bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and Genetic Features of a Large Monocentric Series of Familial Non-Medullary Thyroid Cancers
Authors: Cirello Valentina , Colombo Carla , Karapanou Olga , Pogliaghi Gabriele , Persani Luca , Fugazzola Laura
Published: January 2021

Several low penetration susceptibility risk loci or genes have been proposed in recent years with a possible causative role for familial non-medullary thyroid cancer (FNMTC), though the results are still not conclusive or reliable. Among all the candidates, here fully reviewed, a new extremely rare germline variant c.3607A>G (p.Y1203H) of the DUOX2 gene, has been recently reported to co-segregate with the affected members of one non-syndromic FNMTC family. We aimed to validate this finding in our series of 33 unrelated FNMTC Italian families, previously found to be negative for two susceptibility germline variants in the HABP2 and MAP2K5 genes. Unfortunately, the DUOX2 p.Y1203H variant was not found in either the 74 affected or the 12 not affected family members of our series. We obtained interesting data by comparing the clinico-pathological data of the affected members of our kindreds with a large consecutive series of sporadic cases, followed at our site. We found that familial tumors had a statistically significant more aggressive presentation at diagnosis, though not resulting in a worst outcome. In conclusion, we report genetic and clinical data in a large series of FNMTC kindreds. Our families are negative for variants reported as likely causative, namely those lying in the HABP2, MAP2K5 and DUOX2 genes. The extensive review of the current knowledge on the genetic risk factors for non-syndromic FNMTCs underlies how the management of these tumors remains mainly clinical. Despite the more aggressive presentation of familial cases, an appropriate treatment leads to an outcome similar to that observed for sporadic cases.
Sulfite Alters the Mitochondrial Network in Molybdenum Cofactor Deficiency
Authors: Mellis Anna-Theresa , Roeper Juliane , Misko Albert L. , Kohl Joshua , Schwarz Guenter
Published: January 2021

Molybdenum cofactor deficiency (MoCD) is an autosomal recessive disorder belonging to the large family of inborn errors in metabolism. Patients typically present with encephalopathy and seizures early after birth and develop severe neurodegeneration within the first few weeks of life. The main pathomechanism underlying MoCD is the loss of function of sulfite oxidase (SO), a molybdenum cofactor (Moco) dependent enzyme located in mitochondrial intermembrane space. SO catalyzes the oxidation of sulfite (SO32–) to sulfate (SO42–) in the terminal reaction of cysteine catabolism, and in the absence of its activity, sulfurous compounds such as SO32–, S-sulfocysteine, and thiosulfate accumulate in patients. Despite growing evidence that these compounds affect neuronal and mitochondrial function, the molecular basis of neuronal dysfunction and cell death in MoCD is still poorly understood. Here we show that mitochondria are severely affected by the loss of SO activity. SO-deficient mouse embryonic fibroblasts display reduced growth rates and impaired ATP production when cultured in galactose, which is an indicator of mitochondrial dysfunction. We also found that mitochondria in SO-deficient cells form a highly interconnected network compared to controls while displaying a slight decrease in motility and unchanged mitochondrial mass. Moreover, we show that the mitochondrial network is directly influenced by SO32–, as a moderate elevation of SO32– lead to the formation of an interconnected mitochondrial network, while high SO32– levels induced fragmentation. Finally, we found a highly interconnected mitochondrial network in MoCD patient-derived fibroblasts, similar to our findings in mouse-derived fibroblasts. We therefore conclude that altered mitochondrial dynamics are an important contributor to the disease phenotype and suggest that MoCD should be included among the mitochondrial disorders.
Epstein-Barr Virus Early Protein BFRF1 Suppresses IFN-β Activity by Inhibiting the Activation of IRF3
Authors: Wang Ping , Deng Yangxi , Guo Yingjie , Xu Zuo , Li Yiwen , Ou Xiaowen , Xie Li , Lu Manjiao , Zhong Jiayi , Li Bolin , Hu Li , Deng Shenyu , Peng Tao , Cai Mingsheng , Li Meili
Published: January 2021

Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis that is closely associated with several human malignant diseases, while type I interferon (IFN-I) plays an important role against EBV infection. As we all know, EBV can encode some proteins to inhibit the production of IFN-I, but it’s not clear whether other proteins also take part in this progress. EBV early lytic protein BFRF1 is shown to be involved in viral maturation, however, whether BFRF1 participates in the host innate immune response is still not well known. In this study, we found BFRF1 could down-regulate sendai virus-induced IFN-β promoter activity and mRNA expression of IFN-β and ISG54 during BFRF1 plasmid transfection and EBV lytic infection, but BFRF1 could not affect the promoter activity of NF-κB or IRF7. Specifically, BFRF1 could co-localize and interact with IKKi. Although BFRF1 did not interfere the interaction between IKKi and IRF3, it could block the kinase activity of IKKi, which finally inhibited the phosphorylation, dimerization, and nuclear translocation of IRF3. Taken together, BFRF1 may play a critical role in disrupting the host innate immunity by suppressing IFN-β activity during EBV lytic cycle.
The IL-17/IL-23 Axis and Its Genetic Contribution to Psoriatic Arthritis
Authors: Vecellio Matteo , Hake Vivien Xanath , Davidson Connor , Carena Maria Cristina , Wordsworth B. Paul , Selmi Carlo
Published: January 2021

