bluuebunny/crossref_metadata_2025 huggingface dataset:
Re-Programming Autoreactive T Cells Into T-Regulatory Type 1 Cells for the Treatment of Autoimmunity
Authors: Solé Patricia , Santamaria Pere
Published: July 2021

Systemic delivery of peptide-major histocompatibility complex (pMHC) class II-based nanomedicines can re-program cognate autoantigen-experienced CD4+ T cells into disease-suppressing T-regulatory type 1 (TR1)-like cells. In turn, these TR1-like cells trigger the formation of complex regulatory cell networks that can effectively suppress organ-specific autoimmunity without impairing normal immunity. In this review, we summarize our current understanding of the transcriptional, phenotypic and functional make up of TR1-like cells as described in the literature. The true identity and direct precursors of these cells remain unclear, in particular whether TR1-like cells comprise a single terminally-differentiated lymphocyte population with distinct transcriptional and epigenetic features, or a collection of phenotypically different subsets sharing key regulatory properties. We propose that detailed transcriptional and epigenetic characterization of homogeneous pools of TR1-like cells will unravel this conundrum.
Gut Microbiome and Metabolites in Systemic Lupus Erythematosus: Link, Mechanisms and Intervention
Authors: Zhang Lingshu , Qing Pingying , Yang Hang , Wu Yongkang , Liu Yi , Luo Yubin
Published: July 2021

Systemic lupus erythematosus (SLE), often considered the prototype of autoimmune diseases, is characterized by over-activation of the autoimmune system with abnormal functions of innate and adaptive immune cells and the production of a large number of autoantibodies against nuclear components. Given the highly complex and heterogeneous nature of SLE, the pathogenesis of this disease remains incompletely understood and is presumed to involve both genetic and environmental factors. Currently, disturbance of the gut microbiota has emerged as a novel player involved in the pathogenesis of SLE. With in-depth research, the understanding of the intestinal bacteria-host interaction in SLE is much more comprehensive. Recent years have also seen an increase in metabolomics studies in SLE with the attempt to identify potential biomarkers for diagnosis or disease activity monitoring. An intricate relationship between gut microbiome changes and metabolic alterations could help explain the mechanisms by which gut bacteria play roles in the pathogenesis of SLE. Here, we review the role of microbiota dysbiosis in the aetiology of SLE and how intestinal microbiota interact with the host metabolism axis. A proposed treatment strategy for SLE based on gut microbiome (GM) regulation is also discussed in this review. Increasing our understanding of gut microbiota and their function in lupus will provide us with novel opportunities to develop effective and precise diagnostic strategies and to explore potential microbiota-based treatments for patients with lupus.
Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus Infection
Authors: Marim Fernanda Martins , Teixeira Danielle Cunha , Queiroz-Junior Celso Martins , Valiate Bruno Vinicius Santos , Alves-Filho Jose Carlos , Cunha Thiago Mattar , Dantzer Robert , Teixeira Mauro Martins , Teixeira Antonio Lucio , Costa Vivian Vasconcelos
Published: July 2021

Zika virus (ZIKV) is an arbovirus belonging to Flaviviridae family that emerged as a global health threat due to its association with microcephaly and other severe neurological complications, including Guillain-Barré Syndrome (GBS) and Congenital Zika Syndrome (CZS). ZIKV disease has been linked to neuroinflammation and neuronal cell death. Neurodegenerative processes may be exacerbated by metabolites produced by the kynurenine pathway, an important pathway for the degradation of tryptophan, which induces neuronal dysfunction due to enhanced excitotoxicity. Here, we exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking a target enzyme of the kynurenine pathway, the Indoleamine 2,3-dioxygenase (IDO-1). RT-PCR analysis showed increased levels of IDO-1 RNA expression in undifferentiated primary neurons isolated from wild type (WT) mice infected by ZIKV ex vivo, as well as in the brain of ZIKV-infected A129 mice. Pharmacological inhibition of IDO-1 enzyme with 1-methyl-D-tryptophan (1-MT), in both in vitro and in vivo systems, led to significant reduction of ZIKV-induced neuronal death without interfering with the ability of ZIKV to replicate in those cells. Furthermore, in vivo analyses using both genetically modified mice (IDO-/- mice) and A129 mice treated with 1-MT resulted in reduced microgliosis, astrogliosis and Caspase-3 positive cells in the brain of ZIKV-infected A129 mice. Interestingly, increased levels of CCL5 and CXCL-1 chemokines were found in the brain of 1-MT treated-mice. Together, our data indicate that IDO-1 blockade provides a neuroprotective effect against ZIKV-induced neurodegeneration, and this is amenable to inhibition by pharmacological treatment.
Mapping Autoantibodies in Children With Acute Rheumatic Fever
Authors: McGregor Reuben , Tay Mei Lin , Carlton Lauren H. , Hanson-Manful Paulina , Raynes Jeremy M. , Forsyth Wasan O. , Brewster Diane T. , Middleditch Martin J. , Bennett Julie , Martin William John , Wilson Nigel , Atatoa Carr Polly , Baker Michael G. , Moreland Nicole J.
Published: July 2021

Background

Acute rheumatic fever (ARF) is a serious sequela of Group A Streptococcus (GAS) infection associated with significant global mortality. Pathogenesis remains poorly understood, with the current prevailing hypothesis based on molecular mimicry and the notion that antibodies generated in response to GAS infection cross-react with cardiac proteins such as myosin. Contemporary investigations of the broader autoantibody response in ARF are needed to both inform pathogenesis models and identify new biomarkers for the disease.

