bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of Notch Signaling Stimulates Osteoclastogenesis From the Common Trilineage Progenitor Under Inflammatory Conditions
Authors: Filipović Maša , Flegar Darja , Šućur Alan , Šisl Dino , Kavazović Inga , Antica Mariastefania , Kelava Tomislav , Kovačić Nataša , Grčević Danka
Published: July 2022

Osteoclasts, macrophages and dendritic cells (DCs) can be derived from a common trilineage myeloid progenitor of hematopoietic origin. Progenitor commitment is susceptible to regulation through Notch signaling. Our aim was to determine the effects of Notch modulation on trilineage progenitor commitment and functional properties of differentiated cells under inflammatory conditions. We used the conditional inducible CX3CR1CreERT2 mouse strain to achieve overexpression of the Notch 1 intracellular domain (NICD1) or to inhibit Notch signaling via deletion of the transcription factor RBP-J in a bone marrow population, used as a source of the trilineage progenitor (CD45+Ly6G−CD3−B220−NK1.1−CD11b–/loCD115+). Cre-recombinase, under the control of the CX3CR1 promoter, expressed in the monocyte/macrophage lineage, was induced in vitro by 4-hydroxytamoxifen. Differentiation of osteoclasts was induced by M-CSF/RANKL; macrophages by M-CSF; DCs by IL-4/GM-CSF, and inflammation by LPS. Functionally, DCs were tested for the ability to process and present antigen, macrophages to phagocytose E. coli particles, and osteoclasts to resorb bone and express tartrate-resistant acid phosphatase (TRAP). We found that Notch 1 signal activation suppressed osteoclast formation, whereas disruption of the Notch canonical pathway enhanced osteoclastogenesis, resulting in a higher number and size of osteoclasts. RANK protein and Ctsk gene expression were upregulated in osteoclastogenic cultures from RBP-J+ mice, with the opposing results in NICD1+ mice. Notch modulation did not affect the number of in vitro differentiated macrophages and DCs. However, RBP-J deletion stimulated Il12b and Cd86 expression in macrophages and DCs, respectively. Functional assays under inflammatory conditions confirmed that Notch silencing amplifies TRAP expression by osteoclasts, whereas the enhanced phagocytosis by macrophages was observed in both NICD1+ and RBP-J+ strains. Finally, antigen presentation by LPS-stimulated DCs was significantly downregulated with NICD1 overexpression. This experimental setting allowed us to define a cell-autonomous response to Notch signaling at the trilineage progenitor stage. Although Notch signaling modulation affected the activity of all three lineages, the major effect was observed in osteoclasts, resulting in enhanced differentiation and function with inhibition of canonical Notch signaling. Our results indicate that Notch signaling participates as the negative regulator of osteoclast activity during inflammation, which may be relevant in immune and bone diseases.
Mast Cell and Basophil Granule Proteases - In Vivo Targets and Function
Authors: Hellman Lars , Akula Srinivas , Fu Zhirong , Wernersson Sara
Published: July 2022

Proteases are stored in very large amounts within abundant cytoplasmic granules of mast cells (MCs), and in lower amounts in basophils. These proteases are stored in their active form in complex with negatively charged proteoglycans, such as heparin and chondroitin sulfate, ready for rapid release upon MC and basophil activation. The absolute majority of these proteases belong to the large family of chymotrypsin related serine proteases. Three such enzymes are found in human MCs, a chymotryptic enzyme, the chymase, a tryptic enzyme, the tryptase and cathepsin G. Cathepsin G has in primates both chymase and tryptase activity. MCs also express a MC specific exopeptidase, carboxypeptidase A3 (CPA3). The targets and thereby the functions of these enzymes have for many years been the major question of the field. However, the fact that some of these enzymes have a relatively broad specificity has made it difficult to obtain reliable information about the biologically most important targets for these enzymes. Under optimal conditions they may cleave a relatively large number of potential targets. Three of these enzymes, the chymase, the tryptase and CPA3, have been shown to inactivate several venoms from snakes, scorpions, bees and Gila monster. The chymase has also been shown to cleave several connective tissue components and thereby to be an important player in connective tissue homeostasis. This enzyme can also generate angiotensin II (Ang II) by cleavage of Ang I and have thereby a role in blood pressure regulation. It also display anticoagulant activity by cleaving fibrinogen and thrombin. A regulatory function on excessive TH2 immunity has also been observed for both the chymase and the tryptase by cleavage of a highly selective set of cytokines and chemokines. The chymase also appear to have a protective role against ectoparasites such as ticks, mosquitos and leeches by the cleavage of their anticoagulant proteins. We here review the data that has accumulated concerning the potentialin vivofunctions of these enzymes and we discuss how this information sheds new light on the role of MCs and basophils in health and disease.
Regenerative Role of T Cells in Nerve Repair and Functional Recovery
Authors: Tang Xiaoxuan , Li Qiaoyuan , Huang Tingting , Zhang Han , Chen Xiaoli , Ling Jue , Yang Yumin
Published: July 2022

The immune system is essential in the process of nerve repair after injury. Successful modulation of the immune response is regarded as an effective approach to improving treatment outcomes. T cells play an important role in the immune response of the nervous system, and their beneficial roles in promoting regeneration have been increasingly recognized. However, the diversity of T-cell subsets also delivers both neuroprotective and neurodegenerative functions. Therefore, this review mainly discusses the beneficial impact of T-cell subsets in the repair of both peripheral nervous system and central nervous system injuries and introduces studies on various therapies based on T-cell regulation. Further discoveries in T-cell mechanisms and multifunctional biomaterials will provide novel strategies for nerve regeneration.
Basin-Scale Underway Quantitative Survey of Surface Microplankton Using Affordable Collection and Imaging Tools Deployed From Tara
Authors: Mériguet Zoé , Oddone Anna , Le Guen David , Pollina Thibaut , Bazile Romain , Moulin Clémentine , Troublé Romain , Prakash Manu , de Vargas Colomban , Lombard Fabien
Published: July 2022