Psoriatic arthritis (PsA) is a chronic inflammatory disease belonging to the family of spondyloarthropathies (SpA). PsA commonly aggravates psoriasis of the skin and frequently manifests as an oligoarthritis with axial skeletal involvement and extraarticular manifestations including dactylitis, enthesitis, and uveitis. The weight of genetic predisposition to psoriasis and PsA is illustrated by the concordance rates in monozygotic twins which clearly demonstrate that genomics is insufficient to induce the clinical phenotype. The association of PsA with several single nucleotide polymorphisms (SNPs) at the IL23R locus and the involvement of Th17 cells in the immunopathogenesis of PsA clearly put the IL-23/IL-17 axis in the spotlight. The IL-23 and IL-17 cytokines have a pivotal role in the chronic inflammation of the synovium in PsA and are also prominent in the skin lesions of those with PsA. In this review, we focus on the genetic association of the IL-23/IL-17 axis with PsA and the contribution of these master cytokines in the pathophysiology of the disease, highlighting the main cell types incriminated in PsA and their specific role in the peripheral blood, lesional skin and joints of patients. We then provide an overview of the approved biologic drugs targeting the IL-23/IL-17 axis and discuss the advantages of genetic stratification to enhance personalized therapies in PsA.
Seasonal Occurrence, Horizontal Movements, and Habitat Use Patterns of Whale Sharks (Rhincodon typus) in the Gulf of Mexico
Authors: Hoffmayer Eric R. , McKinney Jennifer A. , Franks James S. , Hendon Jill M. , Driggers William B. , Falterman Brett J. , Galuardi Benjamin , Byrne Michael E.
Published: January 2021

In the northern Gulf of Mexico (GOM), whale sharks (Rhincodon typus) form large aggregations at continental shelf-edge banks during summer; however, knowledge of movements once they leave aggregation sites is limited. Here we report on the seasonal occurrence of whale sharks in the northern GOM based on over 800 whale shark sightings from 1989 to 2016, as well as the movements of 42 whale sharks tagged with satellite-linked and popup satellite archival transmitting tags from 2008 to 2015. Sightings data were most numerous during summer and fall often with aggregations of individuals reported along the continental shelf break. Most sharks (66%) were tagged during this time at Ewing Bank, a known aggregation site off the coast of Louisiana. Whale shark track duration ranged from three to 366 days and all tagged individuals, which ranged from 4.5 to 12.0 m in total length, remained within the GOM. Sightings data revealed that whale sharks occurred primarily in continental shelf and shelf-edge waters (81%) whereas tag data revealed the sharks primarily inhabited continental slope and open ocean waters (91%) of the GOM. Much of their time spent in open ocean waters was associated with the edge of the Loop Current and associated mesoscale eddies. During cooler months, there was a net movement southward, corresponding with the time of reduced sighting reports. Several sharks migrated to the southwest GOM during fall and winter, suggesting this region could be important overwintering habitat and possibly represents another seasonal aggregation site. The three long-term tracked whale sharks exhibited interannual site fidelity, returning one year later to the vicinity where they were originally tagged. The increased habitat use of north central GOM waters by whale sharks as summer foraging grounds and potential interannual site fidelity to Ewing Bank demonstrate the importance of this region for this species.
Small Cetacean in a Human High-Use Area: Trends in Harbor Porpoise Abundance in the North Sea Over Two Decades
Authors: Nachtsheim Dominik A. , Viquerat Sacha , Ramírez-Martínez Nadya C. , Unger Bianca , Siebert Ursula , Gilles Anita
Published: January 2021

The North Sea is one of the most heavily used shelf regions worldwide with a diversity of human impacts, including shipping, pollution, fisheries, and offshore constructions. These stressors on the environment can have consequences for marine organisms, such as our study species, the harbor porpoise (Phocoena phocoena), which is regarded as a sentinel species and hence has a high conservation priority in the European Union (EU). As EU member states are obliged to monitor the population status, the present study aims to estimate trends in absolute harbor porpoise abundance in the German North Sea based on almost two decades of aerial surveys (2002–2019) using line-transect methodology. Furthermore, we were interested in trends in three Natura2000 Special Areas of Conservation (SACs), which include the harbor porpoise as designated feature. Trends were estimated for each SAC and two seasons (spring and summer) as well as the complete area of the German North Sea. For the trend analysis we applied a Bayesian framework to a series of replicated visual surveys, allowing to propagate the error structure of the original abundance estimates to the final trend estimate and designed to deal with spatio-temporal heterogeneity and other sources of uncertainty. In general, harbor porpoise abundance decreased in northern areas and increased in the south, such as in the SAC Borkum Reef Ground. A particularly strong decline with a high probability (94.9%) was detected in the core area and main reproduction site in summer, the SAC Sylt Outer Reef (−3.79% per year). The overall trend for the German North Sea revealed a decrease in harbor porpoise abundance over the whole study period (−1.79% per year) with high probability (95.1%). The assessment of these trends in abundance based on systematic monitoring should now form the basis for adaptive management, especially in the SAC Sylt Outer Reef, where the underlying causes and drivers for the large decline remain unknown and deserve further investigation, also in a regional North Sea wide context.
High Prevalence of Hypocalcemia in Non-severe COVID-19 Patients: A Retrospective Case-Control Study
Authors: Pal Rimesh , Ram Sant , Zohmangaihi Deepy , Biswas Indranil , Suri Vikas , Yaddanapudi Laxmi N. , Malhotra Pankaj , Soni Shiv L. , Puri Goverdhan D. , Bhalla Ashish , Bhadada Sanjay K.
Published: January 2021

Purpose: To compare serum total calcium and phosphate levels in patients with non-severe COVID-19 with age, sex, and serum 25-hydroxyvitamin D level matched healthy adult cohort.

