bluuebunny/crossref_metadata_2025_split huggingface dataset:
Doxycycline Treatment of Mansonella perstans–Infected Individuals Affects Immune Cell Activation and Causes Long-term T-cell Polarization
Authors: Aniagyei Wilfred , Adjei Jonathan Kofi , Adankwah Ernest , Seyfarth Julia , Mayatepek Ertan , Antwi Berko Daniel , Sakyi Samuel Asamoah , Batsa Debrah Linda , Debrah Alexander Yaw , Hoerauf Achim , Owusu Dorcas O , Phillips Richard O , Jacobsen Marc 
Published: June 2022

Abstract

Background
Doxycycline is used for treatment of Mansonella perstans infection. Immune modulatory effects of both M. perstans and doxycycline have been described but long-term implications on host immune response are not defined. Here we determined multiple immune parameters of M. perstans–infected individuals before and after doxycycline treatment to characterize doxycycline effects on host T-cell immunity.

Methods
Immune characterization of doxycycline-treated M. perstans–infected individuals was performed as part of an open-label randomized clinical trial. Immune cell population phenotyping by flow cytometry and functional in vitro T-cell assays were performed at baseline, 6 months, and “long term” (18–24 months) after treatment start. Treatment efficacy, based on peripheral blood microfilaria (mf) burden, was correlated with immune parameters and effects on immune response against concomitant Mycobacterium tuberculosis infection were determined.

Results
Immune population phenotyping indicated changes in functional T-cell responses after doxycycline treatment. Constitutive and superantigen-induced T-cell activation and polarization towards T-helper type (TH) 1 phenotype at baseline declined after doxycycline treatment, whereas low proportions of TH17 and TH1* cells at baseline increased significantly at follow-up. In accordance, long-term decline in antigen-specific TH1 responses against concomitant M. tuberculosis infection was seen. Notably, only TH17 and TH1* changes after 6 months and TH17 at baseline were negatively correlated with M. perstans microfilaria burden or reduction, whereas long-term changes were not associated with treatment efficacy.

Conclusions
We found long-term immune modulatory effects of doxycycline treatment leading to decreased constitutive T-cell activation, polarization towards TH17/TH1*, and impaired immune response against concomitant M. tuberculosis infection.
Who Should Get Vaccinated First? Limits of Solidarity during the First Week of the Danish Vaccination Programme
Authors: Schaeffer Merlin , Haderup Larsen Mikkel 
Published: June 2022

AbstractThe coronavirus disease 2019 (COVID-19) pandemic resulted in several acute shortages of healthcare provision and thereby posed a challenge to solidarity among citizens of welfare states. One example was the limited number of vaccine batches at the outset of European COVID-19 vaccination campaigns. This resulted in a rare constellation in which citizens faced both a unifying collective threat but also a scarcity of healthcare resources that necessitated the prioritization of certain groups for an early vaccination. On that premise, we conducted a survey experiment during the first week of the Danish vaccination programme. Our results demonstrate that citizens judged who deserves early access to preventive healthcare along established lines of welfare chauvinism. Fictitious diabetes patients with a Muslim name and those who recently immigrated were regarded as less deserving of an early vaccination. That said, concerns over responsibility for one’s hardship and anti-social free-rider behaviour drive citizens considerations, too. Contra our hypotheses, we find only weak evidence that immigrants or Muslims are penalized more harshly for an irresponsible lifestyle or free-rider behaviour. Compared with previous research, we study a unique moment in history and are the first to disentangle minority status from stereotypes about their anti-social free-riding behaviour and irresponsibly unhealthy lifestyles.
Production of nascent ribosome precursors within the nucleolar microenvironment of Saccharomyces cerevisiae
Authors: Lin Samantha , Rajan Suchita , Lemberg Sofia , Altawil Mark , Anderson Katherine , Bryant Ruth , Cappeta Sebastian , Chin Brandon , Hamdan Isabella , Hamer Annelise , Hyzny Rachel , Karp Andrew , Lee Daniel , Lim Alexandria , Nayak Medha , Palaniappan Vishnu , Park Soomin , Satishkumar Sarika , Seth Anika , Sri Dasari Uva , Toppari Emili , Vyas Ayush , Walker Julianne , Weston Evan , Zafar Atif , Zielke Cecelia , Mahabeleshwar Ganapati H , Tartakoff Alan M 
Published: June 2022