Methods

This study has utilised a multi-platform approach to profile circulating autoantibodies in ARF. Sera from patients with ARF, matched healthy controls and patients with uncomplicated GAS pharyngitis were initially analysed for autoreactivity using high content protein arrays (Protoarray, 9000 autoantigens), and further explored using a second protein array platform (HuProt Array, 16,000 autoantigens) and 2-D gel electrophoresis of heart tissue combined with mass spectrometry. Selected autoantigens were orthogonally validated using conventional immunoassays with sera from an ARF case-control study (n=79 cases and n=89 matched healthy controls) and a related study of GAS pharyngitis (n=39) conducted in New Zealand.

Results

Global analysis of the protein array data showed an increase in total autoantigen reactivity in ARF patients compared with controls, as well as marked heterogeneity in the autoantibody profiles between ARF patients. Autoantigens previously implicated in ARF pathogenesis, such as myosin and collagens were detected, as were novel candidates. Disease pathway analysis revealed several autoantigens within pathways linked to arthritic and myocardial disease. Orthogonal validation of three novel autoantigens (PTPN2, DMD and ANXA6) showed significant elevation of serum antibodies in ARF (p < 0.05), and further highlighted heterogeneity with patients reactive to different combinations of the three antigens.

Conclusions

The broad yet heterogenous elevation of autoantibodies observed suggests epitope spreading, and an expansion of the autoantibody repertoire, likely plays a key role in ARF pathogenesis and disease progression. Multiple autoantigens may be needed as diagnostic biomarkers to capture this heterogeneity.
Reefscape Genomics: Leveraging Advances in 3D Imaging to Assess Fine-Scale Patterns of Genomic Variation on Coral Reefs
Authors: Bongaerts Pim , Dubé Caroline E. , Prata Katharine E. , Gijsbers Johanna C. , Achlatis Michelle , Hernandez-Agreda Alejandra
Published: July 2021

Coral reefs across the world are undergoing rapid deterioration, and understanding the ecological and evolutionary processes that govern these ecosystems is critical to our ability to protect them. Molecular ecological studies have been instrumental in advancing such understanding, and while initially focused primarily on broad-scale patterns, they have gradually uncovered the prevalence of local genetic structuring. Genome-wide sequencing approaches have provided new opportunities to understand both neutral and adaptive contributions to this largely unexplained diversity, but fine-scale assessments have been hampered by challenges associated with aquatic environments, in terms of (geo)referencing, seafloor characterization, and in situ phenotyping. Here, we discuss the potential of “reefscape genomics,” leveraging recent advances in underwater imaging to enable spatially explicit genomic studies on coral reefs. More specifically, we consider how (close-range) photogrammetry approaches enable (1) fine-scale spatial mapping of benthic target organisms, (2) repeatable characterization of the abiotic and biotic reefscape, and (3) simultaneous in situ mass-phenotyping. The spatially explicit consideration of genomic data –combined with detailed environmental and phenotypic characterization– opens up the opportunity for fine-scale landscape genomic approaches on coral reefs (and other marine ecosystems). Such approaches enable assessment of the spatio-temporal drivers and adaptive potential of the extensive genetic structuring and cryptic diversity encountered in benthic invertebrates, such as reef-building corals. Considering the threats that coral reefs are facing worldwide, we believe that reefscape genomics represents a promising advancement of our molecular ecological toolkit to help inform how we can most effectively conserve and restore coral reef ecosystems into the future.
210Po/210Pb Disequilibria and Its Estimate of Particulate Organic Carbon Export Around Prydz Bay, Antarctica
Authors: Hu Huina , Liu Xiao , Ren Chunyan , Jia Renming , Qiu Yusheng , Zheng Minfang , Chen Min
Published: July 2021

Due to the remoteness and difficulty of sampling, the 210Po and 210Pb data are scarce in the Southern Ocean. Here, the activity concentrations of 210Po and 210Pb around Prydz Bay in austral summer were determined to understand their spatial variation and evaluate the dynamics of particle organic matter (POM). The activity concentrations of dissolved 210Po (D210Po) and 210Pb (D210Pb) range from 0.47 to 3.20 Bq⋅m–3 and from 1.15 to 2.97 Bq⋅m–3, respectively, with the lower values in the shelf. The particulate 210Po (P210Po) and 210Pb (P210Pb) are lower in the open ocean and increase to the coastal waters, among which the circumpolar deep water (CDW) is the lowest. The activity concentration of total 210Pb (T210Pb) ranges from 1.26 Bq⋅m–3 to 3.16 Bq⋅m–3, with a higher value in CDW, which is ascribed to radiogenic production from 226Ra and subsequent lateral transport. Occasionally a high value of T210Po occurs in deep water (>3.00 Bq⋅m–3), which may be caused by the remineralization of POM. The disequilibria between T210Po and T210Pb appears throughout the water column at most stations. The average T210Po/T210Pb)A.R. in the euphotic zone is 0.66, reflecting the effect of strong particle scavenging. There is a good positive correlation between the solid-liquid ratio of 210Po and POC, while 210Pb does not, indicating that particulate organic matter regulates the biogeochemical cycle of 210Po around Prydz Bay. Based on the 210Po/210Pb disequilibria, the export flux of POC in the water column is estimated to be 0.8–31.9 mmol m–2 d–1, with the higher values in the shelf.
Current Application of Beta-Tricalcium Phosphate in Bone Repair and Its Mechanism to Regulate Osteogenesis
Authors: Lu Haiping , Zhou Yinghong , Ma Yaping , Xiao Lan , Ji Wenjun , Zhang Yi , Wang Xin
Published: July 2021