Methods: In this retrospective case-control study, medical records of patients (≥18 years) diagnosed as non-severe COVID-19 admitted at and discharged from our tertiary care institution during the period from April 10, 2020 and June 20, 2020 were retrieved. Baseline investigations, notably, serum calcium, phosphate, albumin, magnesium, 25-hydroxyvitamin D, and C-reactive protein (CRP), were performed at admission before any form of calcium or vitamin D supplementation were considered. The biochemical parameters were compared with age, sex, and 25-hydroxyvitamin D matched healthy adult controls (1:1 ratio) derived from the Chandigarh Urban Bone Epidemiological Study (CUBES).

Results: After exclusion, 72 patients with non-severe COVID-19 (63 mild and 9 moderate disease) and an equal number of healthy controls were included in the final analysis. Age, sex, serum 25-hydroxyvitamin D, and albumin levels were matched between the 2 groups. Hypovitaminosis D and hypocalcemia were seen in 97 and 67% of the patients, respectively. The patients had lower serum calcium (P value <0.001) and phosphate (P = 0.007) compared with the controls. There was no statistically significant correlation between serum calcium and CRP.

Conclusions: Hypocalcemia is highly prevalent even in COVID-19 patients with non-severe disease probably implying that hypocalcemia is intrinsic to the disease. Prospective studies with larger number of patients are required to prove this hypothesis and unravel the underlying pathophysiological mechanisms.
In-cell Solid-State NMR Studies of Antimicrobial Peptides
Authors: Separovic Frances , Keizer David W. , Sani Marc-Antoine
Published: January 2021

Antimicrobial peptides (AMPs) have attracted attention as alternatives to classic antibiotics due to their expected limited pressure on bacterial resistance mechanisms. Yet, their modes of action, in particular in vivo, remain to be elucidated. In situ atomistic-scale details of complex biomolecular assemblies is a challenging requirement for deciphering the complex modes of action of AMPs. The large diversity of molecules that modulate complex interactions limits the resolution achievable using imaging methodology. Herein, the latest advances in in-cell solid-state NMR (ssNMR) are discussed, which demonstrate the power of this non-invasive technique to provide atomic details of molecular structure and dynamics. Practical requirements for investigations of intact bacteria are discussed. An overview of recent in situ NMR investigations of the architecture and metabolism of bacteria and the effect of AMPs on various bacterial structures is presented. In-cell ssNMR revealed that the studied AMPs have a disruptive action on the molecular packing of bacterial membranes and DNA. Despite the limited number of studies, in-cell ssNMR is emerging as a powerful technique to monitor in situ the interplay between bacteria and AMPs.
Mycobacterium tuberculosis Cells Surviving in the Continued Presence of Bactericidal Concentrations of Rifampicin in vitro Develop Negatively Charged Thickened Capsular Outer Layer That Restricts Permeability to the Antibiotic
Authors: Sebastian Jees , Nair Rashmi Ravindran , Swaminath Sharmada , Ajitkumar Parthasarathi
Published: January 2021

Majority of the cells in the bacterial populations exposed to lethal concentrations of antibiotics for prolonged duration succumbs to the antibiotics’ sterilizing activity. The remaining cells survive by diverse mechanisms that include reduced permeability of the antibiotics. However, in the cells surviving in the continued presence of lethal concentrations of antibiotics, it is not known whether any cell surface alterations occur that in turn may reduce permeability of the antibiotics. Here we report the presence of a highly negatively charged, hydrophilic, thickened capsular outer layer (TCOL) on a small proportion of the rifampicin surviving population (RSP) of Mycobacterium tuberculosis (Mtb) cells upon prolonged continuous exposure to bactericidal concentrations of rifampicin in vitro. The TCOL reduced the intracellular entry of 5-carboxyfluorescein-rifampicin (5-FAM-rifampicin), a fluorochrome-conjugated rifampicin permeability probe of negligible bacteriocidal activity but comparable properties. Gentle mechanical removal of the TCOL enabled significant increase in the 5-FAM-rifampicin permeability. Zeta potential measurements of the cells’ surface charge and hexadecane assay for cell surface hydrophobicity showed that the TCOL imparted high negative charge and polar nature to the cells’ surface. Flow cytometry using the MLP and RSP cells, stained with calcofluor white, which specifically binds glucose/mannose units in β (1 → 4) or β (1 → 3) linkages, revealed the presence of lower content of polysaccharides containing such residues in the TCOL. GC-MS analyses of the TCOL and the normal capsular outer layer (NCOL) of MLP cells showed elevated levels of α-D-glucopyranoside, mannose, arabinose, galactose, and their derivatives in the TCOL, indicating the presence of high content of polysaccharides with these residues. We hypothesize that the significantly high thickness and the elevated negative charge of the TCOL might have functioned as a physical barrier restricting the permeability of the relatively non-polar rifampicin. This might have reduced intracellular rifampicin concentration enabling the cells’ survival in the continued presence of high doses of rifampicin. In the context of our earlier report on the de novo emergence of rifampicin-resistant genetic mutants of Mtb from the population surviving under lethal doses of the antibiotic, the present findings attain clinical significance if a subpopulation of the tubercle bacilli in tuberculosis patients possesses TCOL.
An Updated Global Species Diversity and Phylogeny in the Forest Pathogenic Genus Heterobasidion (Basidiomycota, Russulales)
Authors: Yuan Yuan , Chen Jia-Jia , Korhonen Kari , Martin Francis , Dai Yu-Cheng
Published: January 2021

