bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defective monocyte enzymatic function and an inhibitory immune phenotype in HIV-exposed uninfected African infants in the era of anti-retroviral therapy
Authors: Afran Louise , Jambo Kondwani C. , Nedi Wilfred , Miles David JC , Kiran Anmol , Banda Dominic H , Kamg’ona Ralph , Tembo Dumizulu , Burger Annette , Nastouli Eleni , Ferne Brigit , Mwandumba Henry C , Moss Paul , Goldblatt David , Rowland-Jones Sarah , Finn Adam , Heyderman Robert S 
Published: July 2021

SummaryHIV-Exposed Uninfected (HEU) infants are a rapidly expanding population in sub-Saharan Africa and are highly susceptible to disease caused by encapsulated bacteria in the first year of life. The mechanism of this increased risk is still poorly understood. We therefore investigated if HIV exposure dysregulates HEU infant immunity and if this is amplified by human herpes virus infection (HHV). Here, we compared monocyte enzymatic function, innate and adaptive immune cell phenotype, and vaccine-induced antibody responses between HEU and HUU infants. We demonstrate altered monocyte phagosomal function and B cell subset homeostasis, and lower vaccine-induced anti-Haemophilus influenzae type b(Hib)and anti-Tetanus Toxoid (TT) IgG titers in HEU compared to HUU infants. There was no difference in the prevalence of HHV infection between HEU and HUU infants. Our findings suggest that even in the era of antiretroviral therapy (ART)-mediated viral suppression, HIV exposure dysregulates monocyte and B cell function during a vulnerable period of immune maturation in infancy. This may contribute to the high rates of invasive bacterial disease and pneumonia in HEU infants.
Diagnostic performance of a novel digital immunoassay (RapidTesta SARS-CoV-2): a prospective observational study with 1,127 nasopharyngeal samples
Authors: Suzuki Hiromichi , Akashi Yusaku , Ueda Atsuo , Kiyasu Yoshihiko , Takeuchi Yuto , Maehara Yuta , Ochiai Yasushi , Okuyama Shinya , Notake Shigeyuki , Nakamura Koji , Ishikawa Hiroichi 
Published: July 2021

AbstractIntroductionDigital immunoassays are generally regarded as superior tests for the detection of infectious disease pathogens, but there have been insufficient data concerning SARS-CoV-2 immunoassays.MethodsWe prospectively evaluated a novel digital immunoassay (RapidTesta SARS-CoV-2). Two nasopharyngeal samples were simultaneously collected for antigen tests and RT-PCR. Real-time RT-PCR for SARS-CoV-2, using a method developed by the National Institute of Infectious Diseases, Japan, served as the reference RT-PCR method.ResultsDuring the study period, 1,127 nasopharyngeal samples (symptomatic patients: 802, asymptomatic patients: 325) were evaluated. For digital immunoassay antigen tests, the sensitivity was 78.3% (95% CI: 67.3%–87.1%) and the specificity was 97.6% (95% CI: 96.5%–98.5%). When technicians visually analyzed the antigen test results, the sensitivity was 71.6% (95% CI: 59.9%–81.5%) and the specificity was 99.2% (95% CI: 98.5%–99.7%). Among symptomatic patients, the sensitivity was 89.4% (95% CI; 76.9%–96.5%) with digital immunoassay antigen tests, and 85.1% (95% CI; 71.7%–93.8%) with visually analyzed the antigen test, respectively.ConclusionsThe findings indicated that RapidTesta SARS-CoV-2 analysis with the DIA device had sufficient analytical performance for the detection of SARS-CoV-2 in nasopharyngeal samples. When positive DIA results are recorded without a visually recognizable red line at the positive line location on the test cassette, additional RT-PCR evaluation should be performed.
Interventional Neurorehabilitation for Promoting Functional Recovery Post-Craniotomy: A Proof-of-Concept
Authors: Poologaindran Anujan , Profyris Christos , Young Isabella M. , Dadario Nicholas B. , Ahsan Syed A. , Chendeb Kassem , Briggs Robert G. , Teo Charles , Romero-Garcia Rafael , Suckling John , Sughrue Michael E. 
Published: July 2021