Large segmental bone loss and bone resection due to trauma and/or the presence of tumors and cysts often results in a delay in healing or non-union. Currently, the bone autograft is the most frequently used strategy to manage large bone loss. Nevertheless, autograft harvesting has limitations, namely sourcing of autograft material, the requirement of an invasive procedure, and susceptibility to infection. These disadvantages can result in complications and the development of a bone substitute materials offers a potential alternative to overcome these shortcomings. Among the biomaterials under consideration to date, beta-tricalcium phosphate (β-TCP) has emerged as a promising material for bone regeneration applications due to its osteoconductivity and osteoinductivity properties as well as its superior degradation in vivo. However, current evidence suggests the use β-TCP can in fact delay bone healing and mechanisms for this observation are yet to be comprehensively investigated. In this review, we introduce the broad application of β-TCP in tissue engineering and discuss the different approaches that β-TCP scaffolds are customized, including physical modification (e.g., pore size, porosity and roughness) and the incorporation of metal ions, other materials (e.g., bioactive glass) and stem cells (e.g., mesenchymal stem cells). 3D and 4D printed β-TCP-based scaffolds have also been reviewed. We subsequently discuss how β-TCP can regulate osteogenic processes to aid bone repair/healing, namely osteogenic differentiation of mesenchymal stem cells, formation of blood vessels, release of angiogenic growth factors, and blood clot formation. By way of this review, a deeper understanding of the basic mechanisms of β-TCP for bone repair will be achieved which will aid in the optimization of strategies to promote bone repair and regeneration.
Hepatitis B Virus Screening Before Cancer Chemotherapy in Taiwan: A Nationwide Population-Based Study
Authors: Sun Wei-Chih , Tang Pei-Ling , Chen Wen-Chi , Tsay Feng-Woei , Wang Huay-Min , Tsai Tzung-Jiun , Kao Sung-Shuo , Cheng Jin-Shiung , Tsai Wei-Lun
Published: July 2021

Background: Reactivation of the hepatitis B virus (HBV) during cancer chemotherapy is a severe and sometimes fatal complication. In 2009, the National Health Insurance (NHI) in Taiwan recommended and reimbursed screening for HBV infection and prophylactic antiviral therapy before cancer chemotherapy. In this study, we determined the HBV screening rate in patients with cancer undergoing chemotherapy in Taiwan.

Methods: We retrospectively collected data from the National Health Insurance Research Database on patients who received systemic chemotherapy for solid or hematologic cancers from January 2000 through December 2012. We defined HBV screening based on testing for serum HBsAg within 2 years of the first chemotherapy commencement. We calculated overall and annual HBV screening rates in all patients and subgroups of age, gender, cancer type, hospital level, physician's department, and implementation of NHI reimbursement for HBV screening before cancer chemotherapy.

Results: We enrolled 379,639 patients. The overall HBV screening rate was 45.9%. The screening rates were higher in males, those with hematological cancer, those at non-medical centers and medical departments. The HBV screening rates before (2000–2008) and after the implementation of NHI reimbursement (2009–2012) were 38.1 and 57.5%, respectively (p < 0.0001). The most common practice pattern of HBV screening was only HBsAg (64.6%) followed by HBsAg/HBsAb (22.1%), and HBsAg/HBcAb/HBsAb (0.7%) (p < 0.0001). The annual HBV screening rate increased from 31.5 to 66.3% (p < 0.0001). The screening rates of solid and hematological cancers significantly increased by year; however, the trend was greater in solid cancer than in hematological cancer (35.9 and 26.2%, p < 0.0001).

Conclusions: The HBV screening rate before cancer chemotherapy was fair but increased over time. These figures improved after implementing a government-based strategy; however, a mandatory hospital-based strategy might improve awareness of HBV screening and starting prophylactic antiviral therapy before cancer chemotherapy.
Regional Differences in Epidemiological and Clinical Characteristics, Treatment, and Clinical Outcomes of COVID-19 in Wuhan and Remote Areas of Hubei Province
Authors: Ren Honggang , Guo Xingyi , Palazón-Bru Antonio , Yang Pengcheng , Huo Nan , Wang Runsheng , Sun Yu , Hu Qinyong , Yang Hua , Xu Guogang
Published: July 2021

Background: The Coronavirus disease 2019 (COVID-19) pandemic has been a major threat to global health. Regional differences in epidemiological and clinical characteristics, treatment and outcomes of patients have not yet been investigated. This study was conducted to investigate these differences amongCOVID-19 patients in Hubei Province, China.

Methods: This retrospective cross-sectional study analyzed data on 289 COVID-19 patients from designated hospitals in three regions:Urban (Wuhan Union West Hospital), Suburban areas of Wuhan (Hannan Hospital) and Enshi city, between February 8 and 20, 2020. The final date of follow-up was December 14th, 2020. The outcomes were case fatality rate and epidemiological and clinical data.