Heterobasidion species are amongst the most intensively studied polypores because several species are aggressive white rot pathogens of managed coniferous forests mainly in Europe and North America. In the present study, both morphological and multilocus phylogenetic analyses were carried out on Heterobasidion samples from Asia, Oceania, Europe and North America. Three new taxa were found, i.e., H. armandii, H. subinsulare, and H. subparviporum are from Asia and are described as new species. H. ecrustosum is treated as a synonym of H. insulare. So far, six taxa in the H. annosum species complex are recognized. Heterobasidion abietinum, H. annosum, and H. parviporum occur in Europe, H. irregulare, and H. occidentale in North America, and H. subparviporum in East Asia. The North American H. irregulare was introduced to Italy during the Second World War. Species in the H. annosum complex are pathogens of coniferous trees, except H. subparviporum that seems to be a saprotroph. Ten species are found in the H. insulare species complex, all of them are saprotrophs. The pathogenic species are distributed in Europe and North America; the Asian countries should consider the European and North American species as entry plant quarantine fungi. Parallelly, European countries should consider the American H. occidentale and H. irregulare as entry plant quarantine fungi although the latter species is already in Italy, while North America should treat H. abietinum, H. annosum s.s., and H. parviporum as entry plant quarantine fungi. Eight Heterobasidion species found in the Himalayas suggest that the ancestral Heterobasidion species may have occurred in Asia.
Development of a High-Throughput Microfluidic qPCR System for the Quantitative Determination of Quality-Relevant Bacteria in Cheese
Authors: Dreier Matthias , Berthoud Hélène , Shani Noam , Wechsler Daniel , Junier Pilar
Published: January 2021

The composition of the cheese microbiome has an important impact on the sensorial quality and safety of cheese. Therefore, much effort has been made to investigate the microbial community composition of cheese. Quantitative real-time polymerase chain reaction (qPCR) is a well-established method for detecting and quantifying bacteria. High-throughput qPCR (HT-qPCR) using microfluidics brings further advantages by providing fast results and by decreasing the cost per sample. We have developed a HT-qPCR approach for the rapid and cost-efficient quantification of microbial species in cheese by designing qPCR assays targeting 24 species/subspecies commonly found in cheese. Primer pairs were evaluated on the Biomark (Fluidigm) microfluidic HT-qPCR system using DNA from single strains and from artificial mock communities. The qPCR assays worked efficiently under identical PCR conditions, and the validation showed satisfying inclusivity, exclusivity, and amplification efficiencies. Preliminary results obtained from the HT-qPCR analysis of DNA samples of model cheeses made with the addition of adjunct cultures confirmed the potential of the microfluidic HT-qPCR system to screen for selected bacterial species in the cheese microbiome. HT-qPCR data of DNA samples of two downgraded commercial cheeses showed that this approach provides valuable information that can help to identify the microbial origin of quality defects. This newly developed HT-qPCR system is a promising approach that will allow simultaneous monitoring of quality-relevant species in fermented foods with high bacterial diversity, thereby opening up new perspectives for the control and assurance of high product quality.
SCN1A IVS5N+5 G>A Polymorphism and Risk of Febrile Seizure and Epilepsy: A Systematic Review and Meta-Analysis
Authors: Hao Jindou , Liu Haiying , Ma Jiying , Liu Guosheng , Dong Guoqing , Liu Peihui , Xiao Fei
Published: January 2021

Background: Previous studies had investigated the association between polymorphism of IVS5N+5 G>A in SCN1A and the risk of febrile seizure and epilepsy. However, the results were inconsistent. We aimed to conduct a systematic review and meta-analysis to evaluate the association between SCN1A IVS5N+5 G>A polymorphism and risk of febrile seizures and epilepsy.

Methods: We searched Embase, Medline, Scopus, and CNKI for studies on the association between SCN1A IVS5N+5 G>A polymorphism and risk of febrile seizures and epilepsy up to 19 February 2020. We pooled odds ratios (ORs) and 95% confidence intervals (CIs) by different genetic models. To explore the source of heterogeneity, we performed the subgroup analysis by ethnicity and source of control.

Results: We included a total of 12 studies in the meta-analysis. We found a significant negative association between G allele SCN1A IVS5N+5 G>A polymorphism, febrile seizures [G vs. A: OR (95% CI): 0.690 (0.530–0.897); GG vs. AA: 0.503 (0.279–0.908); AG vs. AA: 0.581 (0.460–0.733); GG + AG vs. AA: 0.543 (0.436–0.677); AA + GG vs. AG: 1.309 (1.061–1.615)], and epilepsy [G vs. A: 0.822 (0.750–0.902); GG vs. AA: 0.655 (0.515–0.832); AG vs. AA: 0.780 (0.705–0.862); GG vs. AG + AA: 0.769 (0.625–0.947); GG + AG vs. AA: 0.743 (0.663–0.833); AA + GG vs. AG: 1.093 (1.001–1.193)]. The subgroup analysis shows the association varied by type of disease, ethnicity, and source of control.

Conclusion: The present meta-analysis suggests that G allele in SCN1A IVS5N+5 G>A polymorphism is a protective factor of febrile seizures and epilepsy. It is possible to determine the vulnerability of each individual to develop febrile seizures or epilepsy genotype by these genetic variants. Future studies with better study designs are needed to confirm the results.