ABSTRACTPurposeThe human brain is a highly plastic ‘complex’ network –it is highly resilient to damage and capable of self-reorganisation after a large perturbation. Clinically, neurological deficits secondary to iatrogenic injury have very few active treatments. New imaging and stimulation technologies, though, offer promising therapeutic avenues to accelerate post-operative recovery trajectories. In this study, we sought to establish the safety profile for ‘interventional neurorehabilitation’: connectome-based therapeutic brain stimulation to drive cortical reorganisation and promote functional recovery post-craniotomy.MethodsIn n=34 glioma patients who experienced post-operative motor or language deficits, we used connectomics to construct single-subject cortical networks. Based on their clinical and connectivity deficit, patients underwent network-specific Transcranial Magnetic Stimulation (TMS) sessions daily over five consecutive days. Patients were then assessed for TMS-related side effects and improvements.Results31/34 (91%) patients were successfully recruited and enrolled for TMS treatment within two weeks of glioma surgery. No seizures or serious complications occurred during TMS rehabilitation and one-week post-stimulation. Transient headaches were reported in 4/31 patients but improved after a single session. No neurological worsening was observed while a benefit was noted in 28/31 patients post-TMS. We present two clinical vignettes and a video demonstration of interventional neurorehabilitation.ConclusionsFor the first time, we demonstrate the safety profile and ability to recruit, enrol, and complete TMS acutely post-craniotomy in a high seizure risk population. Given the lack of randomisation and controls in this study, prospective randomised sham-controlled stimulation trials are now warranted to establish the efficacy of interventional neurorehabilitation following craniotomy.
Metal concentrations in breastmilk of Fuzhou nursing mothers associates with dietary and lifestyle factors
Authors: Qi Lin , Chiang Vic Shao-Chih , Lu Qiu-Yan , Wen Jing-yuan , Xu Rongxian 
Published: July 2021

AbstractMetal intake greatly influences physiological development during infancy. For infants, breastmilk is the major route of metal exposure. The metal status of their nursing mothers is affected by lifestyle and nutritional factors. However, the relationship between these factors and breastmilk metal concentration is largely unknown.The present study provided food frequency questionnaires to be completed by 113 nursing mothers from Fujian Provincial Hospital. Their breastmilk samples were analysed for the metal concentrations using inductively coupled plasma mass spectrometery (ICP-MS). Based on the outcome of the questionnaires and ICP-MS results, a total of 94 samples were deemed valid for further data analyses.Results showed levels of breastmilk lead (Pb) and iron (Fe) were outside the reference range from authoritative data. Correlation analyses found Pb levels to negatively associate with dietary fibre intake. Additionally, Fe levels were negatively associated with alcohol and dairy consumption. In terms of Zn levels, it was positively associated with tea and vitamin B1 intake. Zn was also negatively associated with seafood consumption.The study concluded dietary factors to associate with metal levels within breastmilk. Recommendations were made to increase consumption of dietary fibre, tea and foods rich in vitamin B1 for gestational and postpartum women. Conversely, alcohol consumption continues to be discouraged for this population. Furthermore, careful considerations need to be taken for levels of dairy and seafood intake to minimize metal metabolism disruptions. Infant metal exposure requires critical attention and this needs to be initiated through the diet and lifestyle of their nursing mothers.
Viral loads observed under competing strain dynamics
Authors: Hay James A. , Kennedy-Shaffer Lee , Mina Michael J. 
Published: July 2021

AbstractA plausible mechanism for the increased transmissibility of SARS-CoV-2 variants of concern (VOCs) results from VOC infections causing higher viral loads in infected hosts. However, investigating this hypothesis using routine RT-qPCR testing data is challenging because the population-distribution of viral loads changes depending on the epidemic growth rate; lower cycle threshold (Ct) values for a VOC lineage may simply reflect increasing incidence relative to preexisting lineages. To understand the extent to which viral loads observed under routine surveillance systems reflect viral kinetics or population dynamics, we used a mathematical model of competing strain dynamics and simulated Ct values for variants with different viral kinetics. We found that comparisons of Ct values obtained under random cross-sectional surveillance were highly biased unless samples were obtained at times when the variants had comparable growth rates. Conversely, comparing Ct values from symptom-based testing was largely unaffected by epidemic dynamics, and accounting for the time between symptom onset and sample collection date further reduced the risk of statistical errors. Finally, we show how a single cross-sectional sample of Ct values can be used to jointly estimate differences in viral kinetics and epidemic growth rates between variants. Epidemic dynamics should be accounted for when investigating strain-specific viral kinetics using virologic surveillance data, and findings should be corroborated with longitudinal viral kinetics studies.
Effect of vaccination and of prior infection on infectiousness of vaccine breakthrough infections and reinfections
Authors: Abu-Raddad Laith J. , Chemaitelly Hiam , Ayoub Houssein H. , Tang Patrick , Coyle Peter , Hasan Mohammad R. , Yassine Hadi M. , Benslimane Fatiha M. , Al Khatib Hebah A. , Kanaani Zaina Al , Kuwari Einas Al , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Abdul Rahim Hanan F. , Nasrallah Gheyath K. , Al Kuwari Mohamed Ghaith , Butt Adeel A. , Al Romaihi Hamad Eid , Khal Abdullatif Al , Al-Thani Mohamed H. , Bertollini Roberto 
Published: July 2021