Results: Urban Wuhan experienced a significantly higher case fatality rate (21.5%) than suburban Wuhan (5.23%) and rural area of Enshi (3.51%). Urban Wuhan had a higher proportion of patients on mechanical ventilation (24.05%) than suburban Wuhan (0%) and rural Enshi (3.57%). Treatment with glucocorticoids was equivalent in urban and suburban Wuhan (46.84 and 45.75%, respectively) and higher than Enshi (25.00%). Urban Wuhan had a higher proportion of patients with abnormal tests including liver function and serum electrolytes and a higher rate of pneumonia (p < 0.01 for all). Urban Wuhan also had a higher incidence of respiratory failure, heart disease, liver disease and shock, compared with the other two regions (all p < 0.05).

Conclusions: Our findings revealed that there are regional differences in COVID-19. These findings provide novel insights into the distribution of appropriate resources for the prevention, control and treatment of COVID-19 for the global community.
Microbial Diversity and Activity During the Biodegradation in Seawater of Various Substitutes to Conventional Plastic Cotton Swab Sticks
Authors: Jacquin Justine , Callac Nolwenn , Cheng Jingguang , Giraud Carolane , Gorand Yonko , Denoual Clement , Pujo-Pay Mireille , Conan Pascal , Meistertzheim Anne-Leila , Barbe Valerie , Bruzaud Stéphane , Ghiglione Jean-François
Published: July 2021

The European Parliament recently approved a new law banning single-use plastic items for 2021 such as plastic plates, cutlery, straws, cotton swabs, and balloon sticks. Transition to a bioeconomy involves the substitution of these banned products with biodegradable materials. Several materials such as polylactic acid (PLA), polybutylene adipate terephthalate (PBAT), poly(butylene succinate) (PBS), polyhydroxybutyrate-valerate (PHBV), Bioplast, and Mater-Bi could be good candidates to substitute cotton swabs, but their biodegradability needs to be tested under marine conditions. In this study, we described the microbial life growing on these materials, and we evaluated their biodegradability in seawater, compared with controls made of non-biodegradable polypropylene (PP) or biodegradable cellulose. During the first 40 days in seawater, we detected clear changes in bacterial diversity (Illumina sequencing of 16S rRNA gene) and heterotrophic activity (incorporation of3H-leucine) that coincided with the classic succession of initial colonization, growth, and maturation phases of a biofilm. Biodegradability of the cotton swab sticks was then tested during another 94 days under strict diet conditions with the different plastics as sole carbon source. The drastic decrease of the bacterial activity on PP, PLA, and PBS suggested no bacterial attack of these materials, whereas the bacterial activity in PBAT, Bioplast, Mater-Bi, and PHBV presented similar responses to the cellulose positive control. Interestingly, the different bacterial diversity trends observed for biodegradable vs. non-biodegradable plastics allowed to describe potential new candidates involved in the degradation of these materials under marine conditions. This better understanding of the bacterial diversity and activity dynamics during the colonization and biodegradation processes contributes to an expanding baseline to understand plastic biodegradation in marine conditions and provide a foundation for further decisions on the replacement of the banned single-used plastics.
Influence of Filter Pore Size on Composition and Relative Abundance of Bacterial Communities and Select Host-Specific MST Markers in Coastal Waters of Southern Lake Michigan
Authors: Byappanahalli Muruleedhara N. , Nevers Meredith B. , Shively Dawn , Nakatsu Cindy H. , Kinzelman Julie L. , Phanikumar Mantha S.
Published: July 2021

Water clarity is often the primary guiding factor in determining whether a prefiltration step is needed to increase volumes processed for a range of microbial endpoints. In this study, we evaluate the effect of filter pore size on the bacterial communities detected by 16S rRNA gene sequencing and incidence of two host-specific microbial source tracking (MST) markers in a range of coastal waters from southern Lake Michigan, using two independent data sets collected in 2015 (bacterial communities) and 2016–2017 (MST markers). Water samples were collected from river, shoreline, and offshore areas. For bacterial communities, each sample was filtered through a 5.0-μm filter, followed by filtration through a 0.22-μm filter, resulting in 70 and 143 filter pairs for bacterial communities and MST markers, respectively. Following DNA extraction, the bacterial communities were compared using 16S rRNA gene amplicons of the V3–V4 region sequenced on a MiSeq Illumina platform. Presence of human (Bacteroides HF183) and gull (Gull2, Catellicoccus marimammalium) host-specific MST markers were detected by qPCR. Actinobacteriota, Bacteroidota, and Proteobacteria, collectively represented 96.9% and 93.9% of the relative proportion of all phyla in the 0.22- and 5.0-μm pore size filters, respectively. There were more families detected in the 5.0-μm pore size filter (368) than the 0.22-μm (228). There were significant differences in the number of taxa between the two filter sizes at all levels of taxonomic classification according to linear discriminant analysis (LDA) effect size (LEfSe) with as many as 986 taxa from both filter sizes at LDA effect sizes greater than 2.0. Overall, the Gull2 marker was found in higher abundance on the 5.0-μm filter than 0.22 μm with the reverse pattern for the HF183 marker. This discrepancy could lead to problems with identifying microbial sources of contamination. Collectively, these results highlight the importance of analyzing pre- and final filters for a wide range of microbial endpoints, including host-specific MST markers routinely used in water quality monitoring programs. Analysis of both filters may increase costs but provides more complete genomic data via increased sample volume for characterizing microbial communities in coastal waters.
Pairwise Interactions of Three Related Pseudomonas Species in Plant Roots and Inert Surfaces
Authors: Tovi Nesli , Orevi Tomer , Grinberg Maor , Kashtan Nadav , Hadar Yitzhak , Minz Dror
Published: July 2021

