection during pregnancy is unknown. In this study, we investigated the role of TLR2 in congenital toxoplasmosis using TLR2-deficient (TLR2−/−) mice.T. gondiiinfection on gestational day 12.5 (Gd12.5) induced more abnormal pregnancy, including premature birth and stillbirth, in wild-type mice than in TLR2−/−mice. Multiple calcifications were observed in the placentas of the infected wild-type mice. At Gd18.5 (6days postinfection), the parasite numbers in the placenta and uterus and the histological changes did not differ significantly between the wild-type and TLR2−/−mice. However,T. gondiiinfection reduced the mRNA expression of interleukin-12p40 (IL-12p40) and increased IL-4 and IL-10 mRNAs in the placentas of the wild-type mice. In contrast, the placentas of the TLR2−/−mice showed no changes in the expression of these cytokines, including IL-6 and tumor necrosis factor α, in response toT. gondiiinfection. Serum interferon-γ levels were significantly lower in the infected TLR2−/−mice than in the infected wild-type mice on Gd18.5. Thus, the TLR2−/−mice were less susceptible to the induction of immune responses byT. gondiiinfection during late pregnancy. Therefore, TLR2 signaling may play a role in the development of disease states during pregnancy, specifically placental hypofunction.
Overview on Chikungunya Virus Infection: From Epidemiology to State-of-the-Art Experimental Models
Authors: Constant Larissa E. C. , Rajsfus Bia F. , Carneiro Pedro H. , Sisnande Tháyna , Mohana-Borges Ronaldo , Allonso Diego
Published: October 2021

Chikungunya virus (CHIKV) is currently one of the most relevant arboviruses to public health. It is a member of the Togaviridae family and alphavirus genus and causes an arthritogenic disease known as chikungunya fever (CHIKF). It is characterized by a multifaceted disease, which is distinguished from other arbovirus infections by the intense and debilitating arthralgia that can last for months or years in some individuals. Despite the great social and economic burden caused by CHIKV infection, there is no vaccine or specific antiviral drugs currently available. Recent outbreaks have shown a change in the severity profile of the disease in which atypical and severe manifestation lead to hundreds of deaths, reinforcing the necessity to understand the replication and pathogenesis processes. CHIKF is a complex disease resultant from the infection of a plethora of cell types. Although there are several in vivo models for studying CHIKV infection, none of them reproduces integrally the disease signature observed in humans, which is a challenge for vaccine and drug development. Therefore, understanding the potentials and limitations of the state-of-the-art experimental models is imperative to advance in the field. In this context, the present review outlines the present knowledge on CHIKV epidemiology, replication, pathogenesis, and immunity and also brings a critical perspective on the current in vitro and in vivo state-of-the-art experimental models of CHIKF.
Therapeutic Effects of the Bcl-2 Inhibitor on Bleomycin-induced Pulmonary Fibrosis in Mice
Authors: He Yicheng , Li Fei , Zhang Chao , Geng Xinwei , Syeda Madiha Zahra , Du Xufei , Shao Zhehua , Hua Wen , Li Wen , Chen Zhihua , Ying Songmin , Shen Huahao
Published: October 2021

Idiopathic pulmonary fibrosis (IPF) is a distressing lung disorder with poor prognosis and high mortality rates. Limited therapeutic options for IPF is a major clinical challenge. Well-known for its anti-apoptotic properties, B-cell lymphoma 2 (Bcl-2) plays a critical role in the pathology of malignancies and inflammatory diseases, including IPF. In this study, we aimed to investigate the therapeutic effect of a Bcl-2 homology domain 3 mimetic inhibitor, ABT-199, on bleomycin (BLM)-induced pulmonary fibrosis in mice, and explore possible underlying mechanism. The lung inflammation and fibrosis model was established by intratracheal instillation of a single dose of BLM. We observed elevated Bcl-2 in the alveolar macrophages and fibroblasts derived from BLM-instilled mice from day 7. Further, we obtained in vivo evidence that early therapeutic treatment with Bcl-2 inhibitor ABT-199 from day 3, and late treatment from day 10, both alleviated airway inflammation and lung fibrosis induced by BLM. Our data suggest that ABT-199 might be an effective antifibrotic agent that interferes with profibrogenic cells, which may be a promising therapy in the treatment of clinical IPF patients.
Neurovascular Coupling Is Impaired in Hypertensive and Diabetic Subjects Without Symptomatic Cerebrovascular Disease
Authors: Monteiro Ana , Castro Pedro , Pereira Gilberto , Ferreira Carmen , Sorond Farzaneh , Milstead Andrew , Higgins James P. , Polónia Jorge , Azevedo Elsa
Published: October 2021