Study Registration: This study was registered in the International Prospective register of systematic reviews (PROSPERO, CRD42020163318).
Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation
Authors: Alquezar Carolina , Arya Shruti , Kao Aimee W.
Published: January 2021

Post-translational modifications (PTMs) on tau have long been recognized as affecting protein function and contributing to neurodegeneration. The explosion of information on potential and observed PTMs on tau provides an opportunity to better understand these modifications in the context of tau homeostasis, which becomes perturbed with aging and disease. Prevailing views regard tau as a protein that undergoes abnormal phosphorylation prior to its accumulation into the toxic aggregates implicated in Alzheimer's disease (AD) and other tauopathies. However, the phosphorylation of tau may, in fact, represent part of the normal but interrupted function and catabolism of the protein. In addition to phosphorylation, tau undergoes another forms of post-translational modification including (but not limited to), acetylation, ubiquitination, glycation, glycosylation, SUMOylation, methylation, oxidation, and nitration. A holistic appreciation of how these PTMs regulate tau during health and are potentially hijacked in disease remains elusive. Recent studies have reinforced the idea that PTMs play a critical role in tau localization, protein-protein interactions, maintenance of levels, and modifying aggregate structure. These studies also provide tantalizing clues into the possibility that neurons actively choose how tau is post-translationally modified, in potentially competitive and combinatorial ways, to achieve broad, cellular programs commensurate with the distinctive environmental conditions found during development, aging, stress, and disease. Here, we review tau PTMs and describe what is currently known about their functional impacts. In addition, we classify these PTMs from the perspectives of protein localization, electrostatics, and stability, which all contribute to normal tau function and homeostasis. Finally, we assess the potential impact of tau PTMs on tau solubility and aggregation. Tau occupies an undoubtedly important position in the biology of neurodegenerative diseases. This review aims to provide an integrated perspective of how post-translational modifications actively, purposefully, and dynamically remodel tau function, clearance, and aggregation. In doing so, we hope to enable a more comprehensive understanding of tau PTMs that will positively impact future studies.
Macula Structure and Microvascular Changes in Recent Small Subcortical Infarct Patients
Authors: Cao Yungang , Yan Jueyue , Zhan Zhenxiang , Liang Yuanbo , Han Zhao
Published: January 2021

Purpose: This study aimed to assess the macula structure and capillaries in the macula and optic nerve head in recent small subcortical infarct (RSSI) patients.

Methods: This observational cross-sectional study included 40 RSSI patients and 46 healthy controls. Optical coherence tomography angiography was used to image the capillaries in the macula and optic nerve head. An inbuilt algorithm was used to measure the densities in the microvasculature of the macula [superficial retinal capillary plexus (SRCP) and deep retinal capillary plexus (DRCP)] and optic nerve head [radial peripapillary capillary (RPC)] and thickness around the optic nerve head, peripapillary retinal nerve fiber layer (pRNFL).

Results: Densities in RPC (P < 0.001), SRCP (P = 0.001), and DRCP (P = 0.003) were reduced in RSSI patients when compared with healthy controls. The pRNFL thickness was thinner (P < 0.001) in RSSI patients than healthy controls. In the RSSI group, the SRCP density significantly correlated with the DRCP density (rho = 0.381, P = 0.042). The pRNFL thickness displayed a significant relationship with the RPC density (rho = 0.482, P = 0.003) in the RSSI group.

Conclusions: RSSI patients showed interrupted capillary plexuses leading to its significant impairment and neurodegeneration. Our report provides insight into the macula capillary microcirculation changes in RSSI.
Researcher Perspectives on Data Sharing in Deep Brain Stimulation
Authors: Zuk Peter , Sanchez Clarissa E. , Kostick Kristin , Torgerson Laura , Muñoz Katrina A. , Hsu Rebecca , Kalwani Lavina , Sierra-Mercado Demetrio , Robinson Jill O. , Outram Simon , Koenig Barbara A. , Pereira Stacey , McGuire Amy L. , Lázaro-Muñoz Gabriel
Published: January 2021

The expansion of research on deep brain stimulation (DBS) and adaptive DBS (aDBS) raises important neuroethics and policy questions related to data sharing. However, there has been little empirical research on the perspectives of experts developing these technologies. We conducted semi-structured, open-ended interviews with aDBS researchers regarding their data sharing practices and their perspectives on ethical and policy issues related to sharing. Researchers expressed support for and a commitment to sharing, with most saying that they were either sharing their data or would share in the future and that doing so was important for advancing the field. However, those who are sharing reported a variety of sharing partners, suggesting heterogeneity in sharing practices and lack of the broad sharing that would reflect principles of open science. Researchers described several concerns and barriers related to sharing, including privacy and confidentiality, the usability of shared data by others, ownership and control of data (including potential commercialization), and limited resources for sharing. They also suggested potential solutions to these challenges, including additional safeguards to address privacy issues, standardization and transparency in analysis to address issues of data usability, professional norms and heightened cooperation to address issues of ownership and control, and streamlining of data transmission to address resource limitations. Researchers also offered a range of views on the sensitivity of neural activity data (NAD) and data related to mental health in the context of sharing. These findings are an important input to deliberations by researchers, policymakers, neuroethicists, and other stakeholders as they navigate ethics and policy questions related to aDBS research.
Overloaded Adeno-Associated Virus as a Novel Gene Therapeutic Tool for Otoferlin-Related Deafness
Authors: Rankovic Vladan , Vogl Christian , Dörje Nele M. , Bahader Iman , Duque-Afonso Carlos J. , Thirumalai Anupriya , Weber Thomas , Kusch Kathrin , Strenzke Nicola , Moser Tobias
Published: January 2021