Bacteria are social organisms that interact extensively within and between species while responding to external stimuli from their environments. Designing synthetic microbial communities can enable efficient and beneficial microbiome implementation in many areas. However, in order to design an efficient community, one must consider the interactions between their members. Using a reductionist approach, we examined pairwise interactions of three related Pseudomonas species in various microenvironments including plant roots and inert surfaces. Our results show that the step between monoculture and co-culture is already very complex. Monoculture root colonization patterns demonstrate that each isolate occupied a particular location on wheat roots, such as root tip, distance from the tip, or scattered along the root. However, pairwise colonization outcomes on the root did not follow the bacterial behavior in monoculture, suggesting various interaction patterns. In addition, we show that interspecies interactions on a microscale on inert surface take part in co-culture colonization and that the interactions are affected by the presence of root extracts and depend on its source. The understanding of interrelationships on the root may contribute to future attempts to manipulate and improve bacterial colonization and to intervene with root microbiomes to construct and design effective synthetic microbial consortia.
Protein Phosphatase 1 Regulates Human Cytomegalovirus Protein Translation by Restraining AMPK Signaling
Authors: Stecher Carmen , Marinkov Sanja , Mayr-Harting Lucia , Katic Ana , Kastner Marie-Theres , Rieder-Rommer Franz J. J. , Lin Xionghao , Nekhai Sergei , Steininger Christoph
Published: July 2021

Human cytomegalovirus (HCMV) carries the human protein phosphatase 1 (PP1) and other human proteins important for protein translation in its tegument layer for a rapid supply upon infection. However, the biological relevance behind PP1 incorporation and its role during infection is unclear. Additionally, PP1 is a difficult molecular target due to its promiscuity and similarities between the catalytic domain of multiple phosphatases. In this study, we circumvented these shortcomings by using 1E7-03, a small molecule protein–protein interaction inhibitor, as a molecular tool of noncatalytic PP1 inhibition. 1E7-03 treatment of human fibroblasts severely impaired HCMV replication and viral protein translation. More specifically, PP1 inhibition led to the deregulation of metabolic signaling pathways starting at very early time points post-infection. This effect was at least partly mediated by the prevention of AMP-activated protein kinase dephosphorylation, leading to elongation factor 2 hyperphosphorylation and reduced translation rates. These findings reveal an important mechanism of PP1 for lytic HCMV infection.
A Novel Small Molecule Neurotrophin-3 Analogue Promotes Inner Ear Neurite Outgrowth and Synaptogenesis In vitro
Authors: Kempfle Judith S. , Duro Marlon V. , Zhang Andrea , Amador Carolina D. , Kuang Richard , Lu Ryan , Kashemirov Boris A. , Edge Albert S. , McKenna Charles E. , Jung David H.
Published: July 2021

Sensorineural hearing loss is irreversible and is associated with the loss of spiral ganglion neurons (SGNs) and sensory hair cells within the inner ear. Improving spiral ganglion neuron (SGN) survival, neurite outgrowth, and synaptogenesis could lead to significant gains for hearing-impaired patients. There has therefore been intense interest in the use of neurotrophic factors in the inner ear to promote both survival of SGNs and re-wiring of sensory hair cells by surviving SGNs. Neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) represent the primary neurotrophins in the inner ear during development and throughout adulthood, and have demonstrated potential for SGN survival and neurite outgrowth. We have pioneered a hybrid molecule approach to maximize SGN stimulation in vivo, in which small molecule analogues of neurotrophins are linked to bisphosphonates, which in turn bind to cochlear bone. We have previously shown that a small molecule BDNF analogue coupled to risedronate binds to bone matrix and promotes SGN neurite outgrowth and synaptogenesis in vitro. Because NT-3 has been shown in a variety of contexts to have a greater regenerative capacity in the cochlea than BDNF, we sought to develop a similar approach for NT-3. 1Aa is a small molecule analogue of NT-3 that has been shown to activate cells through TrkC, the NT-3 receptor, although its activity on SGNs has not previously been described. Herein we describe the design and synthesis of 1Aa and a covalent conjugate of 1Aa with risedronate, Ris-1Aa. We demonstrate that both 1Aa and Ris-1Aa stimulate neurite outgrowth in SGN cultures at a significantly higher level compared to controls. Ris-1Aa maintained its neurotrophic activity when bound to hydroxyapatite, the primary mineral component of bone. Both 1Aa and Ris-1Aa promote significant synaptic regeneration in cochlear explant cultures, and both 1Aa and Ris-1Aa appear to act at least partly through TrkC. Our results provide the first evidence that a small molecule analogue of NT-3 can stimulate SGNs and promote regeneration of synapses between SGNs and inner hair cells. Our findings support the promise of hydroxyapatite-targeting bisphosphonate conjugation as a novel strategy to deliver neurotrophic agents to SGNs encased within cochlear bone.
Overexpression of mGluR7 in the Prefrontal Cortex Attenuates Autistic Behaviors in Mice
Authors: Wang Xiaona , Gao Chao , Zhang Yaodong , Hu Shunan , Qiao Yidan , Zhao Zhengqin , Gou Lingshan , Song Jijun , Wang Qi
Published: July 2021