The mechanistic link between hypertension, diabetes and cerebral small vessel disease (CSVD) is still poorly understood. We hypothesized that hypertension and diabetes could impair cerebrovascular regulation prior to irreversibly established cerebrovascular disease. In this study, 52 hypertensive patients [54% males; age 64 ± 11 years; 58% with comorbid diabetes mellitus (DM)] without symptomatic cerebrovascular disease underwent transcranial Doppler (TCD) monitoring in the middle (MCA) and posterior (PCA) cerebral arteries, to assess vasoreactivity to carbon dioxide (VRCO2) and neurovascular coupling (NVC). 1.5T magnetic resonance imaging was also performed and white matter hyperintensity volume was automatically segmented from FLAIR sequences. TCD data from 17 healthy controls were obtained for comparison (47% males; age 60 ± 16 years). Hypertensive patients showed significant impairment of NVC in the PCA, with reduced increment in cerebral blood flow velocity during visual stimulation (22.4 ± 9.2 vs. 31.6 ± 5.7, p < 0.001), as well as disturbed NVC time-varying properties, with slower response (lower rate time: 0.00 ± 0.02 vs. 0.03 ± 6.81, p = 0.001), and reduced system oscillation (reduced natural frequency: 0.18 ± 0.08 vs. 0.22 ± 0.06, p < 0.001), when compared to controls. VRCO2 remained relatively preserved in MCA and PCA. These results were worse in hypertensive diabetic patients, with lower natural frequency (p = 0.043) than non-diabetic patients. White matter disease burden did not predict worse NVC. These findings suggest that hypertensive diabetic patients may have a precocious impairment of NVC, already occurring without symptomatic CSVD. Future research is warranted to evaluate whether NVC assessment could be useful as an early, non-invasive, surrogate marker for CSVD.
Activation of Microbiota Sensing – Free Fatty Acid Receptor 2 Signaling Ameliorates Amyloid-β Induced Neurotoxicity by Modulating Proteolysis-Senescence Axis
Authors: Razazan Atefeh , Karunakar Prashantha , Mishra Sidharth P. , Sharma Shailesh , Miller Brandi , Jain Shalini , Yadav Hariom
Published: October 2021

Multiple emerging evidence indicates that the gut microbiota contributes to the pathology of Alzheimer’s disease (AD)—a debilitating public health problem in older adults. However, strategies to beneficially modulate gut microbiota and its sensing signaling pathways remain largely unknown. Here, we screened, validated, and established the agonists of free fatty acid receptor 2 (FFAR2) signaling, which senses beneficial signals from short chain fatty acids (SCFAs) produced by microbiota. The abundance of SCFAs, is often low in the gut of older adults with AD. We demonstrated that inhibition of FFAR2 signaling increases amyloid-beta (Aβ) stimulated neuronal toxicity. Thus, we screened FFAR2 agonists using an in-silico library of more than 144,000 natural compounds and selected 15 of them based on binding with FFAR2-agonist active sites. Fenchol (a natural compound commonly present in basil) was recognized as a potential FFAR2 stimulator in neuronal cells and demonstrated protective effects against Aβ-stimulated neurodegeneration in an FFAR2-dependent manner. In addition, Fenchol reduced AD-like phenotypes, such as Aβ-accumulation, and impaired chemotaxis behavior in Caenorhabditis (C.) elegans and mice models, by increasing Aβ-clearance via the promotion of proteolysis and reduced senescence in neuronal cells. These results suggest that the inhibition of FFAR2 signaling promotes Aβ-induced neurodegeneration, while the activation of FFAR2 by Fenchol ameliorates these abnormalities by promoting proteolytic Aβ-clearance and reducing cellular senescence. Thus, stimulation of FFAR2 signaling by Fenchol as a natural compound can be a therapeutic approach to ameliorate AD pathology.
SynapseJ: An Automated, Synapse Identification Macro for ImageJ
Authors: Moreno Manrique Juan Felipe , Voit Parker R. , Windsor Kathryn E. , Karla Aamuktha R. , Rodriguez Sierra R. , Beaudoin Gerard M. J.
Published: October 2021