AbstractSARS-CoV-2 breakthrough infections in vaccinated individuals and in those who had a prior infection have been observed globally, but the transmission potential of these infections is unknown. The RT-qPCR cycle threshold (Ct) value is inversely correlated with viral load and culturable virus. Here, we investigated differences in RT-qPCR Ct values across Qatar’s national cohorts of primary infections, reinfections, BNT162b2 (Pfizer-BioNTech) breakthrough infections, and mRNA-1273 (Moderna) breakthrough infections. Through matched-cohort analyses of the randomly diagnosed infections, the mean Ct value was higher in all cohorts of breakthrough infections compared to the cohort of primary infections in unvaccinated individuals. The Ct value was 1.3 (95% CI: 0.9-1.8) cycles higher for BNT162b2 breakthrough infections, 3.2 (95% CI: 1.8-4.5) cycles higher for mRNA-1273 breakthrough infections, and 4.0 (95% CI: 3.4-4.6) cycles higher for reinfections in unvaccinated individuals. Assuming a linear relationship between viral load and infectiousness, these differences imply that breakthrough infections are at least 50% less infectious than primary infections in unvaccinated individuals. Public health benefits of vaccination may have been underestimated, as COVID-19 vaccines not only protect against acquisition of infection, but also appear to protect against transmission of infection.
Coronavirus vaccination rates in cultural areas in Germany
Authors: Spahn Claudia , Hipp Anna Maria , Richter Bernhard , Nusseck Manfred 
Published: July 2021

AbstractVaccination rates can provide useful information about potential risks of infection in a given population. In this study, the vaccination rates and attitudes toward vaccination in cultural sectors, i.e. music areas, have been investigated. In total, 4341 persons in four different areas including visitors of classical music and musicals as well as professional and amateur musicians participated in this survey. Results showed rates of 86% recovered or vaccinated at least once and 54.5% fully vaccinated. These vaccination rates were considerably higher compared to the general population. Vaccination hesitancy was half that of the general population at 6.4%. The findings of this large sample indicate that in the field of music culture there is a high vaccination rate and a low rejection of vaccination on the part of the audience and the performers. The risk of infection can therefore be assumed as very low and the opening of cultural events can thus be recommended.
Transmission-selective muscle pathology induced by active propagation of mutant huntingtin across the human neuromuscular synapse
Authors: Margarita Dinamarca C. , Colombo Laura , Urszulax Brykczynska , Amandine Grimm , Natalia Tousiaki E. , Isabelle Fruh , Hossain Imtiaz , Daniela Gabriel , Anne Eckert , Matthias Müller , Eline Pecho-Vrieseling 
Published: July 2021

AbstractA potential explanation for the spatiotemporal accumulation of pathological lesions in the brain of patients with neurodegenerative protein misfolding diseases (PMDs) is cell-to-cell transmission of aggregation-prone, misfolded proteins. Little is known about central to peripheral transmission and its contribution to pathology. We show that transmission of Huntington’s disease- (HD-) associated mutant HTT exon 1 (mHTTEx1) occurs across the neuromuscular junctions in human iPSC cultures and in vivo in wild-type mice. We found that transmission is an active and dynamic process, that happens prior to aggregate formation and is regulated by synaptic activity. Furthermore, we find that transmitted mHTTEx1 causes HD-relevant pathology at a molecular and functional level in human muscle cells, even in the presence of ubiquitous expression mHTTEx1. With this work we uncover a casual-link between mHTTEx1 synaptic transmission and pathology, highlighting the therapeutic potential in blocking toxic protein transmission in PMDs.
“Submandibular Injection of Indoleamine 2,3-Dioxygenase Galectin-3 Fusion Protein Inhibits and Prevents Periodontal Disease Progression Over 12 Weeks”
Authors: Rocha Fernanda , Graves Christina , Altitinchi Ali , Farhadi Shaheen A. , Macias Sabrina L. , Wanchoo Arun , Hudalla Gregory A. , Keselowsky Benjamin G. , Wallet Shannon M. 
Published: July 2021