Autism spectrum disorder (ASD) is associated with a range of abnormalities pertaining to socialization, communication, repetitive behaviors, and restricted interests. Owing to its complexity, the etiology of ASD remains incompletely understood. The presynaptic G protein-coupled glutamate receptor metabotropic glutamate receptor 7 (mGluR7) is known to be essential for synaptic transmission and is also tightly linked with ASD incidence. Herein, we report that prefrontal cortex (PFC) mGluR7 protein levels were decreased in C57BL/6J mice exposed to valproic acid (VPA) and BTBR T+ Itpr3tf/J mice. The overexpression of mGluR7 in the PFC of these mice using a lentiviral vector was sufficient to reduce the severity of ASD-like behavioral patterns such that animals exhibited decreases in abnormal social interactions and communication, anxiety-like, and stereotyped/repetitive behaviors. Intriguingly, patch-clamp recordings revealed that the overexpression of mGluR7 suppressed neuronal excitability by inhibiting action potential discharge frequencies, together with enhanced action potential threshold and increased rheobase. These data offer a scientific basis for the additional study of mGluR7 as a promising therapeutic target in ASD and related neurodevelopmental disorders.
Astrocytic Ca2+ Signaling in Epilepsy
Authors: Heuser Kjell , Enger Rune
Published: July 2021

Epilepsy is one of the most common neurological disorders – estimated to affect at least 65 million worldwide. Most of the epilepsy research has so far focused on how to dampen neuronal discharges and to explain how changes in intrinsic neuronal activity or network function cause seizures. As a result, pharmacological therapy has largely been limited to symptomatic treatment targeted at neurons. Given the expanding spectrum of functions ascribed to the non-neuronal constituents of the brain, in both physiological brain function and in brain disorders, it is natural to closely consider the roles of astrocytes in epilepsy. It is now widely accepted that astrocytes are key controllers of the composition of the extracellular fluids, and may directly interact with neurons by releasing gliotransmitters. A central tenet is that astrocytic intracellular Ca2+ signals promote release of such signaling substances, either through synaptic or non-synaptic mechanisms. Accruing evidence suggests that astrocytic Ca2+ signals play important roles in both seizures and epilepsy, and this review aims to highlight the current knowledge of the roles of this central astrocytic signaling mechanism in ictogenesis and epileptogenesis.
Time-Varying Light Exposure in Chronobiology and Sleep Research Experiments
Authors: Spitschan Manuel
Published: July 2021

Light exposure profoundly affects human physiology and behavior through circadian and neuroendocrine photoreception primarily through the melanopsin-containing intrinsically photosensitive retinal ganglion cells. Recent research has explored the possibility of using temporally patterned stimuli to manipulate circadian and neuroendocrine responses to light. This mini-review, geared to chronobiologists, sleep researchers, and scientists in adjacent disciplines, has two objectives: (1) introduce basic concepts in time-varying stimuli and (2) provide a checklist-based set of recommendations for documenting time-varying light exposures based on current best practices and standards.
Regional Difference in Myelination in Monocarboxylate Transporter 8 Deficiency: Case Reports and Literature Review of Cases in Japan
Authors: Iwayama Hideyuki , Tanaka Tatsushi , Aoyama Kohei , Moroto Masaharu , Adachi Shinsuke , Fujisawa Yasuko , Matsuura Hiroki , Takano Kyoko , Mizuno Haruo , Okumura Akihisa
Published: July 2021

Background: Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transmembrane transporter protein. MCT8 deficiency induces severe X-linked psychomotor retardation. Previous reports have documented delayed myelination in the central white matter (WM) in these patients; however, the regional pattern of myelination has not been fully elucidated. Here, we describe the regional evaluation of myelination in four patients with MCT8 deficiency. We also reviewed the myelination status of previously reported Japanese patients with MCT8 deficiency based on magnetic resonance imaging (MRI).

Case Reports: Four patients were genetically diagnosed with MCT8 deficiency at the age of 4–9 months. In infancy, MRI signal of myelination was observed mainly in the cerebellar WM, posterior limb of internal capsule, and the optic radiation. There was progression of myelination with increase in age.

Discussion: We identified 36 patients with MCT8 deficiency from 25 families reported from Japan. The available MRI images were obtained at the age of <2 years in 13 patients, between 2 and 4 years in six patients, between 4 and 6 years in three patients, and at ≥6 years in eight patients. Cerebellar WM, posterior limb of internal capsule, and optic radiation showed MRI signal of myelination by the age of 2 years, followed by centrum semiovale and corpus callosum by the age of 4 years. Most regions except for deep anterior WM showed MRI signal of myelination at the age of 6 years.

Conclusion: The sequential pattern of myelination in patients with MCT8 deficiency was largely similar to that in normal children; however, delayed myelination of the deep anterior WM was a remarkable finding. Further studies are required to characterize the imaging features of patients with MCT8 deficiency.
Secondary White Matter Injury and Therapeutic Targets After Subarachnoid Hemorrhage
Authors: Ru Xufang , Gao Ling , Zhou Jiru , Li Qiang , Zuo Shilun , Chen Yujie , Liu Zhi , Feng Hua
Published: July 2021