Abstract
35S rRNA transcripts include a 5′-external transcribed spacer followed by rRNAs of the small and large ribosomal subunits. Their processing yields massive precursors that include dozens of assembly factor proteins. In Saccharomyces cerevisiae, nucleolar assembly factors form 2 coaxial layers/volumes around ribosomal DNA. Most of these factors are cyclically recruited from a latent state to an operative state, and are extensively conserved. The layers match, at least approximately, known subcompartments found in higher eukaryotic cells. ∼80% of assembly factors are essential. The number of copies of these assembly factors is comparable to the number of nascent transcripts. Moreover, they exhibit “isoelectric balance,” with RNA-binding candidate “nucleator” assembly factors being notably basic. The physical properties of pre-small subunit and pre-large subunit assembly factors are similar, as are their 19 motif signatures detected by hierarchical clustering, unlike motif signatures of the 5′-external transcribed spacer rRNP. Additionally, many assembly factors lack shared motifs. Taken together with the progression of rRNP composition during subunit maturation, and the realization that the ribosomal DNA cable is initially bathed in a subunit-nonspecific assembly factor reservoir/microenvironment, we propose a “3-step subdomain assembly model”: Step (1): predominantly basic assembly factors sequentially nucleate sites along nascent rRNA; Step (2): the resulting rRNPs recruit numerous less basic assembly factors along with notably basic ribosomal proteins; Step (3): rRNPs in nearby subdomains consolidate. Cleavages of rRNA then promote release of rRNPs to the nucleoplasm, likely facilitated by the persistence of assembly factors that were already associated with nucleolar precursors.
The bHLH transcription factor AcB2 regulates anthocyanin biosynthesis in onion (Allium cepa L.)
Authors: Li Xiaojie , Cao Linjiao , Jiao Bangbang , Yang Haifeng , Ma Changsheng , Liang Yi 
Published: June 2022

Abstract
Onion bulb color is a key breeding trait. The red bulb color is caused by the presence of anthocyanins, which are products of the flavonoid synthesis pathway. Research on flavonoid regulation in onion is lagging compared with that in other crops. AcB2 encodes a bHLH transcription factor, and its transcription is positively associated with anthocyanin accumulation and correlated with the expression of AcMYB1, which is an activator in the flavonoid biosynthetic pathway in onion. Phylogenetic analysis showed that AcB2 was grouped into the TRANSPARENT TESTA 8 (TT8) clade of the bHLH IIIf subgroup. The AcB2 protein contained an MYB-interacting region and physically interacted with AcMYB1 in yeast and tobacco leaves. AcMYB1 directly bound to the promoters of anthocyanidin synthase (AcANS) and flavonoid 3-hydroxylase 1 (AcF3H1) and activated their expression. The coexpression of AcB2 with AcMYB1 in Arabidopsis thaliana protoplasts dramatically increased the expression of AcANS and AcF3H1 compared with that under the expression of AcMYB1 alone. Transient co-overexpression of AcB2 with AcMYB1 induced anthocyanin accumulation in the epithelial cells of onion bulbs. Complementation of the Arabidopsis tt8-1 mutant with AcB2 restored pigmentation defects in tt8-1. In addition, AcB2 physically interacted with AtTT2 in yeast cells and tobacco leaves, indicating that the functions of AcB2 were similar to those of AtTT8. Together, these results demonstrated that AcB2 enhanced the function of AcMYB1 in upregulating anthocyanin biosynthesis in onion, which provided a theoretical basis for breeding onions with higher anthocyanin contents.
Neighbourhood socioeconomic improvement, residential mobility and premature death: a population-based cohort study and inverse probability of treatment weighting analysis
Authors: Buajitti Emmalin , Rosella Laura C 
Published: June 2022

Abstract

Background
Causal inference using area-level socioeconomic measures is challenging due to risks of residual confounding and imprecise specification of the neighbourhood-level social exposure. By using multi-linked longitudinal data to address these common limitations, our study aimed to identify protective effects of neighbourhood socioeconomic improvement on premature mortality risk.

Methods
We used data from the Canadian Community Health Survey, linked to health administrative data, including longitudinal residential history. Individuals aged 25–69, living in low-socioeconomic status (SES) areas at survey date (n = 8335), were followed up for neighbourhood socioeconomic improvement within 5 years. We captured premature mortality (death before age 75) until 2016. We estimated protective effects of neighbourhood socioeconomic improvement exposures using Cox proportional hazards models. Stabilized inverse probability of treatment weights (IPTW) were used to account for confounding by baseline health, social and behavioural characteristics. Separate analyses were carried out for three exposure specifications: any improvement, improvement by residential mobility (i.e. movers) or improvement in place (non-movers).