While electron microscopy represents the gold standard for detection of synapses, a number of limitations prevent its broad applicability. A key method for detecting synapses is immunostaining for markers of pre- and post-synaptic proteins, which can infer a synapse based upon the apposition of the two markers. While immunostaining and imaging techniques have improved to allow for identification of synapses in tissue, analysis and identification of these appositions are not facile, and there has been a lack of tools to accurately identify these appositions. Here, we delineate a macro that uses open-source and freely available ImageJ or FIJI for analysis of multichannel, z-stack confocal images. With use of a high magnification with a high NA objective, we outline two methods to identify puncta in either sparsely or densely labeled images. Puncta from each channel are used to eliminate non-apposed puncta and are subsequently linked with their cognate from the other channel. These methods are applied to analysis of a pre-synaptic marker, bassoon, with two different post-synaptic markers, gephyrin and N-methyl-d-aspartate (NMDA) receptor subunit 1 (NR1). Using gephyrin as an inhibitory, post-synaptic scaffolding protein, we identify inhibitory synapses in basolateral amygdala, central amygdala, arcuate and the ventromedial hypothalamus. Systematic variation of the settings identify the parameters most critical for this analysis. Identification of specifically overlapping puncta allows for correlation of morphometry data between each channel. Finally, we extend the analysis to only examine puncta overlapping with a cytoplasmic marker of specific cell types, a distinct advantage beyond electron microscopy. Bassoon puncta are restricted to virally transduced, pedunculopontine tegmental nucleus (PPN) axons expressing yellow fluorescent protein. NR1 puncta are restricted to tyrosine hydroxylase labeled dopaminergic neurons of the substantia nigra pars compacta (SNc). The macro identifies bassoon-NR1 overlap throughout the image, or those only restricted to the PPN-SNc connections. Thus, we have extended the available analysis tools that can be used to study synapses in situ. Our analysis code is freely available and open-source allowing for further innovation.
The Relative Contributions of Visual and Proprioceptive Inputs on Hand Localization in Early Childhood
Authors: Ratcliffe Natasha , Greenfield Katie , Ropar Danielle , Howard Ellen M. , Newport Roger
Published: October 2021

Forming an accurate representation of the body relies on the integration of information from multiple sensory inputs. Both vision and proprioception are important for body localization. Whilst adults have been shown to integrate these sources in an optimal fashion, few studies have investigated how children integrate visual and proprioceptive information when localizing the body. The current study used a mediated reality device called MIRAGE to explore how the brain weighs visual and proprioceptive information in a hand localization task across early childhood. Sixty-four children aged 4–11 years estimated the position of their index finger after viewing congruent or incongruent visuo-proprioceptive information regarding hand position. A developmental trajectory analysis was carried out to explore the effect of age on condition. An age effect was only found in the incongruent condition which resulted in greater mislocalization of the hand toward the visual representation as age increased. Estimates by younger children were closer to the true location of the hand compared to those by older children indicating less weighting of visual information. Regression analyses showed localizations errors in the incongruent seen condition could not be explained by proprioceptive accuracy or by general attention or social differences. This suggests that the way in which visual and proprioceptive information are integrated optimizes throughout development, with the bias toward visual information increasing with age.
Patient, Caregiver, and Decliner Perspectives on Whether to Enroll in Adaptive Deep Brain Stimulation Research
Authors: Outram Simon , Muñoz Katrina A. , Kostick-Quenet Kristin , Sanchez Clarissa E. , Kalwani Lavina , Lavingia Richa , Torgerson Laura , Sierra-Mercado Demetrio , Robinson Jill O. , Pereira Stacey , Koenig Barbara A. , Starr Philip A. , Gunduz Aysegul , Foote Kelly D. , Okun Michael S. , Goodman Wayne K. , McGuire Amy L. , Zuk Peter , Lázaro-Muñoz Gabriel
Published: October 2021