World ocean plankton quantitative biodiversity data are still severely limited due to the high cost and logistical constraints associated to oceanographic vessels and collection/analytic devices. Here, we report the first use of an affordable and open-source plankton collection and imaging kit designed for citizen biological oceanography, composed of a high-speed surface plankton net, the Coryphaena, together with a portable in-flux automated imaging device, the PlanktoScope. We deployed this kit in December 2020 along a latitudinal transect across the Atlantic Ocean on board the schooner Tara, during the first Leg of her ‘Mission Microbiomes’. The citizen-science instruments were benchmarked and compared at sea to state-of-the-art protocols applied in previous Tara expeditions, i.e. on-board water pumping and filtration system and the FlowCam to respectively sample and image total micro-plankton. Results show that the Coryphaena can collect pristine micro-plankton at speed up to 11 knots, generating quantitative imaging data comparable to those obtained from total, on-board filtered water, and that the PlanktoScope and FlowCam provide comparable data. Overall, the new citizen tools provided a complete picture of surface micro-plankton composition, biogeography and biogeochemistry, opening the way toward a global, cooperative, and frugal plankton observatory network at planetary scale.
Respiratory Polygraphy Patterns and Risk of Recurrent Cardiovascular Events in Patients With Acute Coronary Syndrome
Authors: Zapater Andrea , Solelhac Geoffroy , Sánchez-de-la-Torre Alicia , Gracia-Lavedan Esther , Benitez Ivan David , Torres Gerard , De Batlle Jordi , Haba-Rubio José , Berger Mathieu , Abad Jorge , Duran-Cantolla Joaquín , Urrutia Amaia , Mediano Olga , Masdeu María José , Ordax-Carbajo Estrella , Masa Juan Fernando , De la Peña Mónica , Mayos Mercé , Coloma Ramon , Montserrat Josep María , Chiner Eusebi , Mínguez Olga , Pascual Lydia , Cortijo Anunciación , Martínez Dolores , Dalmases Mireia , Lee Chi-Hang , McEvoy R. Doug , Barbé Ferran , Heinzer Raphael , Sánchez-de-la-Torre Manuel ,   Spanish Sleep Network
Published: July 2022

Introduction

Obstructive sleep apnea (OSA) severity is based on the apnea-hypopnea index (AHI). The AHI is a simplistic measure that is inadequate for capturing disease severity and its consequences in cardiovascular diseases (CVDs). Deleterious effects of OSA have been suggested to influence the prognosis of specific endotypes of patients with acute coronary syndrome (ACS). We aim to identify respiratory polygraphy (RP) patterns that contribute to identifying the risk of recurrent cardiovascular events in patients with ACS.

Methods

Post hoc analysis of the ISAACC study, including 723 patients admitted for a first ACS (NCT01335087) in which RP was performed. To identify specific RP patterns, a principal component analysis (PCA) was performed using six RP parameters: AHI, oxygen desaturation index, mean and minimum oxygen saturation (SaO2), average duration of events and percentage of time with SaO2 < 90%. An independent HypnoLaus population-based cohort was used to validate the RP components.

Results

From the ISAACC study, PCA showed that two RP components accounted for 70% of the variance in the RP data. These components were validated in the HypnoLaus cohort, with two similar RP components that explained 71.3% of the variance in the RP data. The first component (component 1) was mainly characterized by low mean SaO2 and obstructive respiratory events with severe desaturation, and the second component (component 2) was characterized by high mean SaO2 and long-duration obstructive respiratory events without severe desaturation. In the ISAACC cohort, component 2 was associated with an increased risk of recurrent cardiovascular events in the third tertile with an adjusted hazard ratio (95% CI) of 2.44 (1.07 to 5.56; p-value = 0.03) compared to first tertile. For component 1, no significant association was found for the risk of recurrent cardiovascular events.

Conclusion

A RP component, mainly characterized by intermittent hypoxemia, is associated with a high risk of recurrent cardiovascular events in patients without previous CVD who have suffered a first ACS.
Management of the Adnexal Mass: Considerations for the Family Medicine Physician
Authors: Bullock Brian , Larkin Lisa , Turker Lauren , Stampler Kate
Published: July 2022

Ovarian cancer is the most deadly gynecological cancer, so proper assessment of a pelvic mass is necessary in order to determine which are at high risk for malignancy and should be referred to a gynecologic oncologist. However, in a family medicine setting, evaluation and treatment of these masses can be challenging due to a lack of resources. A number of risk assessment tools are available to family medicine physicians, including imaging techniques, imaging systems, and blood-based biomarker assays each with their respective pros and cons, and varying ability to detect malignancy in pelvic masses. Effective utilization of these assessment tools can inform the care pathway for patients which present with an adnexal mass, such as expectant management for those with a low risk of malignancy, or referral to a gynecologic oncologist for surgery and staging, for those at high risk of malignancy. Triaging patients to the appropriate care pathway improves patient outcomes and satisfaction, and family medicine physicians can play a key role in this decision-making process.
Two Years of Evolutionary Dynamics of SARS-CoV-2 in Mexico, With Emphasis on the Variants of Concern
Authors: Flores-Alanis Alejandro , Delgado Gabriela , Espinosa-Camacho Luis F. , Rodríguez-Gómez Flor , Cruz-Rangel Armando , Sandner-Miranda Luisa , Cravioto Alejandro , Morales-Espinosa Rosario
Published: July 2022

Background

The advance of the COVID-19 pandemic and spread of SARS-CoV-2 around the world has generated the emergence of new genomic variants. Those variants with possible clinical and therapeutic implications have been classified as variants of concern (VOCs) and variants of interest (VOIs).