Results
Overall, 36.9% of the study cohort experienced neighbourhood socioeconomic improvement either by residential mobility or improvement in place. There were noted differences in baseline health status, demographics and individual SES between exposure groups. IPTW survival models showed a modest protective effect on premature mortality risk of socioeconomic improvement overall (HR = 0.86; 95% CI 0.63, 1.18). Effects were stronger for improvement in place (HR = 0.67; 95% CI 0.48, 0.93) than for improvement by residential mobility (HR = 1.07, 95% 0.67, 1.51).

Conclusions
Our study provides robust evidence that specific neighbourhood socioeconomic improvement exposures are important for determining mortality risks.
Clustered Mendelian randomization analyses identify distinct and opposing pathways in the association between genetically influenced insulin-like growth factor-1 and type 2 diabetes mellitus
Authors: Wang Wenyi , Tesfay Ephrem Baraki , van Klinken Jan Bert , Willems van Dijk Ko , Bartke Andrzej , van Heemst Diana , Noordam Raymond 
Published: June 2022

Abstract

Background
There is inconsistent evidence for the causal role of serum insulin-like growth factor-1 (IGF-1) concentration in the pathogenesis of human age-related diseases such as type 2 diabetes (T2D). Here, we investigated the association between IGF-1 and T2D using (clustered) Mendelian randomization (MR) analyses in the UK Biobank.

Methods
We conducted Cox proportional hazard analyses in 451 232 European-ancestry individuals of the UK Biobank (55.3% women, mean age at recruitment 56.6 years), among which 13 247 individuals developed type 2 diabetes during up to 12 years of follow-up. In addition, we conducted two-sample MR analyses based on independent single nucleotide polymorphisms (SNPs) associated with IGF-1. Given the heterogeneity between the MR effect estimates of individual instruments (P-value for Q statistic = 4.03e−145), we also conducted clustered MR analyses. Biological pathway analyses of the identified clusters were performed by over-representation analyses.

Results
In the Cox proportional hazard models, with IGF-1 concentrations stratified in quintiles, we observed that participants in the lowest quintile had the highest relative risk of type 2 diabetes [hazard ratio (HR): 1.31; 95% CI: 1.23–1.39). In contrast, in the two-sample MR analyses, higher genetically influenced IGF-1 was associated with a higher risk of type 2 diabetes. Based on the heterogeneous distribution of MR effect estimates of individual instruments, six clusters of genetically determined IGF-1 associated either with a lower or a higher risk of type 2 diabetes were identified. The main clusters in which a higher IGF-1 was associated with a lower risk of type 2 diabetes consisted of instruments mapping to genes in the growth hormone signalling pathway, whereas the main clusters in which a higher IGF-1 was associated with a higher risk of type 2 diabetes consisted of instruments mapping to genes in pathways related to amino acid metabolism and genomic integrity.

Conclusions
The IGF-1-associated SNPs used as genetic instruments in MR analyses showed a heterogeneous distribution of MR effect estimates on the risk of type 2 diabetes. This was likely explained by differences in the underlying molecular pathways that increase IGF-1 concentration and differentially mediate the effects of IGF-1 on type 2 diabetes.
On Orthogonal Local Models of Hodge Type
Authors: Zachos Ioannis 
Published: June 2022

Abstract
We study local models that describe the singularities of Shimura varieties of non-PEL type for orthogonal groups at primes where the level subgroup is given by the stabilizer of a single lattice. In particular, we use the Pappas–Zhu construction and we give explicit equations that describe an open subset around the “worst” point of orthogonal local models given by a single lattice. These equations display the affine chart of the local model as a hypersurface in a determinantal scheme. Using this, we prove that the special fiber of the local model is reduced and Cohen–Macaulay.
3D anisotropic TEM modeling with loop source using model reduction method
Authors: Lu Kailiang , Fan Ya'nan , Zhou Jianmei , Li Xiu , Li He , Fan Kerui 
Published: June 2022