AbstractA major challenge in the treatment of chronic inflammatory diseases including periodontal diseases is the development of therapeutics to safely and specifically direct resolution of inflammation in a localized manner. Here we demonstrate the efficacy of a novel approach that addresses this unmet clinical need. Using an enzyme fusion protein of indoleamine 2,3-dioxygenase 1 (IDO) and galectin-3 (Gal3) with tissue-anchored and thus localized immunomodulatory properties, we prevented and halted progression of induced polymicrobial periodontal disease. Efficacy was achieved with repeated treatment with IDO-Gal3 and was measured by effects on mandibular bone loss, soft tissue inflammation and local T cell plasticity. Specifically, both prophylactic and therapeutic administration of IDO-Gal3 were effective in reducing vertical mandibular bone loss and loss of mandibular bone volume and bone thickness induced by chronic polymicrobial infection. The efficacy observed is at least in part due to localized regulation of innate immune mediators such as IL-1β, IL-6 and IL-8 as well as chemoattractants including IP-10, MCP-1 and MIP-1α, while enhancing the expression of immunoregulatory cytokines such as IL-10. In addition, IDO-Gal3 treatment suppressed the induction of pathogenic CD4+Th1, CD8+Tc1, CD4+Th1/Th17, and CD8+Tc1/Tc17, while promoting the induction of homeostatic CD4+Th17, CD8+Tc17 and CD4+Tregs. Importantly, the efficacy of prophylactically and therapeutically administered IDO-Gal-3 is not dependent on bacterial burden as there were no appreciable effects on bacterial burden following either method of administration. Lastly, therapeutic rather than prophylactic administration of IDO-Gal3 is most effective in preventing mandibular bone loss through more robust innate and adaptive immune modulation. Together these and our previously published data indicate that therapeutic administration of IDO-Gal3 addresses the clinical needs for adjunctive therapeutics to treat active and/or established periodontal diseases.
Ageing and the ipsilateral M1 BOLD response: a connectivity study
Authors: Tak Yae Won , Knights Ethan , Henson Richard , Zeidman Peter 
Published: July 2021

AbstractYoung people exhibit a negative BOLD response in ipsilateral primary motor cortex (M1) when making unilateral movements, such as button presses. This negative BOLD response becomes more positive as people age. Here we investigated why this occurs, in terms of the underlying effective connectivity and haemodynamics. We applied dynamic causal modelling (DCM) to task fMRI data from 635 participants aged 18-88 from the Cam-CAN dataset, who performed a cued button pressing task with their right hand. We found that connectivity from contralateral supplementary motor area (SMA) and dorsal premotor cortex (PMd) to ipsilateral M1 became more positive with age, explaining 44% of the variability across people in ipsilateral M1 responses. Neurovascular and haemodynamic parameters in the model were not able to explain the age-related shift to positive BOLD. Our results add to a body of evidence implicating neural, rather than vascular factors as the predominant cause of negative BOLD – while emphasising the importance of inter-hemispheric connectivity. This study provides a foundation for investigating the clinical and lifestyle factors that determine the sign and amplitude of the M1 BOLD response, which could serve as a proxy for neural and vascular health, via the underlying neurovascular mechanisms.
Nephrotoxicity of Calcineurin Inhibitors in kidney epithelial cells is independent of Calcineurin and NFAT signaling
Authors: Karolin Andrea , Escher Geneviève , Rudloff Stefan , Sidler Daniel 
Published: July 2021

AbstractBackgroundCalcineurin inhibitors (CNI) such as Cyclosporine A (CsA) and Tacrolimus (FK506) are commonly used after renal transplantation in order to suppress the immune system. In lymphoid cells, CsA acts via the Calcineurin-NFAT axis, whereas in non-lymphoid cells, such as kidney epithelial cells, CsA induces Calcineurin inhibitor toxicity (CNT). Up to date, it is unknown via which off-targets CsA induces CNT in kidney epithelial cells.MethodsIn vitro experiments using a surrogate marker to measure CNT induction as well as in vivo studies with acute CNT, were used in order to elucidate the underlying molecular mechanism.ResultsInhibition of the NFAT axis does not show any nephrotoxicity. However, inhibition of p38 and PI3K/Akt Kinases showed induction of nephrotoxicity.ConclusionsThese findings show that CsA acts NFAT independent on kidney epithelial cells. Moreover, inhibition of certain protein kinases mimic CsA activity on kidney epithelial cells indicating that p38 and PI3K/Akt kinase pathways might be involved in CNT progression on kidney epithelial cells.
Multi-omics investigation of tacrolimus nephrotoxicity
Authors: Aouad Hassan , Faucher Quentin , Sauvage François-Ludovic , Pinault Emilie , Barrot Claire-Cécile , Arnion Hélène , Marquet Pierre , Essig Marie 
Published: July 2021