Objective

This study aims to describe the COVID-19 pandemic and build the evolutionary and demographic dynamics of SARS-CoV-2 populations in Mexico, with emphasis on VOCs.

Methods

30,645 complete genomes of SARS-CoV-2 from Mexico were obtained from GISAID databases up to January 25, 2022. A lineage assignment and phylogenetic analysis was completed, and demographic history for Alpha, Gamma, Delta and Omicron VOCs, and the Mexican variant (B.1.1.519) was performed.

Results

148 variants were detected among the 30,645 genomes analyzed with the Delta variant being the most prevalent in the country, representing 49.7% of all genomes.

Conclusion

The COVID-19 pandemic in Mexico was caused by several introductions of SARS-CoV-2, mainly from the United States of America and Europe, followed by local transmission. Regional molecular epidemiological surveillance must implement to detect emergence, introductions and spread of new variants with biologically important mutations.
Characteristics of Gut Microbiota in Patients With Clear Cell Renal Cell Carcinoma
Authors: Chen Yang , Ma Junjie , Dong Yunze , Yang Ziyu , Zhao Na , Liu Qian , Zhai Wei , Zheng Junhua
Published: July 2022

Different gut microbiota is implicated in different diseases, including cancer. However, gut microbiota differences between individuals with clear cell renal cell carcinoma (ccRCC) and healthy individuals are unclear. Here, we analyzed gut microbiota composition in 51 ccRCC patients and 40 healthy controls using 16S rRNA sequencing analysis. We observed that Blautia, Streptococcus, [Ruminococcus]_torques_group, Romboutsia, and [Eubacterium]_hallii_group were dominant and positively associated with ccRCC. We isolated and cultured Streptococcus lutetiensis to characterize specific gut microbiota that promotes ccRCC and found that it promoted in vitro ccRCC proliferation, migration, and invasion via the TGF-signaling pathway. Interactions identified between the gut microbiota and ccRCC suggest the gut microbiota could serve as a potential non-invasive tool for predicting ccRCC risk and also function as a cancer therapy target.
An Integrated Omics Approach Uncovers the Novel Effector Ecp20-2 Required for Full Virulence of Cladosporium fulvum on Tomato
Authors: Karimi-Jashni Mansoor , Maeda Kazuya , Yazdanpanah Farzaneh , de Wit Pierre J. G. M. , Iida Yuichiro
Published: July 2022

The fungus Cladosporium fulvum causes the leaf mould in tomatoes. During the colonization of the host, it secretes plenty of effector proteins into the plant apoplast to suppress the plant’s immune system. Here, we characterized and functionally analyzed the Ecp20-2 gene of C. fulvum using combined omics approaches. RNA-sequencing of susceptible tomato plants inoculated with C. fulvum race 0WU showed strongly induced expression of the Ecp20-2 gene. Strong upregulation of expression of the Ecp20-2 gene was confirmed by qPCR, and levels were comparable to those of other known effectors of C. fulvum. The Ecp20-2 gene encodes a small secreted protein of 149 amino acids with a predicted signal peptide of 17 amino acids. Mass spectrometry of apoplastic fluids from infected tomato leaves revealed the presence of several peptides originating from the Ecp20-2 protein, indicating that the protein is secreted and likely functions in the apoplast. In the genome of C. fulvum, Ecp20-2 is surrounded by various repetitive elements, but no allelic variation was detected in the coding region of Ecp20-2 among 120 C. fulvum isolates collected in Japan. Δecp20-2 deletion mutants of strain 0WU of C. fulvum showed decreased virulence, supporting that Ecp20-2 is an effector required for full virulence of the fungus. Virulence assays confirmed a significant reduction of fungal biomass in plants inoculated with Δecp20-2 mutants compared to those inoculated with wild-type, Δecp20-2-complemented mutants, and ectopic transformants. Sequence similarity analysis showed the presence of Ecp20-2 homologs in the genomes of several Dothideomycete fungi. The Ecp20-2 protein shows the best 3D homology with the PevD1 effector of Verticillium dahliae, which interacts with and inhibits the activity of the pathogenesis-related protein PR5, which is involved in the immunity of several host plants.
Direct Metagenomic Diagnosis of Community-Acquired Meningitis: State of the Art
Authors: Morsli Madjid , Lavigne Jean Philippe , Drancourt Michel
Published: July 2022