Hearing impairment is the most common sensory disorder in humans. So far, rehabilitation of profoundly deaf subjects relies on direct stimulation of the auditory nerve through cochlear implants. However, in some forms of genetic hearing impairment, the organ of Corti is structurally intact and therapeutic replacement of the mutated gene could potentially restore near natural hearing. In the case of defects of the otoferlin gene (OTOF), such gene therapy is hindered by the size of the coding sequence (~6 kb) exceeding the cargo capacity (<5 kb) of the preferred viral vector, adeno-associated virus (AAV). Recently, a dual-AAV approach was used to partially restore hearing in deaf otoferlin knock-out (Otof-KO) mice. Here, we employed in vitro and in vivo approaches to assess the gene-therapeutic potential of naturally-occurring and newly-developed synthetic AAVs overloaded with the full-length Otof coding sequence. Upon early postnatal injection into the cochlea of Otof-KO mice, overloaded AAVs drove specific expression of otoferlin in ~30% of all IHCs, as demonstrated by immunofluorescence labeling and polymerase chain reaction. Recordings of auditory brainstem responses and a behavioral assay demonstrated partial restoration of hearing. Together, our results suggest that viral gene therapy of DFNB9—using a single overloaded AAV vector—is indeed feasible, reducing the complexity of gene transfer compared to dual-AAV approaches.
The Impact of Artificial Sweeteners on Body Weight Control and Glucose Homeostasis
Authors: Pang Michelle D. , Goossens Gijs H. , Blaak Ellen E.
Published: January 2021

A poor diet is one of the leading causes for non-communicable diseases. Due to the increasing prevalence of overweight and obesity, there is a strong focus on dietary overconsumption and energy restriction. Many strategies focus on improving energy balance to achieve successful weight loss. One of the strategies to lower energy intake is refraining from sugars and replacing them with artificial sweeteners, which maintain the palatability without ingesting calories. Nevertheless, the safety and health benefits of artificial sweeteners consumption remain a topic of debate within the scientific community and society at large. Notably, artificial sweeteners are metabolized differently from each other due to their different properties. Therefore, the difference in metabolic fate of artificial sweeteners may underlie conflicting findings that have been reported related to their effects on body weight control, glucose homeostasis, and underlying biological mechanisms. Thus, extrapolation of the metabolic effects of a single artificial sweetener to all artificial sweeteners is not appropriate. Although many rodent studies have assessed the metabolic effects of artificial sweeteners, long-term studies in humans are scarce. The majority of clinical studies performed thus far report no significant effects or beneficial effects of artificial sweeteners on body weight and glycemic control, but it should be emphasized that the study duration of most studies was limited. Clearly, further well-controlled, long-term human studies investigating the effects of different artificial sweeteners and their impact on gut microbiota, body weight regulation and glucose homeostasis, as well as the underlying mechanisms, are warranted.
The Survival Benefit and Safety of Splenectomy for Gastric Cancer With Total Gastrectomy: Updated Results†
Authors: Yang Kun , Zang Zhi-Yun , Niu Kai-Fan , Sun Li-Fei , Zhang Wei-Han , Zhang Yue-Xin , Chen Xiao-Long , Zhou Zong-Guang , Hu Jian-Kun
Published: January 2021

Background

Splenectomy was traditionally performed to dissect the splenic hilar lymph nodes. Considering the important functions of spleen, whether splenectomy would bring beneficial to gastric cancer patients is debatable. This meta-analysis aimed to make an updated evaluation on the effectiveness and safety of splenectomy.

Methods

Literature searches were performed to identify eligible RCTs concerning effectiveness or safety of splenectomy with gastrectomy from PubMed, MEDLINE, CBMdisc, EMBASE, and Cochrane Central Register of Controlled Trials. Two reviewers completed the study selection, data extraction, and quality assessment independently. The meta-analyses were performed by RevMan 5.3.

Results

A total of 971 patients from four studies were included (485 in splenectomy group and 486 in spleen preservation group). Splenectomy did not increase 5-year overall survival rate (RR=1.05, 95% CI: 0.96, 1.16) or increase postoperative mortality (RR=1.21, 95% CI: 0.41, 3.54). However, the analysis demonstrated that gastrectomy with splenectomy had significantly higher incidence of postoperative complications (RR=1.80, 95% CI: 1.33, 2.45). No significant differences were found in terms of the number of resected lymph nodes and reoperation rate; however, splenectomy had a tendency to prolong the duration of surgery and hospital stays. Subgroup analyses indicated that splenectomy could not increase overall survival rate for either whole or proximal gastric cancer. Sensitivity analyses also found similar results compared to the primary analyses.

Conclusions

Splenectomy cannot benefit the survival of patients with tumor located at lesser curvature, and it could instead increase postoperative morbidity.
RETRACTED: Mir-124 Attenuates STAT3-Mediated TH17 Differentiation in Colitis-Driven Colon Cancer
Authors: Lin Shiyong , Liu Qianwen , Wen Jing , Bai Kunhao , Guo Yandong , Wang Jing
Published: January 2021

Background

Inflammation often induces regeneration to repair the tissue damage. However, chronic inflammation can transform temporary hyperplasia into a fertile ground for tumorigenesis. Here, we demonstrate that the miR-124 acts as a safeguard to inhibit the pro-inflammatory production and reparative regeneration.