Aneurysmal subarachnoid hemorrhage (SAH) is one of the special stroke subtypes with high mortality and mobility. Although the mortality of SAH has decreased by 50% over the past two decades due to advances in neurosurgery and management of neurocritical care, more than 70% of survivors suffer from varying degrees of neurological deficits and cognitive impairments, leaving a heavy burden on individuals, families, and the society. Recent studies have shown that white matter is vulnerable to SAH, and white matter injuries may be one of the causes of long-term neurological deficits caused by SAH. Attention has recently focused on the pivotal role of white matter injury in the pathophysiological processes after SAH, mainly related to mechanical damage caused by increased intracerebral pressure and the metabolic damage induced by blood degradation and hypoxia. In the present review, we sought to summarize the pathophysiology processes and mechanisms of white matter injury after SAH, with a view to providing new strategies for the prevention and treatment of long-term cognitive dysfunction after SAH.
Multimodal Atlas of the Murine Inner Ear: From Embryo to Adult
Authors: Bryant Jean-Paul , Chandrashekhar Vikram , Cappadona Anthony J. , Lookian Pashayar P. , Chandrashekhar Vibhu , Donahue Danielle R. , Munasinghe Jeeva B. , Kim H. Jeffrey , Vortmeyer Alexander O. , Heiss John D. , Zhuang Zhengping , Rosenblum Jared S.
Published: July 2021

The inner ear is a complex organ housed within the petrous bone of the skull. Its intimate relationship with the brain enables the transmission of auditory and vestibular signals via cranial nerves. Development of this structure from neural crest begins in utero and continues into early adulthood. However, the anatomy of the murine inner ear has only been well-characterized from early embryogenesis to post-natal day 6. Inner ear and skull base development continue into the post-natal period in mice and early adulthood in humans. Traditional methods used to evaluate the inner ear in animal models, such as histologic sectioning or paint-fill and corrosion, cannot visualize this complex anatomy in situ. Further, as the petrous bone ossifies in the postnatal period, these traditional techniques become increasingly difficult. Advances in modern imaging, including high resolution Micro-CT and MRI, now allow for 3D visualization of the in situ anatomy of organs such as the inner ear. Here, we present a longitudinal atlas of the murine inner ear using high resolution ex vivo Micro-CT and MRI.
The Efficacy and Safety of Acupuncture for Prophylaxis of Vestibular Migraine: A Study Protocol for a Randomized Controlled Trial
Authors: Hu Tianye , Hu Hantong , Chen Feng , Jiang Bin , Shen Fengfei , Su Yingying , Yang Mengyi , Hu Jin
Published: July 2021

Introduction:With a high incidence rate and low diagnosis rate, vestibular migraine (VM) can seriously affect the quality of life of patients, but it remains difficult to manage by current treatment options. Acupuncture may be a potential treatment option for VM prophylaxis, but the currently available evidence is still uncertain. Therefore, this trial aims to evaluate the efficacy and safety of acupuncture for VM prophylaxis.

Methods:This is a 28-week parallel, randomized, controlled clinical trial including 4 weeks of baseline, 8 weeks of treatment, and 16 weeks of follow-up. A total of 72 participants will be randomly assigned to two groups. The participants will receive acupuncture in the experimental group, while the participants in the control group will be treated with venlafaxine. The primary outcome measures are change in vertigo/migraine days and vertigo/migraine attacks, vertigo severity, and migraine intensity per 4 weeks from baseline. The secondary outcome measures are change in doses of rescue medication, anxiety level, depression level, and quality of life per 4 weeks from baseline. Adverse events will be recorded for safety evaluation.

Discussion:This study will investigate the efficacy and safety of acupuncture for VM prophylaxis. The results will contribute to determining whether acupuncture can serve as an optional treatment strategy for treating VM.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT0464088.
Intrinsic Network Brain Dysfunction Correlates With Temporal Complexity in Generalized Anxiety Disorder and Panic Disorder
Authors: Xu Li , Xu Huazhen , Ding Huachen , Li Jinyang , Wang Chun
Published: July 2021

Background: Generalized anxiety disorder (GAD) and panic disorder (PD) are the two severe subtypes of anxiety disorders (ADs), which are similar in clinical manifestation, pathogenesis, and treatment. Earlier studies have taken a whole-brain perspective on GAD and PD in the assumption that intrinsic fluctuations are static throughout the entire scan. However, it has recently been suggested that the dynamic alternations in functional connectivity (FC) may reflect the changes in macroscopic neural activity patterns underlying the critical aspects of cognition and behavior, and thus may act as biomarkers of disease.

Methods: In this study, the resting-state functional MRI (fMRI) data were collected from 26 patients with GAD, 22 patients with PD, and 26 healthy controls (HCs). We investigated dynamic functional connectivity (DFC) by using the group spatial independent component analysis, a sliding window approach, and the k-means clustering methods. For group comparisons, the temporal properties of DFC states were analyzed statistically.

Results: The dynamic analysis demonstrated two discrete connectivity “States” across the entire group, namely, a more segregated State I and a strongly integrated State II. Compared with HCs, patients with both GAD and PD spent more time in the weakly within-network State I, while performing fewer transitions and dwelling shorter in the integrated State II. Additionally, the analysis of DFC strength showed that connections associated with ADs were identified including the regions that belonged to default mode (DM), executive control (EC), and salience (SA) networks, especially the connections between SA and DM networks. However, no significant difference was found between the GAD and PD groups in temporal features and connection strength.

Conclusions: More common but less specific alterations were detected in the GAD and PD groups, which implied that they might have similar state-dependent neurophysiological mechanisms and, in addition, could hopefully help us better understand their abnormal affective and cognitive performances in the clinic.
Investigation of the Relationship Between Subjective Symptoms of Visual Fatigue and Visual Functions
Authors: Zheng Fuhao , Hou Fang , Chen Ruru , Mei Jianhui , Huang Pingping , Chen Bingzhen , Wang Yuwen
Published: July 2021

Purpose

To investigate whether the severity of symptoms of visual fatigue might be associated with clinical visual measures and basic visual functions, such as accommodation, vergence, and contrast sensitivity.