Current routine diagnosis of community-acquired meningitis (CAM) by multiplex real-time polymerase chain reaction (RT-PCR) is limited in the number of tested pathogens and their full characterisation, requiring additional in vitro investigations to disclose genotype and antimicrobial susceptibility. We reviewed 51 studies published through December 2021 reporting metagenomic next generation sequencing (mNGS) directly applied to the cerebrospinal fluid (CSF). This approach, potentially circumventing the above-mentioned limitations, indicated 1,248 investigated patients, and 617 patients dually investigated by routine diagnosis and mNGS, in whom 116 microbes were detected, including 50 by mNGS only, nine by routine methods only, and 57 by both routine methods and mNGS. Of 217 discordant CSF findings, 103 CSF samples were documented by mNGS only, 87 CSF samples by routine methods only, and 27 CSF samples in which the pathogen identified by mNGS was different than that found using routine methods. Overall, mNGS allowed for diagnosis and genomic surveillance of CAM causative pathogens in real-time, with a cost which is competitive with current routine multiplex RT-PCR. mNGS could be implemented at point-of-care (POC) laboratories as a part of routine investigations to improve the diagnosis and molecular epidemiology of CAM, particularly in the event of failure of routine assays.
The Natural History of Spinocerebellar Ataxia Type 3 in Mainland China: A 2-Year Cohort Study
Authors: Peng Yun , Peng Linliu , Chen Zhao , Peng Huirong , Wang Puzhi , Zhang Youming , Li Yangping , Wang Chunrong , Shi Yuting , Hou Xuan , Long Zhe , Yuan Hongyu , Wan Na , Wan Linlin , Xu Keqin , Lei Lijing , Wang Shang , He Lang , Xie Yue , Gong Yiqing , Deng Qi , Zou Guangdong , Tang Zhichao , Shen Lu , Xia Kun , Qiu Rong , Klockgether Thomas , Tang Beisha , Jiang Hong
Published: July 2022

Objective

The natural history of spinocerebellar ataxia type 3 (SCA3) has been reported in several populations and shows heterogeneity in progression rate and affecting factors. However, it remains unexplored in the population of Mainland China. This study aimed to identify the disease progression rate and its potential affecting factors in patients with SCA3 in Mainland China.

Participants and Methods

We enrolled patients with genetically confirmed SCA3 in Mainland China. Patients were seen at three visits, i.e., baseline, 1 year, and 2 years. The primary outcome was the Scale for the Assessment and Rating of Ataxia (SARA), and the secondary outcomes were the Inventory of Non-Ataxia Signs (INAS) as well as the SCA Functional Index (SCAFI).

Results

Between 1 October 2015, and 30 September 2016, we enrolled 263 patients with SCA3. We analyzed 247 patients with at least one follow-up visit. The annual progression rate of SARA was 1.49 points per year (SE 0.08, 95% confidence interval [CI] 1.33–1.65, p < 0.0001). The annual progression rates of INAS and SCAFI were 0.56 points per year (SE 0.05, 95% CI 0.47–0.66, p < 0.001) and −0.30 points per year (SE 0.01, 95% CI −0.33∼-0.28, p < 0.001), respectively. Faster progression in SARA was associated with longer length of the expanded allele of ATXN3 (p < 0.0001); faster progression in INAS was associated with lower INAS at baseline (p < 0.0001); faster decline in SCAFI was associated with shorter length of the normal allele of ATXN3 (p = 0.036) and higher SCAFI at baseline (p < 0.0001).

Conclusion

Our results provide quantitative data on the disease progression of patients with SCA3 in Mainland China and its corresponding affecting factors, which could facilitate the sample size calculation and patient stratification in future clinical trials.

Trial Registration

This study was registered with Chictr.org on 15 September 2015, number ChiCTR-OOC-15007124.
How We See Black and White: The Role of Midget Ganglion Cells
Authors: Rezeanu Dragos , Neitz Maureen , Neitz Jay
Published: July 2022

According to classical opponent color theory, hue sensations are mediated by spectrally opponent neurons that are excited by some wavelengths of light and inhibited by others, while black-and-white sensations are mediated by spectrally non-opponent neurons that respond with the same sign to all wavelengths. However, careful consideration of the morphology and physiology of spectrally opponent L vs. M midget retinal ganglion cells (RGCs) in the primate retina indicates that they are ideally suited to mediate black-and-white sensations and poorly suited to mediate color. Here we present a computational model that demonstrates how the cortex could use unsupervised learning to efficiently separate the signals from L vs. M midget RGCs into distinct signals for black and white based only correlation of activity over time. The model also reveals why it is unlikely that these same ganglion cells could simultaneously mediate our perception of red and green, and shows how, in theory, a separate small population of midget RGCs with input from S, M, and L cones would be ideally suited to mediating hue perception.
Where Actions Meet Outcomes: Medial Prefrontal Cortex, Central Thalamus, and the Basal Ganglia
Authors: Mair Robert G. , Francoeur Miranda J. , Krell Erin M. , Gibson Brett M.
Published: July 2022

Medial prefrontal cortex (mPFC) interacts with distributed networks that give rise to goal-directed behavior through afferent and efferent connections with multiple thalamic nuclei and recurrent basal ganglia-thalamocortical circuits. Recent studies have revealed individual roles for different thalamic nuclei: mediodorsal (MD) regulation of signaling properties in mPFC neurons, intralaminar control of cortico-basal ganglia networks, ventral medial facilitation of integrative motor function, and hippocampal functions supported by ventral midline and anterior nuclei. Large scale mapping studies have identified functionally distinct cortico-basal ganglia-thalamocortical subnetworks that provide a structural basis for understanding information processing and functional heterogeneity within the basal ganglia. Behavioral analyses comparing functional deficits produced by lesions or inactivation of specific thalamic nuclei or subregions of mPFC or the basal ganglia have elucidated the interdependent roles of these areas in adaptive goal-directed behavior. Electrophysiological recordings of mPFC neurons in rats performing delayed non-matching-to position (DNMTP) and other complex decision making tasks have revealed populations of neurons with activity related to actions and outcomes that underlie these behaviors. These include responses related to motor preparation, instrumental actions, movement, anticipation and delivery of action outcomes, memory delay, and spatial context. Comparison of results for mPFC, MD, and ventral pallidum (VP) suggest critical roles for mPFC in prospective processes that precede actions, MD for reinforcing task-relevant responses in mPFC, and VP for providing feedback about action outcomes. Synthesis of electrophysiological and behavioral results indicates that different networks connecting mPFC with thalamus and the basal ganglia are organized to support distinct functions that allow organisms to act efficiently to obtain intended outcomes.
Altered Synaptic Transmission and Excitability of Cerebellar Nuclear Neurons in a Mouse Model of Duchenne Muscular Dystrophy
Authors: Kreko-Pierce Tabita , Pugh Jason R.
Published: July 2022

