bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of Contrast-Enhanced 3-Dimensional T2-Weighted Volume Isotropic Turbo Spin Echo Acquisition Sequence in the Diagnosis of Prolactin-Secreting Pituitary Microadenomas
Authors: Guo Rui , Wu Yue , Guo Guangcheng , Zhou Haiyang , Liu Shoutang , Yao Zhenwei , Xiao Yunping
Published: November 2021

Objective

This study aimed to investigate the value of contrast-enhanced 3-dimensional (3D) T2-weighted (T2W) Volume Isotropic Turbo Spin Echo Acquisition (VISTA) sequence in prolactin-secreting pituitary adenoma diagnosis.

Methods

We enrolled 158 patients with hyperprolactinemia. Coronal dynamic contrast-enhanced (DCE) T1 spin echo and T2W VISTA sequences were performed. The detection of pituitary microadenomas in 3 imaging groups (DCE magnetic resonance imaging [MRI], VISTA, and DCE MRI + VISTA) were compared using McNemar test and χ2 test.

Results

The DCE MRI + VISTA group detected 28 more pituitary microlesions than DCE MRI alone. Among these, 20 lesions were clearly observed on VISTA images but were negative on DCE MRI. The combined sequences showed higher sensitivity (85.3%) and diagnostic accuracy (89.2%) for adenoma detection than any of the sequences alone (P < 0.01). We noted that in 65.7% of the patients with adenoma (46 of 70), a “hypointense rim” was present around the lesion on the VISTA images. Of them, 11 patients underwent surgery. Histopathology confirmed that the “hypointense rim” was a pseudocapsular structure at the edge of the adenoma.

Conclusions

For patients with hyperprolactinemia, the 3D T2W VISTA sequence is an important supplement to DCE MRI, because it could improve the detection rate of pituitary microadenomas.
Normal Magnetic Resonance Imaging Appearance of Marrow Adjacent to the Sacroiliac Joints in Children During Development
Authors: Storey Troy , Borgia Roberto Ezequiel , Merritt Parker , Woolnough Leandra
Published: November 2021

Objective

On magnetic resonance imaging (MRI) for sacroiliitis, increased T2 marrow signal can be misinterpreted as marrow edema. We hypothesize that a changing but predictable pattern for marrow signal intensity adjacent to the sacroiliac joints is present from infancy through skeletal maturity. The purpose of our study is to characterize the distribution of increased T2 signal intensity within the marrow adjacent to the sacroiliac joints in healthy children.

Subjects and Methods

A retrospective review of the electronic health record identified 345 children who underwent MRI examination of the sacrum, sacroiliac joints, or pelvis. Those with underlying disease that may potentially alter sacroiliac marrow signal were excluded. Sixty children, 30 girls and 30 boys, were assessed for T2 marrow signal intensity greater than the interforaminal sacrum and less than or equivalent to the primary spongiosa of the posterior iliac crests at the S1, S2, and S3 levels. The width of increased T2 signal intensity at each sacral level, right and left sides, ilium, and sacrum was measured (mm). The Mann-Whitney U test was used to determine if there were differences between skeletally immature and skeletally mature subjects; defined as aged 15 years for girls and 17 years for boys.

Results

When 30 girls and 30 boys are assessed, the width of increased T2 marrow signal adjacent to the sacroiliac joints is significantly greater in skeletally immature than in skeletal mature female subjects for right S1 sacral side (P = 0.0100), left S1 sacral side (P = 0.0119), right S2 sacral side (P = 0.037), left S2 sacral side (P = 0.0020), and in male subjects for the right S2 sacral side (P = 0.0178), right S2 iliac side (P = 0.0415), right S3 sacral side (P = 0.0024), and left S3 sacral side (P = 0.0037). There were insufficient subjects for whom the ilii extended beyond the S2 sacral segments to assess for the S3 iliac sides.

Conclusions

Healthy children and adolescents have increased T2 signal intensity within the sacral marrow adjacent to the sacroiliac joints, likely the vascular primary spongiosum, which is greater in adolescence compared with skeletal maturity. Knowledge of this normal pattern is beneficial in interpreting MRI examinations for the presence of sacroiliitis.
Age-related Changes in Computed Tomography Density of Thyroid Gland in Children: A Single-Center Retrospective Study in Northern China
Authors: Yi Xiaoli , Zhao Pengfei , Song Qinwei , Yuan Xinyu , Wang Zhenchang
Published: November 2021

Objective

The thyroid gland normally presents as a hyperdense organ on noncontrast computed tomography (CT) in adults. The correlation between thyroid gland CT density and its functional status has been studied; however, little is known regarding its density in children with normal thyroid functions. We aimed to assess the correlation between thyroid gland CT density and age in children with normal thyroid functions.