Methods

In this study, 104 students were recruited (25 males, 79 females, Age 23.4 ± 2.5) for this study. Those with high myopia, strabismus, anisometropia, eye disease or history of ophthalmological surgery were excluded. The included subjects completed a questionnaire that assesses the severity of visual fatigue. Then, binocular accommodative facility, vergence facility and contrast sensitivity using a quick contrast sensitivity function approach were measured in a random sequence. Next, the correlations between each symptom of visual fatigue in the questionnaire and accommodative facility, vergence facility and contrast sensitivity were examined.

Results

Factor analysis indicated that visual fatigue, as captured by the scores of a subset of the questionnaire items, could be strongly related to binocular accommodative facility and binocular contrast sensitivity, but not to vergence facility. We also found that binocular accommodative facility and contrast sensitivity at high spatial frequencies are related.

Conclusion

Our findings suggest that visual fatigue is related to the ability of human observers to encode visual details through their binocular vision.
Cell-Type-Specific High Throughput Toxicity Testing in Human Midbrain Organoids
Authors: Renner Henrik , Becker Katharina J. , Kagermeier Theresa E. , Grabos Martha , Eliat Farsam , Günther Patrick , Schöler Hans R. , Bruder Jan M.
Published: July 2021

Toxicity testing is a crucial step in the development and approval of chemical compounds for human contact and consumption. However, existing model systems often fall short in their prediction of human toxicity in vivo because they may not sufficiently recapitulate human physiology. The complexity of three-dimensional (3D) human organ-like cell culture systems (“organoids”) can generate potentially more relevant models of human physiology and disease, including toxicity predictions. However, so far, the inherent biological heterogeneity and cumbersome generation and analysis of organoids has rendered efficient, unbiased, high throughput evaluation of toxic effects in these systems challenging. Recent advances in both standardization and quantitative fluorescent imaging enabled us to dissect the toxicities of compound exposure to separate cellular subpopulations within human organoids at the single-cell level in a framework that is compatible with high throughput approaches. Screening a library of 84 compounds in standardized human automated midbrain organoids (AMOs) generated from two independent cell lines correctly recognized known nigrostriatal toxicants. This approach further identified the flame retardant 3,3′,5,5′-tetrabromobisphenol A (TBBPA) as a selective toxicant for dopaminergic neurons in the context of human midbrain-like tissues for the first time. Results were verified with high reproducibility in more detailed dose-response experiments. Further, we demonstrate higher sensitivity in 3D AMOs than in 2D cultures to the known neurotoxic effects of the pesticide lindane. Overall, the automated nature of our workflow is freely scalable and demonstrates the feasibility of quantitatively assessing cell-type-specific toxicity in human organoids in vitro.
Plasticity of GluN1 at Ventral Hippocampal Synapses in the Infralimbic Cortex
Authors: Castillo-Ocampo Yesenia , Colón María , Hernández Anixa , Lopez Pablo , Gerena Yamil , Porter James T.
Published: July 2021

Although the infralimbic cortex (IL) is not thought to play a role in fear acquisition, recent experiments found evidence that synaptic plasticity is occurring at ventral hippocampal (vHPC) synapses in IL during auditory fear acquisition as measured by changes in the N-methyl-D-aspartate (NMDA) receptor-mediated currents in male rats. These electrophysiological data suggest that fear conditioning changes the expression of NMDA receptors on vHPC-to-IL synapses. To further evaluate the plasticity of NMDA receptors at this specific synapse, we injected AAV particles expressing channelrhodopsin-EYFP into the vHPC of male and female rats to label vHPC projections with EYFP. To test for NMDA receptor changes in vHPC-to-IL synapses after fear learning, we used fluorescence-activated cell sorting (FACS) to quantify synaptosomes isolated from IL tissue punches that were positive for EYFP and the obligatory GluN1 subunit. More EYFP+/GluN1+ synaptosomes with greater average expression of GluN1 were isolated from male rats exposed to auditory fear conditioning (AFC) than those exposed to context and tones only or to contextual fear conditioning (CFC), suggesting that AFC increased NMDA receptor expression in males. In a second experiment, we found that pairing the tones and shocks was required to induce the molecular changes and that fear extinction did not reverse the changes. In contrast, females showed similar levels of EYFP+/GluN1+ synaptosomes in all behavioral groups. These findings suggest that AFC induces synaptic plasticity of NMDA receptors in the vHPC-to-IL projection in males, while female rats rely on different synaptic mechanisms.
Thalamo-Nucleus Accumbens Projections in Motivated Behaviors and Addiction
Authors: De Groote Aurélie , de Kerchove d’Exaerde Alban
Published: July 2021

The ventral striatum, also called nucleus accumbens (NAc), has long been known to integrate information from cortical, thalamic, midbrain and limbic nuclei to mediate goal-directed behaviors. Until recently thalamic afferents have been overlooked when studying the functions and connectivity of the NAc. However, findings from recent studies have shed light on the importance and roles of precise Thalamus to NAc connections in motivated behaviors and in addiction. In this review, we summarize studies using techniques such as chemo- and optogenetics, electrophysiology and in vivo calcium imaging to elucidate the complex functioning of the thalamo-NAc afferents, with a particular highlight on the projections from the Paraventricular Thalamus (PVT) to the NAc. We will focus on the recent advances in the understanding of the roles of these neuronal connections in motivated behaviors, with a special emphasis on their implications in addiction, from cue-reward association to the mechanisms driving relapse.