Duchenne muscular dystrophy (DMD) is generally regarded as a muscle-wasting disease. However, human patients and animal models of DMD also frequently display non-progressive cognitive deficits and high comorbidity with neurodevelopmental disorders, suggesting impaired central processing. Previous studies have identified the cerebellar circuit, and aberrant inhibitory transmission in Purkinje cells, in particular, as a potential site of dysfunction in the central nervous system (CNS). In this work, we investigate potential dysfunction in the output of the cerebellum, downstream of Purkinje cell (PC) activity. We examined synaptic transmission and firing behavior of excitatory projection neurons of the cerebellar nuclei, the primary output of the cerebellar circuit, in juvenile wild-type and mdx mice, a common mouse model of DMD. Using immunolabeling and electrophysiology, we found a reduced number of PC synaptic contacts, but no change in postsynaptic GABAA receptor expression or clustering in these cells. Furthermore, we found that the replenishment rate of synaptic vesicles in Purkinje terminals is reduced in mdx neurons, suggesting that dysfunction at these synapses may be primarily presynaptic. We also found changes in the excitability of cerebellar nuclear neurons. Specifically, we found greater spontaneous firing but reduced evoked firing from a hyperpolarized baseline in mdx neurons. Analysis of action potential waveforms revealed faster repolarization and greater after-hyperpolarization of evoked action potentials in mdx neurons, suggesting an increased voltage- or calcium- gated potassium current. We did not find evidence of dystrophin protein or messenger RNA (mRNA) expression in wild-type nuclear neurons, suggesting that the changes observed in these cells are likely due to the loss of dystrophin in presynaptic PCs. Together, these data suggest that the loss of dystrophin reduces the dynamic range of synaptic transmission and firing in cerebellar nuclear neurons, potentially disrupting the output of the cerebellar circuit to other brain regions and contributing to cognitive and neurodevelopmental deficits associated with DMD.
The Burden of Progressive Supranuclear Palsy on Patients, Caregivers, and Healthcare Systems by PSP Phenotype: A Cross-Sectional Study
Authors: Pillas Demetris , Klein Alexander , Gasalla Teresa , Avbersek Andreja , Thompson Alexander , Wright Jack , Mellor Jennifer , Scowcroft Anna
Published: July 2022

Progressive supranuclear palsy (PSP) is a rare, relentlessly progressive, ultimately fatal neurodegenerative brain disease. The objective of this study was to assess the burden of PSP on patients, caregivers, and healthcare systems by PSP phenotype. Data were drawn from the Adelphi PSP Disease Specific Programme™, a cross-sectional study of neurologists and people living with PSP in the United States of America, France, Germany, Italy, Spain, and the United Kingdom. All people living with PSP with a reported phenotype were included. PSP phenotype was reported for 242 patients (mean age: 70.2 years, 58% male): PSP-Richardson's syndrome, n = 96; PSP-predominant Parkinsonism, n = 88; PSP-predominant corticobasal syndrome, n = 28; PSP-predominant speech/language disorder, n = 12; PSP-progressive gait freezing, n = 9; PSP-predominant frontal presentation, n = 9. Most patients reported impaired cognitive, motor, behavioral and ocular functionality; 67–100% of patients (across phenotypes) had moderate-to-severe disease at the time of data collection. Post-diagnosis, the majority were provided with a visual and/or mobility aid (55–100%, across phenotypes), and/or required home modification to facilitate their needs (55–78%, across phenotypes). Patients required multiple types of healthcare professionals for disease management (mean 3.6–4.4, across phenotypes), and the majority reported receiving care from at least one caregiver (mean 1.3–1.8, across phenotypes). There is a high burden on patients, caregivers, and healthcare systems across all PSP phenotypes. Although phenotypes manifest different symptoms and are associated with different diagnostic pathways, once diagnosed with PSP, patients typically receive similar care.
Screening of Human Circular RNAs as Biomarkers for Early Onset Detection of Alzheimer’s Disease
Authors: Zheng Da , Tahir Rana Adnan , Yan Yan , Zhao Juan , Quan Zhenzhen , Kang Guixia , Han Ying , Qing Hong
Published: July 2022