Abstract
For model reduction techniques, there have been relatively few studies performed regarding the forward modeling of anisotropic media in comparison to transient electromagnetic (TEM) forward modeling of isotropic media. The transient electromagnetic method (TEM) responses after the current has been turned off can be represented as a homogeneous ordinary differential equation (ODE) with an initial value, and the ODE can be solved using a matrix exponential function. However, the order of the matrix exponential function is large and solving it directly is challenging, thus this study employs the Shift-and-Invert (SAI-Krylov) subspace algorithm. The SAI-Krylov subspace technique is classified as a single-pole approach compared to the multi-pole rational Krylov subspace approach. It only takes one LU factorization of the coefficient matrix, along with hundreds of backward substitutions. The research in this paper shows that the anisotropic medium has little effect on the optimal shift ${\gamma _{opt}}$ and subspace order m. Furthermore, as compared to the mimetic finite volume method (SAI-MFV) of the SAI-Krylov subspace technique, the method proposed in this paper (SAI-FEM) can further improve the computing efficiency by roughly 13%. In contrast to the standard implicit time step iterative technique, the SAI-FEM method does not require discretization in time, and the TEM response at any moment within the off-time period can be easily computed. Next, the accuracy of the SAI-FEM algorithm was verified by 1D solutions for an anisotropic layer model and a 3D anisotropic model. Finally, the electromagnetic characteristics of the anisotropic anomalous body of the center loop device and separated device of the airborne transient electromagnetic method were analyzed, and it was found that horizontal conductivity has a considerable influence on the TEM response of the anisotropic medium.
Born approximation imaging technique for electrical source multi-component TEM
Authors: Fan Ya'nan , Lu Kailiang , Li Xiu , Qi Zhipeng 
Published: June 2022

Abstract
In this study, to obtain higher-resolution geoinformation in the electrical source transient electromagnetic method (TEM) interpretation, the pseudo-seismic Born approximation imaging method is applied to the vertical magnetic induction intensity ${B_z}$ and the horizontal electric field ${E_y}$, which is paralleled to the source. First, the differences between the two components are compared, and the results reveal that different components can reflect varied geological information. ${E_y}$ has a stronger signal and is more sensitive to the high-resistivity layer at a long offset, whereas ${B_z}$ has a greater relative difference in the low-resistivity layer at a short offset. The TEM field is then transformed into the pseudo-wavefield using the wavefield transformation method and the Born approximation pseudo-seismic imaging method is adopted to locate the electrical interface. After calculating the 3D model, the results indicate that the multi-component Born approximate imaging can intuitively and effectively locate the depth of the geological interface. Furthermore, the imaging results of a coal mine located in Gansu Province, China, proves that the proposed method can pinpoint the buried location of the coal goaf as well as the stratum trend. In general, the multi-component pseudo-seismic imaging technique plays a significant role in interpreting the electrical source TEM data.
Noncanonical prokaryotic X family DNA polymerases lack polymerase activity and act as exonucleases
Authors: Prostova Maria , Shilkin Evgeniy , Kulikova Alexandra A , Makarova Alena , Ryazansky Sergei , Kulbachinskiy Andrey 
Published: June 2022

Abstract
The X family polymerases (PolXs) are specialized DNA polymerases that are found in all domains of life. While the main representatives of eukaryotic PolXs, which have dedicated functions in DNA repair, were studied in much detail, the functions and diversity of prokaryotic PolXs have remained largely unexplored. Here, by combining a comprehensive bioinformatic analysis of prokaryotic PolXs and biochemical experiments involving selected recombinant enzymes, we reveal a previously unrecognized group of PolXs that seem to be lacking DNA polymerase activity. The noncanonical PolXs contain substitutions of the key catalytic residues and deletions in their polymerase and dNTP binding sites in the palm and fingers domains, but contain functional nuclease domains, similar to canonical PolXs. We demonstrate that representative noncanonical PolXs from the Deinococcus genus are indeed inactive as DNA polymerases but are highly efficient as 3′-5′ exonucleases. We show that both canonical and noncanonical PolXs are often encoded together with the components of the non-homologous end joining pathway and may therefore participate in double-strand break repair, suggesting an evolutionary conservation of this PolX function. This is a remarkable example of polymerases that have lost their main polymerase activity, but retain accessory functions in DNA processing and repair.
ATRT-03. Adapted Treatment Protocol: Synchronous Atypical Teratoid/Rhabdoid CNS Tumor and Extra CNS Disease
Authors: Jackson Nicole , Torres Marleni , Lecea Eva Glenn , O’Farrell Candelaria , Khatib Ziad , Maher Ossama 
Published: June 2022