This research study provides patient and caregiver perspectives as to whether or not to undergo adaptive deep brain stimulation (aDBS) research. A total of 51 interviews were conducted in a multi-site study including patients undergoing aDBS and their respective caregivers along with persons declining aDBS. Reasons highlighted for undergoing aDBS included hopes for symptom alleviation, declining quality of life, desirability of being in research, and altruism. The primary reasons for not undergoing aDBS issues were practical rather than specific to aDBS technology, although some persons highlighted a desire to not be the first to trial the new technology. These themes are discussed in the context of “push” factors wherein any form of surgical intervention is preferable to none and “pull” factors wherein opportunities to contribute to science combine with hopes and/or expectations for the alleviation of symptoms. We highlight the significance of study design in decision making. aDBS is an innovative technology and not a completely new technology. Many participants expressed value in being part of research as an important consideration. We suggest that there are important implications when comparing patient perspectives vs. theoretical perspectives on the choice for or against aDBS. Additionally, it will be important how we communicate with patients especially in reference to the complexity of study design. Ultimately, this study reveals that there are benefits and potential risks when choosing a research study that involves implantation of a medical device.
Tracking the Migration of Injectable Microdevices in the Rodent Brain Using a 9.4T Magnetic Resonance Imaging Scanner
Authors: Khalifa Adam , Weigand-Whittier Jonah , Farrar Christian T. , Cash Sydney
Published: October 2021

Wirelessly powered microdevices are being miniaturized to improve safety, longevity, and spatial resolution in a wide range of biomedical applications. Some wireless microdevices have reached a point where they can be injected whole into the central nervous system. However, the state-of-the-art floating microdevices have not yet been tested in chronic brain applications, and there is a growing concern that the implants might migrate through neural tissue over time. Using a 9.4T MRI scanner, we attempt to address the migration question by tracking ultra-small devices injected in different areas of the brain (cortico-subcortical) of rats over 5 months. We demonstrate that injectable microdevices smaller than 0.01 mm3 remain anchored in the brain at the targeted injection site over this time period. Based on CD68 (microglia) and GFAP (astrocytes) immunoreactivity to the microdevice, we hypothesize that glial scar formation is preventing the migration of chronically implanted microdevices in the brain over time.
Effects of Mechanosensory Input on the Tracking of Pulsatile Odor Stimuli by Moth Antennal Lobe Neurons
Authors: Tuckman Harrison , Patel Mainak , Lei Hong
Published: October 2021

Air turbulence ensures that in a natural environment insects tend to encounter odor stimuli in a pulsatile fashion. The frequency and duration of odor pulses varies with distance from the source, and hence successful mid-flight odor tracking requires resolution of spatiotemporal pulse dynamics. This requires both olfactory and mechanosensory input (from wind speed), a form of sensory integration observed within the antennal lobe (AL). In this work, we employ a model of the moth AL to study the effect of mechanosensory input on AL responses to pulsatile stimuli; in particular, we examine the ability of model neurons to: (1) encode the temporal length of a stimulus pulse; (2) resolve the temporal dynamics of a high frequency train of brief stimulus pulses. We find that AL glomeruli receiving olfactory input are adept at encoding the temporal length of a stimulus pulse but less effective at tracking the temporal dynamics of a pulse train, while glomeruli receiving mechanosensory input but little olfactory input can efficiently track the temporal dynamics of high frequency pulse delivery but poorly encode the duration of an individual pulse. Furthermore, we show that stronger intrinsic small-conductance calcium-dependent potassium (SK) currents tend to skew cells toward being better trackers of pulse frequency, while weaker SK currents tend to entail better encoding of the temporal length of individual pulses. We speculate a possible functional division of labor within the AL, wherein, for a particular odor, glomeruli receiving strong olfactory input exhibit prolonged spiking responses that facilitate detailed discrimination of odor features, while glomeruli receiving mechanosensory input (but little olfactory input) serve to resolve the temporal dynamics of brief, pulsatile odor encounters. Finally, we discuss how this hypothesis extends to explaining the functional significance of intraglomerular variability in observed phase II response patterns of AL neurons.
Sensory Percepts Elicited by Chronic Macro-Sieve Electrode Stimulation of the Rat Sciatic Nerve
Authors: Chandra Nikhil S. , McCarron Weston M. , Yan Ying , Ruiz Luis C. , Sallinger Eric G. , Birenbaum Nathan K. , Burton Harold , Green Leonard , Moran Daniel W. , Ray Wilson Z. , MacEwan Matthew R.
Published: October 2021

Objective: Intuitive control of conventional prostheses is hampered by their inability to provide the real-time tactile and proprioceptive feedback of natural sensory pathways. The macro-sieve electrode (MSE) is a candidate interface to amputees’ truncated peripheral nerves for introducing sensory feedback from external sensors to facilitate prosthetic control. Its unique geometry enables selective control of the complete nerve cross-section by current steering. Unlike previously studied interfaces that target intact nerve, the MSE’s implantation requires transection and subsequent regeneration of the target nerve. Therefore, a key determinant of the MSE’s suitability for this task is whether it can elicit sensory percepts at low current levels in the face of altered morphology and caliber distribution inherent to axon regeneration. The present in vivo study describes a combined rat sciatic nerve and behavioral model developed to answer this question.