Circular RNAs (circRNAs) are a distinctive type of endogenous non-coding RNAs, and their regulatory roles in neurological disorders have received immense attention. CircRNAs significantly contribute to the regulation of gene expression and progression of neurodegenerative disorders including Alzheimer’s disease (AD). The current study aimed to identify circRNAs as prognostic and potential biomarkers in AD. The differentially expressed circRNAs among subjective cognitive decline, amnestic mild cognitive impairment, and age-matched normal donors were determined through Arraystar Human circRNA Array V2 analysis. The annotations of circRNAs-microRNA interactions were predicted by employing Arraystar’s homemade microRNAs (miRNA) target prediction tool. Bioinformatics analyses comprising gene ontology enrichment, KEGG pathway, and network analysis were conducted. Microarray analysis revealed the 33 upregulated and 11 downregulated differentially expressed circRNAs (FC ≥ 1.5 and p-values ≤ 0.05). The top 10 differentially expressed upregulated and downregulated circRNAs have been chosen for further expression validation through quantitative real-time PCR and subsequently, hsa-circRNA_001481 and hsa_circRNA_000479 were confirmed experimentally. Bioinformatics analyses determined the circRNA-miRNA-mRNA interactions and microRNA response elements to inhibit the expression of miRNAs and mRNA targets. Gene ontology enrichment and KEGG pathways analysis revealed the functional clustering of target mRNAs suggesting the functional verification of these two promising circRNAs. It is concluded that human circRNA_001481 and circRNA_000479 could be utilized as potential biomarkers for the early onset detection of AD and the development of effective therapeutics.
Daily Contributors of Tinnitus Loudness and Distress: An Ecological Momentary Assessment Study
Authors: Simoes Jorge , Bulla Jan , Neff Patrick , Pryss Rüdiger , Marcrum Steven C. , Langguth Berthold , Schlee Winfried
Published: July 2022

Background

Tinnitus is a heterogeneous condition which may be associated with moderate to severe disability, but the reasons why only a subset of individuals is burdened by the condition are not fully clear. Ecological momentary assessment (EMA) allows a better understanding of tinnitus by capturing the fluctuations of tinnitus symptoms, such as distress and loudness, and psychological processes, such as emotional arousal, overall stress, mood, and concentration and how these variables interact over time. Whether any of those variables have an influence over the next day, that is, whether any of these variables are auto- or cross-correlated, is still unanswered.

Objectives

Assess whether behavioral and symptom-related data from tinnitus users from the TrackYourTinnitus (TYT) mobile app have an impact on tinnitus loudness and distress on subsequent days.

Methods

Anonymized data was collected from 278 users of the iOS or Android TYT apps between 2014 and 2020. Tinnitus-related distress, tinnitus loudness, concentration level, mood, emotional arousal, and overall stress level were assessed using either a slider or the Wong-Baker Pain FACES scale via a daily survey. Three modeling strategies were used to investigate whether tinnitus loudness and distress are affected by previous days symptoms or psychological processes: auto- and cross correlations, regressions with elastic net regularization, and subgrouping within group iterative multiple model estimation (S-GIMME).

Results

No autocorrelation or cross-correlation was observed at the group level between the variables assessed. However, application of the regression models with elastic net regularization identified individualized predictors of tinnitus loudness and distress for most participants, with the models including contemporaneous and lagged information from the previous day. S-GIMME corroborated these findings by identifying individualized predictors of tinnitus loudness and distress from the previous day.

Discussion

We showed that tinnitus loudness and tinnitus distress are affected by the contemporaneous and lagged dynamics of behavioral and emotional processes measured through EMA. These effects were seen at the group, and individual levels. The relevance EMA and the implications of the insights derived from it for tinnitus care are discussed, especially considering current trends toward the individualization of tinnitus care.
Descriptive Analysis of Adaptive Behavior in Phelan–McDermid Syndrome and Autism Spectrum Disorder
Authors: Serrada-Tejeda Sergio , Martínez-Piédrola Rosa M. , Máximo-Bocanegra Nuria , Sánchez-Herrera-Baeza Patricia , Pérez-de-Heredia-Torres Marta
Published: July 2022

Introduction

The variety in symptomatology and clinical presentation of individuals diagnosed with Phelan-McDermid Syndrome (PMS) can delay medical diagnosis, so identifying specific neurobehavioral variables and facilitating differential diagnosis with patients with idiopathic Autism Spectrum Disorder (ASD) can guide early detection.

Methods

A descriptive analysis of the level of adaptive behavior in 50 patients diagnosed with PMS was performed (SHANK3deletion: N = 44; SHANKmutation: N = 6). Subsequently, a comparative analysis was performed with 28 children aged between 4 years and 6 years and 11 months (SHANK3deletion = 14; ASD = 14). Differences between the two groups were evaluated and Bonferroni correction was applied for multiple comparisons.

Results

Differences were identified in the variables of communication (z = −2.715, p = 0.007), Self-Direction (z = −2.199, p = 0.028) and social participation (z = −3.190, p = 0.001), with better adaptive behavior skills being observed in participants with a SHANK3mutation. Better adaptive skills in the sample of participants with ASD, were found and statistically significant differences were identified in the variables of academic skills (z = −3.084, p = 0.002), use of community resources (z = −1.889, p = 0.050) and health and safety (z = −2.90, p = 0.004).

Conclusion

Participants with SHANK3mutation show better communication and social participation skills than those with a diagnosis of SHANK3deletion. The observed differences between ASD and individuals with PMS reflect deficits in practical and conceptual adaptive skills that may limit and hinder daily adaptive functioning.
Early Development and the Functional Correlation of Brain Structural Connectivity in Preterm-Born Infants
Authors: Liu Tingting , Zhao Zhiyong , You Yuqing , Gao Fusheng , Lv Ying , Li Mingyan , Ji Chai , Lai Can , Zhang Hongxi , Wu Dan
Published: July 2022