Abstract
Atypical teratoid/rhabdoid tumors (AT/RTs) of the central nervous system (CNS) are rare, aggressive, early childhood tumors with unfavorable prognosis. There have been 31 cases reported of children with AT/RT of the CNS and extra CNS primary tumors. In addition to its aggressive tendencies, malignant rhabdoid tumors (MRTs) of the kidney have also shown a common genetic abnormality-inactivating mutation of SMARC B1/INI-gene. We report a 22-month-old male who presented at 15 months of age with metastatic AT/RT of the posterior fossa and synchronous malignant rhabdoid tumor of the left kidney. MRI of the brain demonstrated a midline posterior fossa mass and left renal mass was noted incidentally on imaging of spine. Pathology was consistent with MRT of the kidney and pathogenic variant was found in the tumor sample, specifically SMARCB1 homozygous/biallelic deletion. Patient underwent a subtotal resection of the posterior fossa tumor and subsequent radical resection of the mass on kidney rhabdoid tumor. He was treated as per ACNS033 protocol with 2 cycles of induction with high-dose methotrexate followed by vincristine, cyclophosphamide, cisplatin, and etoposide with complete response followed by three tandem stem cell transplants with thiotepa and carboplatin for which he has been tolerating and responding favorably. Focal radiation therapy to the brain and flank area is planned at end of therapy. In a large series of synchronous AT/RTs reported in 2017 only 3 of the 31 patients were considered long-term survivors. All received a combination of high dose intrathecal or intravenous chemotherapy, total resection of at least one of the tumors, focal radiation, and autologous peripheral blood stem cell transplant. We demonstrated a case with a favorable response with our treatment. Treatment continues to be challenging given the tumor’s rarity and mortality as there are no standardized protocols or randomized controlled trials.
ATRT-07. Low-grade diffusely infiltrative tumor, SMARCB1-mutant: a clinical and histopathological distinct entity showing epigenetic similarity with ATRT-MYC
Authors: Thomas Christian , Federico Aniello , Bens Susanne , Hellström Mats , Casar-Borota Olivera , Kordes Uwe , Neumann Julia E , Dottermusch Matthias , Rodriguez Fausto E , Lo Andrea C , Cheng Sylvia , Hendson Glenda , Hukin Juliette , Hartmann Christian , Koch Arend , Capper David , Siebert Reiner , Paulus Werner , Nemes Karolina , Johann Pascal D , Frühwald Michael C , Kool Marcel , Hasselblatt Martin 
Published: June 2022

Abstract
Most atypical teratoid/rhabdoid tumors (ATRTs) occur in infants, but children and adolescents may also be affected. ATRTs occurring in older patients often comprise the molecular subgroup ATRT-MYC. Recently, central nervous system low-grade diffusely infiltrative tumor with INI1 deficiency (CNS LGDIT-INI1) has been described as a rare low-grade lesion (Nobusawa et al. Am J Surg Pathol 2020;44:1459-1468). Little is known on the molecular relationship of CNS LGDIT-INI1 and ATRT. We therefore further explored a series of six CNS LGDIT-INI1. The median age of the four males and two females was 16 years (range: 10-28 years). All tumors were of supratentorial location and showed low to moderate cellularity, diffuse growth of inconspicuous small SMARCB1-deficient tumor cells and reactive pleomorphic neuronal and glial cells with retained SMARCB1-staining in the background. In addition, two cases also displayed a high-grade rhabdoid component. After DNA isolation, purification and bisulfite conversion, samples were subjected to DNA methylation profiling (MethylationEPIC BeadChip array). Using DNA methylation-based classification and the Heidelberg Brain Tumor Classifier (version v11b4), all tumors were classified as ATRT-MYC (median calibrated score: 0.97). On t-SNE analysis, DNA methylation profiles grouped closely together in proximity to ATRT-MYC. Follow-up information was available for four cases (including the two cases with a high-grade component). Patients received heterogeneous treatments (including chemotherapy according to AT/RT protocols) and experienced stable disease or complete remission after an observation time of three to 56 months. In conclusion, CNS LGDIT-INI1 is a clinically and histologically distinct entity with relatively favorable outcome. Nevertheless, epigenetic similarity with ATRT-MYC and the potential of malignant progression warrants close follow-up examinations. In line with recent developments of WHO nomenclature, we propose to refer to these tumors as “low-grade diffusely infiltrative tumor, SMARCB1-mutant”.