Approach: Rats learned a go/no-go detection task using auditory stimuli and then underwent surgery to implant the MSE in the sciatic nerve. After healing, they were trained with monopolar electrical stimuli with one multi-channel and eight single-channel stimulus configurations. Psychometric curves derived by the method of constant stimuli (MCS) were used to calculate 50% detection thresholds and associated psychometric slopes. Thresholds and slopes were calculated at two time points 3 weeks apart.

Main Results: For the multi-channel stimulus configuration, the average current required for stimulus detection was 19.37 μA (3.87 nC) per channel. Single-channel thresholds for leads located near the nerve’s center were, on average, half those of leads located near the periphery (54.92 μA vs. 110.71 μA, or 10.98 nC vs. 22.14 nC). Longitudinally, 3 of 5 leads’ thresholds decreased or remained stable over the 3-week span. The remaining two leads’ thresholds increased by 70–74%, possibly due to scarring or device failure.

Significance: This work represents an important first step in establishing the MSE’s viability as a sensory feedback interface. It further lays the groundwork for future experiments that will extend this model to the study of other devices, stimulus parameters, and task paradigms.
Extraction Techniques, Biological Activities and Health Benefits of Marine Algae Enteromorpha prolifera Polysaccharide
Authors: Wassie Teketay , Niu Kaimin , Xie Chunyan , Wang Haihua , Xin Wu
Published: October 2021

There is increasing interest in the use of marine algae as functional food additives for improving human health. Enteromorpha (Ulva) prolifera (E. prolifera) is a seaweed green alga (Chlorophyta) that contains many bioactive compounds, of which polysaccharide is the main component. With the advancement of technology in the methods of extraction and analysis, recent studies in in vitro and animals model showed that polysaccharides derived from E. prolifera exert various biological activities, such as gut microbiota modulation, immunomodulation, antioxidant, antidiabetic, antimicrobial, and hypolipidemic. Research evidence has shown that methods of extraction and molecular modification, such as degradation, carboxymethylation, and sulfonation could alter the biological activities of polysaccharides. Therefore, in this review, we discussed the different extraction techniques, structural-activity relationship, and health benefits of sulfated polysaccharides derived from E. prolifera, and suggested future research avenues. This review helps to advance the extraction techniques and promote the application of marine algae polysaccharides as functional food and therapeutic agent.
Overexpression of Long Non-Coding RNA Linc01315 Predicts Poor Prognosis in Breast Cancer
Authors: Xue Jingyan , Huang Sheng , Chen Jiaying , Chen Yi-zuo , Shao Zhi-min , Wu Jiong , Chi Yayun
Published: October 2021

Background

LncRNAs have been shown to play critical roles in regulating tumorigenesis and tumor progression. Using LncRNAs to predict prognosis and therapeutic response to cancer treatment has been caused for concern, but the predictive value of lncRNAs remains to be explored and underlying mechanisms have not been completely understood.

Methods

The Linc01315 expression level was detected in 282 breast cancer tissues by using quantitative RT-PCR. The association between Linc01315 expression level and clinicopathological features of these breast cancer patients was further analyzed. Multiple regression analysis was used to evaluate Linc01315 predictive value of patients’ prognosis.

Results

Our study revealed that Linc01315 expression level was significantly correlated with vessel invasion (P = 0.028) and tumor subtype (P = 0.039). The Kaplan–Meier survival curves demonstrated that patients with lower Linc01315 expression level had significantly longer disease free survival (DFS) (P = 0.002) and overall survival (OS) (P=0.019). Multiple regression analysis showed that Linc01315 level could be an independent predictive factor for DFS (hazards ratio = 0.613, 95% confidence interval = 0.375-1.003; P = 0.049) and OS (hazards ratio = 0.439, 95% confidence interval = 0.228-0.845; P = 0.014). Further analysis showed that low Linc01315 level patients with endocrine therapy could benefit patients DFS (P=0.037) and OS (P=0.025).