AbstractBackgroundTacrolimus, an immunosuppressive drug prescribed to a majority of transplanted patients is nephrotoxic, through still unclear mechanisms. This study aims to evaluate the impact of tacrolimus on a lineage of proximal tubular cells using a multi-omics approach.MethodsLLC-PK1 cells were exposed to 5 M of tacrolimus for 24h. Intracellular proteins and metabolites, and extracellular metabolites were extracted and analysed by LC-MS/MS. The transcriptional expression of the dysregulated proteins PCK-1, FBP1 and FBP2 was measured using RT-qPCR.ResultsIn our cell model, tacrolimus impacted different metabolic pathways including those of arginine (e.g., citrulline, ornithine) (p < 0.0001), amino acids (e.g., valine, isoleucine, aspartic acid) (p < 0.0001) and pyrimidine (p<0.01). In addition, it induced oxidative stress (p < 0.01) as shown by a decrease in total cell glutathione quantity. It impacted cell energy through an increase in Krebs cycle intermediates (e.g., citrate, aconitate, fumarate) (p < 0.01) and down-regulation of PCK-1 (p < 0.05) and FPB1 (p < 0.01), which are key enzymes in gluconeogenesis. Apart from glucose synthesis, gluconeogenesis is an important process in kidney mediated acid-base balance control.ConclusionThe variations found using this multi-omics approach clearly point towards a dysregulation of energy production in epithelial cells of the renal tubule, and potentially of their functions, that may be implicated in tacrolimus nephrotoxicity in the clinics.
Transcription-coupled DNA repair underlies variation in persister awakening and the emergence of resistance
Authors: Dorien Wilmaerts , Charline Focant , Paul Matthay , Jan Michiels 
Published: July 2021

SummaryPersisters constitute a population of temporarily antibiotic-tolerant variants in an isogenic bacterial population and are considered an important cause of relapsing infections. It is currently unclear how cellular damage inflicted by antibiotic action is reversed upon persister state exit and how this relates to antibiotic resistance development. We demonstrate that persisters, upon fluoroquinolone treatment, accumulate oxidative damage which is repaired through nucleotide excision repair. Detection of the damage occurs via transcription-coupled repair using UvrD-mediated backtracking or Mfd-mediated displacement of the RNA polymerase. This competition results in heterogeneity in persister awakening lags. Most persisters repair the oxidative DNA damage, displaying a mutation rate equal to the untreated population. However, the promutagenic factor Mfd increases the mutation rate in a persister subpopulation. Our data provide in-depth insight in the molecular mechanisms underlying persister survival and pinpoints Mfd as an important molecular factor linking persistence to resistance development.
Chromosome-level genome assembly of Japanese chestnut (Castanea crenata Sieb. et Zucc.) reveals conserved chromosomal segments in woody rosids
Authors: Shirasawa Kenta , Nishio Sogo , Terakami Shingo , Botta Roberto , Torello Marinoni Daniela , Isobe Sachiko 
Published: July 2021

AbstractJapanese chestnut (Castanea crenata Sieb. et Zucc.), unlike other Castanea species, is resistant to most diseases and wasps. However, genomic data of Japanese chestnut that could be used to determine its biotic stress resistance mechanisms have not been reported to date. In this study, we employed long-read sequencing and genetic mapping to generate genome sequences of Japanese chestnut at the chromosome level. Long reads (47.7 Gb; 71.6× genome coverage) were assembled into 781 contigs, with a total length of 721.2 Mb and a contig N50 length of 1.6 Mb. Genome sequences were anchored to the chestnut genetic map, comprising 14,973 single nucleotide polymorphisms (SNPs) and covering 1,807.8 cM map distance, to establish a chromosome-level genome assembly (683.8 Mb), with 69,980 potential protein-encoding genes and 425.5 Mb repetitive sequences. Furthermore, comparative genome structure analysis revealed that Japanese chestnut shares conserved chromosomal segments with woody plants, but not with herbaceous plants, of rosids. Overall, the genome sequence data of Japanese chestnut generated in this study is expected to enhance not only its genetics and genomics but also the evolutionary genomics of woody rosids.