Exuberant axon growth and competitive pruning lead to dramatic and comprehensive changes in white matter pathways of the infant brain during the first few postnatal months, yet the development of structural configuration in early infancy has not been fully characterized. This study aimed to investigate the developmental trajectory of structural connectivity reflecting relative fiber density in 43 preterm-born infants aged 0–3 months of corrected age without any complications utilizing probabilistic tractography based on fiber orientation distribution and to explore the potential function correlation associated with the network properties based on the Chinese Communication Development of Infant at 10 months of corrected age. The findings revealed significant increases in global efficiency, local efficiency, normalized clustering coefficient, and small-worldness (padj < 0.001 for each), while the normalized characteristic path length showed a non-significant decrease with age (padj = 0.118). Furthermore, those findings were validated by another parcelation strategy. In addition, the early local efficiency was found to be significantly correlated with words understood at 10 months of corrected age. A unique developmental pattern of structural networks with enhancing efficiency and the small-world property was found in early infancy, which was different from those of neonates or toddlers. In addition, this study revealed a significant correlation between local efficiency and late language comprehension, which indicated that enhanced structural connectivity may lay the structural foundation for language specialization.
Time Perception for Musical Rhythms: Sensorimotor Perspectives on Entrainment, Simulation, and Prediction
Authors: Ross Jessica M. , Balasubramaniam Ramesh
Published: July 2022

Neural mechanisms supporting time perception in continuously changing sensory environments may be relevant to a broader understanding of how the human brain utilizes time in cognition and action. In this review, we describe current theories of sensorimotor engagement in the support of subsecond timing. We focus on musical timing due to the extensive literature surrounding movement with and perception of musical rhythms. First, we define commonly used but ambiguous concepts including neural entrainment, simulation, and prediction in the context of musical timing. Next, we summarize the literature on sensorimotor timing during perception and performance and describe current theories of sensorimotor engagement in the support of subsecond timing. We review the evidence supporting that sensorimotor engagement is critical in accurate time perception. Finally, potential clinical implications for a sensorimotor perspective of timing are highlighted.
Subregional Differences in Alcohol Modulation of Central Amygdala Neurocircuitry
Authors: Melkumyan Mariam , Silberman Yuval
Published: July 2022

Alcohol use disorder is a highly significant medical condition characterized by an impaired ability to stop or control alcohol use, compulsive alcohol seeking behavior, and withdrawal symptoms in the absence of alcohol. Understanding how alcohol modulates neurocircuitry critical for long term and binge-like alcohol use, such as the central amygdala (CeA), may lead to the development of novel therapeutic strategies to treat alcohol use disorder. In clinical studies, reduction in the volume of the amygdala has been linked with susceptibility to relapse to alcohol use. Preclinical studies have shown the involvement of the CeA in the effects of alcohol use, with lesions of the amygdala showing a reduction in alcohol drinking, and manipulations of cells in the CeA altering alcohol drinking. A great deal of work has shown that acute alcohol, as well as chronic alcohol exposure via intake or dependence models, alters glutamatergic and GABAergic transmission in the CeA. The CeA, however, contains heterogeneous cell populations and distinct subregional differences in neurocircuit architecture which may influence the mechanism by which alcohol modulates CeA function overall. The current review aimed to parse out the differences in alcohol effects on the medial and lateral subregions of the CeA, and what role neuroinflammatory cells and markers, the endocannabinoid system, and the most commonly studied neuropeptide systems play in mediating these effects. A better understanding of alcohol effects on CeA subregional cell type and neurocircuit function may lead to development of more selective pharmacological interventions for alcohol use disorder.
Taurine and Astrocytes: A Homeostatic and Neuroprotective Relationship
Authors: Ramírez-Guerrero Sofía , Guardo-Maya Santiago , Medina-Rincón Germán J. , Orrego-González Eduardo E. , Cabezas-Pérez Ricardo , González-Reyes Rodrigo E.
Published: July 2022

Taurine is considered the most abundant free amino acid in the brain. Even though there are endogenous mechanisms for taurine production in neural cells, an exogenous supply of taurine is required to meet physiological needs. Taurine is required for optimal postnatal brain development; however, its brain concentration decreases with age. Synthesis of taurine in the central nervous system (CNS) occurs predominantly in astrocytes. A metabolic coupling between astrocytes and neurons has been reported, in which astrocytes provide neurons with hypotaurine as a substrate for taurine production. Taurine has antioxidative, osmoregulatory, and anti-inflammatory functions, among other cytoprotective properties. Astrocytes release taurine as a gliotransmitter, promoting both extracellular and intracellular effects in neurons. The extracellular effects include binding to neuronal GABAA and glycine receptors, with subsequent cellular hyperpolarization, and attenuation of N-methyl-D-aspartic acid (NMDA)-mediated glutamate excitotoxicity. Taurine intracellular effects are directed toward calcium homeostatic pathway, reducing calcium overload and thus preventing excitotoxicity, mitochondrial stress, and apoptosis. However, several physiological aspects of taurine remain unclear, such as the existence or not of a specific taurine receptor. Therefore, further research is needed not only in astrocytes and neurons, but also in other glial cells in order to fully comprehend taurine metabolism and function in the brain. Nonetheless, astrocyte’s role in taurine-induced neuroprotective functions should be considered as a promising therapeutic target of several neuroinflammatory, neurodegenerative and psychiatric diseases in the near future. This review provides an overview of the significant relationship between taurine and astrocytes, as well as its homeostatic and neuroprotective role in the nervous system.
Higher Levels of Urinary Thiocyanate, a Biomarker of Cruciferous Vegetable Intake, Were Associated With Lower Risks of Cardiovascular Disease and All-Cause Mortality Among Non-smoking Subjects
Authors: Wang Qiang , King Lei , Wang Pei , Jiang Guanhua , Huang Yue , Dun Changchang , Yin Jiawei , Shan Zhilei , Xu Jian , Liu Liegang
Published: July 2022

Background

Epidemiologic studies on cruciferous vegetable (CV) intake and cardiovascular disease (CVD) were inconclusive.