Conclusion

Our results demonstrate that Linc01315 expression level is significantly correlated with breast cancer patients’ prognosis. Linc01315 may represent an independent prognostic marker and therapeutic target in breast cancer.
Evaluation of Diagnostic Potential of Epigenetically Deregulated MiRNAs in Epithelial Ovarian Cancer
Authors: Kumar Vivek , Gupta Sameer , Chaurasia Amrita , Sachan Manisha
Published: October 2021

Background

Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies among women worldwide. Early diagnosis of EOC could help in ovarian cancer management. MicroRNAs, a class of small non-coding RNA molecules, are known to be involved in post-transcriptional regulation of ~60% of human genes. Aberrantly expressed miRNAs associated with disease progression are confined in lipid or lipoprotein and secreted as extracellular miRNA in body fluid such as plasma, serum, and urine. MiRNAs are stably present in the circulation and recently have gained an importance to serve as a minimally invasive biomarker for early detection of epithelial ovarian cancer.

Methods

Genome-wide methylation pattern of six EOC and two normal ovarian tissue samples revealed differential methylation regions of miRNA gene promoter through MeDIP-NGS sequencing. Based on log2FC and p-value, three hypomethylated miRNAs (miR-205, miR-200c, and miR-141) known to have a potential role in ovarian cancer progression were selected for expression analysis through qRT-PCR. The expression of selected miRNAs was analyzed in 115 tissue (85 EOC, 30 normal) and 65 matched serum (51 EOC and 14 normal) samples.

Results

All three miRNAs (miR-205, miR-200c, and miR-141) showed significantly higher expression in both tissue and serum cohorts when compared with normal controls (p < 0.0001). The receiver operating characteristic curve analysis of miR-205, miR-200c, and miR-141 has area under the curve (AUC) values of 87.6 (p < 0.0001), 78.2 (p < 0.0001), and 86.0 (p < 0.0001), respectively; in advance-stage serum samples, however, ROC has AUC values of 88.1 (p < 0.0001), 78.9 (p < 0.0001), and 86.7 (p < 0.0001), respectively, in early-stage serum samples. The combined diagnostic potential of the three miRNAs in advance-stage serum samples and early-stage serum samples has AUC values of 95.9 (95% CI: 0.925–1.012; sensitivity = 96.6% and specificity = 80.0%) and 98.1 (95% CI: 0.941–1.021; sensitivity = 90.5% and specificity = 100%), respectively.

Conclusion

Our data correlate the epigenetic deregulation of the miRNA genes with their expression. In addition, the miRNA panel (miR-205 + miR-200c + miR-141) has a much higher AUC, sensitivity, and specificity to predict EOC at an early stage in both tissue and serum samples.
Reduced Intensity Conditioning Followed by Allogeneic Hematopoietic Stem Cell Transplantation Is a Good Choice for Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Meta-Analysis of Randomized Controlled Trials
Authors: Song Yanzhi , Yin Zhichao , Ding Jie , Wu Tong
Published: October 2021

Background

Reduced intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been reported to have the same overall survival (OS) as myeloablative conditioning (MAC) for patients with acute myeloid leukemia (AML) in complete remission (CR) and myelodysplastic syndrome (MDS). However, results from different studies are conflicting. Therefore, we conducted a systematic review and meta-analysis guided by PRISMA 2009 to confirm the efficacy and safety of RIC vs. MAC for AML in CR and MDS.

Methods

We search PubMed, Web of Science, Embase, Cochrane central, clinical trial registries and related websites, major conference proceedings, and field-related journals from January 1, 1980, to July 1, 2020, for studies comparing RIC with MAC before the first allo-HSCT in patients with AML in CR or MDS. Only randomized controlled trials (RCTs) were included. OS was the primary endpoint and generic inverse variance method was used to combine hazard ratio (HR) and 95% CI.

Results

We retrieved 7,770 records. Six RCTs with 1,413 participants (711 in RIC, 702 in MAC) were included. RIC had the same OS (HR = 0.95, 95% CI 0.64–1.4, p = 0.80) and cumulative incidence of relapse as MAC (HR = 1.18, 95% CI 0.88–1.59, p = 0.28). Furthermore, RIC significantly reduced non-relapse mortality more than total body irradiation/busulfan-based MAC (HR = 0.53, 95% CI 0.36–0.80, p = 0.002) and had similar long-term OS and graft failure as MAC.

Conclusion

RIC conditioning regimens are recommended as an adequate option of preparative treatment before allo-HSCT for patients with AML in CR or MDS.