Methods

The expression levels of miR-124 and IL-17, IFN-γ were detected by qRT-PCR. TH17 or TH1 cells were detected by flow cytometer, respectively. The binding of STAT3 to the promoter region of IL-17 gene was analyzed by Chip assay. miR-124 binding to the 3′UTR of STAT3 gene was detected by reported plasmid construction and luciferase assay. Furthermore, DSS-induced colitis mice model and T cell transfer model were used to confirm the function of miR-124 in vivo. The related gene expression was analyzed by ELISA and western blot experiments.

Results

The results indicated that miR-124 decrease promotes colon tumorigenesis after Citrobacter rodentium infection and AOM/DSS induced colon cancer murine model. In molecular mechanism, miR-124 targets STAT3 to inhibit TH17 cell polarization and keep TH17 polarization in colonic microenvironment.

Conclusions

Our study strengthened the important role of miR-124 in the regulation of adaptive immune responses and blocking the development of colitis-related cancer.
NUSAP1 Promotes Gastric Cancer Tumorigenesis and Progression by Stabilizing the YAP1 Protein
Authors: Guo Hui , Zou Jianping , Zhou Ling , Zhong Min , He Yan , Huang Shanshan , Chen Jun , Li Junhe , Xiong Jianping , Fang Ziling , Xiang Xiaojun
Published: January 2021

The Yes-associated protein (YAP1) is a main effector of the canonical Hippo pathway, which contributes greatly to tumor initiation, progression, and metastasis in multiple cancers, including gastric cancer (GC). Due to limited knowledge of YAP1 upregulation in cancer, it is a great challenge of therapeutic targets toward the Hippo–YAP1 pathway. Here, we identify nucleolar spindle-associated protein 1 (NUSAP1) as a novel binding partner of YAP1. The upregulation of NUSAP1 is associated with unfavorable clinical outcomes in GC patients, and NUSAP1 depletion impairs its oncogenic properties in vitro and in a xenograft model. Mechanistically, we discovered that NUSAP1 functions as a positive regulator of YAP1 protein stability, thereby inducing the transcription of Hippo pathway downstream target genes, such as CTGF and CYR61. More interestingly, we find that the cancer-promoting effects of NUSAP1 on GC cell growth, migration, and invasion are mainly mediated by YAP1. Furthermore, aberrant expression of NUSAP1 and YAP1 is highly correlated in GC cell lines and tissues. We herein clarify the role of the oncogenic NUSAP1–YAP1 axis in GC tumorigenesis and progression and, therefore, provide novel therapeutic targets for GC treatment.
Exploring the Optimal Chemotherapy Strategy for Locoregionally Advanced Children and Adolescent Nasopharyngeal Carcinoma Based on Pretreatment Epstein-Barr Virus DNA Level in the Era of Intensity Modulated Radiotherapy
Authors: Zeng Ziyi , Chen Chen , Guo Lanlan , Zhang Cheng , Chen Lei , Yuan Chuanping , Lu Lixia
Published: January 2021

Background

The present study aimed to explore the optimal chemotherapy strategy for locoregionally advanced children and adolescent nasopharyngeal carcinoma (LcaNPC), based on the level of pretreatment plasma Epstein-Barr virus DNA (pEBV-DNA) in the era of intensity modulated radiation therapy (IMRT).

Methods

This real-world, retrospective study consecutively reviewed locoregionally advanced nasopharyngeal carcinoma patients younger than 22 years old from 2006 to 2016 in the Sun Yat-sen University Cancer Center. The Kaplan–Meier method with the log-rank test and the Cox regression model were used to investigate the survival outcomes of different chemotherapy intensities and pEBV-DNA. Treatment-related toxicity was also evaluated using the chi-squared test or Fisher’s exact test.

Results

A total of 179 patients were enrolled, including 86 patients in the high-risk group (pEBV-DNA ≥7,500 copies/ml) and 93 patients in the low-risk group (pEBV-DNA <7,500 copies/ml). Among all patients, those receiving low intensity induction chemotherapy (IC courses = 2) had a better 5-year overall survival (OS) than those receiving no IC (P = 0.025) and high intensity IC (IC courses >2) (P = 0.044). In the high-risk group, receipt of low intensity IC showed significant 5-year OS (P = 0.032), progression-free survival (PFS) (P = 0.027), and 5-year distant metastasis-free survival (DMFS) (P = 0.008) benefits compared with not receiving IC. Multivariate analyses identified that not receiving IC was a risk factor compared with low intensity IC for OS (hazard ratio (HR) = 10.933, P = 0.038) among all patients. Moreover, in the high-risk group, not receiving IC was a risk factor for 5-year OS (HR = 10.878, P = 0.038), 5-year PFS (HR = 5.705, P = 0.041), and 5-year DMFS (HR = 10.290, P = 0.040) compared to low intensity IC. There were no differences in survival for patients treated with or without concurrent chemotherapy.

Conclusion

Two courses of platinum-based IC might be the optimal induction chemotherapy intensity to reduce risk of death, progression, and distant metastasis in patients with high pEBV-DNA levels.
Development of a Specific Mini-Barcode From Plastome and its Application for Qualitative and Quantitative Identification of Processed Herbal Products Using DNA Metabarcoding Technique: A Case Study on Senna
Authors: Yu Xiaolei , Tan Wei , Gao Han , Miao Lin , Tian Xiaoxuan
Published: January 2021