Objective

To investigate the associations of urinary thiocyanate, a biomarker of CV intake, with CVD and all-cause mortality among non-smoking adults.

Methods

This prospective cohort study comprised 10,489 non-smoking adults (weighted mean age, 46.8 years; 43.4% male) from the National Health and Nutrition Examination Survey 2001–2014. Non-smokers were defined as subjects with serum cotinine < 3 ng/mL. Urinary thiocyanate was measured with ion chromatography tandem mass spectrometry at baseline, and CVD and all-cause mortality were identified through linkage to National Death Index until December 31, 2015. Cox proportional hazards model was applied to estimate the hazard ratios (HRs) with 95% confidence intervals (CIs) for CVD and all-cause mortality.

Results

A total of 800 deaths, of which 136 died of CVD, were ascertained within a median 7.8 years of follow-up. Urinary thiocyanate was positively correlated with total CV intake among non-smoking adults (rs = 0.088, P < 0.001). Comparing extreme quartiles, the multivariate-adjusted HRs for CVD and all-cause mortality were 0.50 (95% CI: 0.29–0.85) and 0.75 (95% CI: 0.60–0.92), respectively. Each 1 μg/g creatinine increment of log-transformed urinary thiocyanate was associated with a 25% (HR: 0.75; 95% CI: 0.62–0.91) reduced CVD mortality risk and 12% (HR: 0.88; 95% CI: 0.81–0.96) reduced all-cause mortality risk. The documented inverse associations persisted in sensitivity analyses.

Conclusion

Increased levels of urinary thiocyanate, a candidate biomarker of CV intake, were associated with low risks of CVD and total mortality among non-smoking adults. This prospective biomarker-based study provided further evidence to support the cardiovascular benefits of CVs.
CircLONP2 Accelerates Esophageal Squamous Cell Carcinoma Progression via Direct MiR-27b-3p-ZEB1 Axis
Authors: Zhu Cailin , Bi Weiyun , Li Hongtao , Wang Wen
Published: July 2022

Circular RNAs (circRNAs) are important mediators in esophageal squamous cell carcinoma (ESCC) carcinogenesis. We aim to explore the functions and mechanisms of circLONP2 in ESCC progression. The circLONP2 level was evaluated in ESCC samples and cell lines. The role and mechanisms of circLONP2 in ESCC proliferation and migration were demonstrated in vitro. We found that circLONP2 was upregulated in human ESCC and predicts poor overall survival (OS) and disease-free survival (DFS). CircLONP2 promotes ESCC aggressiveness by directly interacting with miR-27b-3p, thus upregulating the expression levels of its target gene ZEB1 by suppressing miR-27b-3p activity. Therefore, we demonstrated that circLONP2/miR-27b-3p/ZEB1 axis promotes ESCC metastasis via regulating epithelial-to-mesenchymal transition (EMT)-related proteins. CircLONP2 may serve as an oncogenic circRNA and as a prognostic biomarker in ESCC progression.
PMS2 Expression With Combination of PD-L1 and TILs for Predicting Survival of Esophageal Squamous Cell Carcinoma
Authors: Jiang Dongxian , Song Qi , Wei Xiaojun , Yu Zixiang , Liu Yufeng , Wang Haixing , Wang Xingxing , Huang Jie , Su Jieakesu , Hong Yang , Xu Yifan , Xu Chen , Hou Yingyong
Published: July 2022

Background

DNA mismatch repair (MMR) deficiency (dMMR) has been recognized as an important biomarker for immunotherapy in esophageal squamous cell carcinoma (ESCC), along with programmed death ligand 1 (PD-L1) expression and/or tumor-infiltrated lymphocytes (TILs). However, in ESCC, MMR protein assessment has not been well studied at present.

Methods

A total of 484 ESCC tissues treated between 2007 and 2010, in our hospital, were enrolled. Immunohistochemical expression of MLH1, MSH2, MSH6, PMS2, and PD-L1 on tissue microarray specimens and clinicopathological features, including TILs, were analyzed retrospectively.

Results

Out of the 484 studied cases, loss of MLH1, MSH2, MSH6, and PMS2 expression were found in 6.8%, 2.1%, 8.7%, and 4.8% patients, respectively. dMMR was found in 65 patients, 37 cases involved in one MMR protein, 17 cases involved in two proteins, 7 cases involved in three proteins, and 4 cases involved in four proteins. There was no significant survival difference between pMMR (MMR-proficient) and dMMR patients (P>0.05). However, 224 patients with low PMS2 expression had better DFS and OS than 260 patients with high PMS2 expression (P=0.006 for DFS and 0.008 for OS), which was identified as an independent prognostic factor in multivariate analyses. Positive PD-L1 expression was detected in 341 (70.5%) samples. In stage I-II disease, patients with PD-L1 expression had better DFS and OS than those without PD-L1 expression(P<0.05), which was not found in stage III-IV disease. With the ITWG system, 40.1% of cases were classified as high TILs. Patients in the high-TILs group tended to have better DFS (P=0.055) and OS (P=0.070) than those in the low-TILs group and the differences were statistically significant in pMMR, high MSH6, or PMS2 expression cases (P<0.05). Also, high PMS2 expression patients with both PD-L1 expression and high TILs, had similar DFS and OS compared with low PMS2 expression patients (P>0.05), which were much better than other high PMS2 expression patients.

Conclusion

The expression level of MMR proteins could also be used as a prognostic factor in ESCC and PMS2 expression outperformed other MMR proteins for predicting survival. The combination of PD-L1 expression and TILs may lead to more efficient risk stratification of ESCC.