Systematic Review Registration

https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=185436.
Investigation of Predictors to Achieve Acceptable Lung Dose in T-Shaped Upper and Middle Esophageal Cancer With IMRT and VMAT
Authors: Shao Yan , Chen Hua , Wang Hao , Duan Yanhua , Feng Aihui , Huang Ying , Gu Hengle , Kong Qing , Xu Zhiyong
Published: October 2021

Purpose

The purpose of this study is to investigate whether there are predictors and cutoff points that can predict the acceptable lung dose using intensity-modulated radiation therapy (IMRT) and volume-modulated arc therapy (VMAT) in radiotherapy for upper ang middle esophageal cancer.

Material and Methods

Eighty-two patients with T-shaped upper-middle esophageal cancer (UMEC) were enrolled in this retrospective study. Jaw-tracking IMRT plan (JT-IMRT), full-arc VMAT plan (F-VMAT), and pactial-arc VMAT plan (P-VMAT) were generated for each patient. Dosimetric parameters such as MLD and V20 of total lung were compared among the three plannings. Ten factors such as PCTVinferior length and PCTVinferior length/total lung length were calculated to find the predictors and cutoff points of the predictors. All patients were divided into two groups according to the cutoff points, and the dosimetric differences between the two groups of the three plans were compared. ANOVA, receiver operating characteristic (ROC) analysis, and Mann–Whitney U-test were performed for comparisons between datasets. A p <0.05 was considered statistically significant.

Result

The quality of the targets of the three plannings was comparable. The total lung dose in P-VMAT was significantly lower than that in JT IMRT and F-VMAT. Monitor unit (MU) of F-VMAT and P-VMAT was significantly lower than that of JT IMRT. ROC analysis showed that among JT IMRT, F-VMAT, and P-VMAT, PCTVi-L, and PCTVi-L/TLL had diagnostic power to predict the suitability of RT plans according to lung dose constraints of our department. For JT IMRT, the cutoff points of PCTVi-L and PCTVi-L/TLL were 16.6 and 0.59. For F-VMAT, the cutoff points of PCTVi-L and PCTVi-L/TLL were 16.75 and 0.62. For P-VMAT, the cutoff points of PCTVi-L and PCTVi-L/TLL were 15.15 and 0.59. After Mann–Whitney U-test analysis, it was found that among the three plannings, the group with lower PCTVi-L and PCTVi-L/TLL could significantly reduce the dose of total lung and heart (p <0.05).

Conclusion

PCTVi-L <16.6 and PCTVi-L/TLL <0.59 for JT IMRT, PCTVi-L <16.75 and PCTVi-L/TLL <0.62 for F-VMAT and PCTVi-L <15.15, and PCTVi-L/TLL <0.59 for P-VMAT can predict whether patients with T-shaped UMEC can meet the lung dose limits of our department.
LncRNA MALAT1 Promotes Tumor Angiogenesis by Regulating MicroRNA-150-5p/VEGFA Signaling in Osteosarcoma: In-Vitro and In-Vivo Analyses
Authors: Vimalraj Selvaraj , Subramanian Raghunandhakumar , Dhanasekaran Anuradha
Published: October 2021

The present study aims to analyze the expression of long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in human osteosarcoma (OS) cells and to investigate its role in OS-induced angiogenesis. MALAT1 expression in OS cells was significantly higher than in normal osteoblasts. The functional analysis indicated that MALAT1 appears to enhance OS-induced angiogenesis, in vitro and in vivo analyses, endothelial cell proliferation and migration, chick embryo angiogenesis assay, and zebrafish xenograft model. Mechanistically, silencing MALAT1 downregulated vascular endothelial growth factor A (VEGFA) expression and upregulated miR-150-5p expression in OS cells, and MALAT1-mediated angiogenic induction by VEGFA in OS microenvironment. Moreover, MALAT1 directly targeted miR-150-5p and miR-150-5p directly target VEGFA in OS. Overexpression of miR-150-5p downregulates VEGFA expression in OS. More notably, we showed that MALAT1 induced angiogenesis in OS microenvironment by upregulating the expression of VEGFA via targeting miR-150-5p. Overall, our findings suggest that MALAT1 promotes angiogenesis by regulating the miR-150-5p/VEGFA signaling in OS microenvironment. The findings of the molecular mechanisms of MALAT1 in tumor angiogenesis offer a new viewpoint on OS treatment.