Herbal products play an important role globally in the pharmaceutical and healthcare industries. However, some specific groups of herbal products are easily adulterated by confused materials on the market, which seriously reduces the products’ quality. Universal conventional DNA barcodes would function poorly since the processed herbal products generally suffer from varying degrees of DNA degradation and DNA mixing during processing or manufacturing. For quality control purposes, an accurate and effective method should be provided for species identification of these herbal products. Here, we provided a strategy of developing the specific mini-barcode using Senna as an example, and by coupling with the metabarcoding technique, it realized the qualitative and quantitative identification of processed herbal products. The plastomes of Senna obtusifolia (L.) H.S.Irwin & Barneby and Senna occidentalis (L.) Link were newly assembled, and the hypervariable coding-regions were identified by comparing their genomes. Then, the specific mini-barcodes were developed based on the identified hypervariable regions. Finally, we applied the DNA metabarcoding technique to the developed mini-barcodes. Results showed that the lengths of plastomes of S. obtusifolia and S. occidentalis were 162,426 and 159,993 bp, respectively. Four hypervariable coding-regions ycf1, rpl23, petL, and matK were identified. Two specific mini-barcodes were successfully developed from matK, and the mini-barcode of primer 647F-847R was proved to be able to qualitatively and quantitatively identify these two processed Senna seeds. Overall, our study established a valuable way to develop the specific mini-barcode, which may provide a new idea for the quality control of processed herbal products.
Sex Differences in the Pro-Angiogenic Response of Human Endothelial Cells: Focus on PFKFB3 and FAK Activation
Authors: Boscaro Carlotta , Trenti Annalisa , Baggio Chiara , Scapin Chiara , Trevisi Lucia , Cignarella Andrea , Bolego Chiara
Published: January 2021

Female hormones and sex-specific factors are established determinants of endothelial function, yet their relative contribution to human endothelium phenotypes has not been defined. Using human umbilical vein endothelial cells (HUVECs) genotyped by donor's sex, we investigated the influence of sex and estrogenic agents on the main steps of the angiogenic process and on key proteins governing HUVEC metabolism and migratory properties. HUVECs from female donors (fHUVECs) showed increased viability (p < 0.01) and growth rate (p < 0.01) compared with those from males (mHUVECs). Despite higher levels of G-protein coupled estrogen receptor (GPER) in fHUVECs (p < 0.001), treatment with 17β-estradiol (E2) and the selective GPER agonist G1 (both 1–100 nM) did not affect HUVEC viability. Migration and tubularization in vitro under physiological conditions were higher in fHUVECs than in mHUVECs (p < 0.05). E2 treatment (1–100 nM) upregulated the glycolytic activator PFKFB3 with higher potency in fHUVECs than in mHUVECs, despite comparable baseline levels. Moreover, Y576/577 phosphorylation of focal adhesion kinase (FAK) was markedly enhanced in fHUVECs (p < 0.001), despite comparable Src activation levels. While the PI3K inhibitor LY294002 (25 µM) inhibited HUVEC migration (p < 0.05), Akt phosphorylation levels in fHUVECs and mHUVECs were comparable. Finally, digitoxin treatment, which inhibits Y576/577 FAK phosphorylation, abolished sexual dimorphism in HUVEC migration. These findings unravel complementary modulation of HUVEC functional phenotypes and signaling molecules involved in angiogenesis by hormone microenvironment and sex-specific factors, and highlight the need for sex-oriented pharmacological targeting of endothelial function.
Identification of Compounds With Glucocorticoid Sparing Effects on Suppression of Chemokine and Cytokine Production by Rheumatoid Arthritis Fibroblast-Like Synoviocytes
Authors: Hosoya Tadashi , Shukla Nikunj M. , Fujita Yuya , Yao Shiyin , Lao Fitzgerald S. , Baba Hiroyuki , Yasuda Shinsuke , Cottam Howard B. , Carson Dennis A. , Hayashi Tomoko , Corr Maripat
Published: January 2021

In recent years target based drug discovery has expanded our therapeutic armamentarium in the treatment of inflammatory and autoimmune diseases. Despite these advances and adverse effects, glucocorticoids remain reliable agents that are used in many of these diseases. The anti-inflammatory mechanisms of glucocorticoids include the suppression of transcription factor activity like nuclear factor kappa B (NF-κB). By reanalyzing data from two prior high throughput screens (HTS) that utilized a NF-κB reporter construct in THP-1 cells, we identified 1824 small molecule synthetic compounds that demonstrated NF-κB suppressive activities similar to the glucocorticoids included in the original >134,000 compound libraries. These 1824 compounds were then rescreened for attenuating NF-κB activity at 5 and 16 h after LPS stimuli in the NF-κB THP-1 reporter cells. After a “Top X” selection approach 122 hit compounds were further tested for toxicity and suppression of LPS induced CXCL8 release in THP-1 cells. Excluding cytotoxic compounds, the remaining active compounds were grouped into chemotype families using Tanimoto based clustering. Promising representatives from clustered chemotype groups were commercially purchased for further testing. Amongst these index compounds a lead chemotype: 1H-pyrazolo [3,4 d] pyrimidin-4-amine, effectively suppressed CXCL8, and TNF production by THP-1 cells when stimulated with LPS, TNF or IL-1ß. Extending these studies to primary cells, these lead compounds also reduced IL-6 and CXCL8 production by TNF stimulated fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients. Importantly a lead 1H-pyrazolo [3,4 d] pyrimidin-4-amine compound demonstrated synergistic effects with dexamethasone when co-administered to TNF stimulated THP-1 cells and RA FLS in suppressing chemokine production. In summary, a cell based HTS approach identified lead compounds that reduced NF-κB activity and chemokine secretion induced by potent immunologic stimuli, and one lead compound that acted synergistically with dexamethasone as an anti-inflammatory agent showing a dose-sparing effect.