Methods

From April 2017 to March 2021, we enrolled 74 patients who had normal thyroid functions within 1 month before or after undergoing neck or cervical spine CT for trauma, neck masses, congenital diseases, and airway stenosis. Their CT images were retrospectively analyzed by 2 independent radiologists. Based on age, patients were divided into 4 groups: infant, preschool-aged, school-aged, and adolescence groups.

Results

Patients with thyroid gland hypodensity in the infant group (70%, 14 of 20) were significantly more numerous than those in preschool-aged (25%, 4 of 16), school-aged (20%, 5 of 25), and adolescence (15.4%, 2 of 13) groups (P = 0.007, 0.001, and 0.002, respectively, Fisher exact test). The mean CT density of the thyroid gland was also lower in the infant group compared with the densities in other age groups. There was a weak positive correlation between thyroid CT density and age (r = 0.264, P = 0.023, linear regression analysis).

Conclusions

Thyroid CT density is related to age in children. The thyroid gland normally has a low density on noncontrast CT in most infants with normal thyroid function.
Toward an Intravoxel Incoherent Motion 2-in-1 Magnetic Resonance Imaging Sequence for Ischemic Stroke Diagnosis? An Initial Clinical Experience With 1.5T Magnetic Resonance
Authors: Pavilla Aude , Gambarota Giulio , Arrigo Alessandro , Saint-Jalmes Hervé , Mejdoubi Mehdi
Published: November 2021

Objective

This initial study aimed to investigate the feasibility of simultaneously measuring perfusion and diffusion including kurtosis features in acute ischemic stroke with the combined intravoxel incoherent motion and non-Gaussian diffusional kurtosis imaging (DKI-IVIM).

Material and Methods

Five ischemic stroke patients underwent a 4-minute diffusion weighted imaging (DWI) protocol, using 8 b values chosen with the Cramer-Rao-Lower-Bound optimization approach, in addition to conventional DWI and arterial spin labeling sequences. Regions of interest in pathological and control regions were analyzed with DKI-IVIM, and parametric maps were reconstructed.

Results

The IVIM diffusion coefficient (D) decreased (P < 0.0001) in the infarcted areas, whereas higher kurtosis coefficient values were found (P = 0.0002). Regarding the perfusion, the individual IVIM perfusion fraction f decreased in 3 matching cases with the cerebral blood flow estimated through arterial spin labeling and the fD* decreased only in 2 patients of those.

Conclusions

When compared with conventional stroke imaging protocol, DKI-IVIM 4-minute 2-in-1 acquisition can provide diffusion results comparable with conventional DWI with complementary kurtosis estimations but a limited robustness regarding perfusion estimations for clinical purpose.
Intravascular Papillary Endothelial Hyperplasia of the Mandible: A Rare Entity
Authors: Luigi Laino , Diana Russo , Luca Fiorillo , Pierluigi Mariani , Gregorio Laino , Cicciù Marco
Published: November 2021

Intravascular papillary endothelial hyperplasia (IPEH) is a lesion characterized by the proliferation of endothelial cells within the lumen of the vessel, it was first described by Masson in 1923.

The pathogenesis of Masson's tumor is still unknown, currently the most accredited hypothesis is the reactive 1. Clinically and symptomatologically it can have different presentations, it is, therefore, of fundamental importance to make a correct differential diagnosis. Diagnosis is mainly based on histological criteria. Intravascular papillary endothelial hyperplasia usually occurs in the skin and subcutaneous tissues, less commonly in the skeleton. The present is the fifth case of intravascular papillary endothelial hyperplasia of the mandible.
Pseudomonas tohonis sp. nov., isolated from the skin of a patient with burn wounds in Japan
Authors: Yamada Kageto , Sasaki Masakazu , Aoki Kotaro , Nagasawa Tatsuya , Murakami Hinako , Ishii Mayumi , Shibuya Kazutoshi , Morita Toshisuke , Ishii Yoshikazu , Tateda Kazuhiro
Published: November 2021

Strain TUM18999T was isolated from the skin of a patient with burn wounds in Japan. The strain was successfully cultured at 20–42 °C (optimum, 30–35 °C) in 1.0–4.0% NaCl (w/v) and at pH 5.5–9.5, optimum pH 5.5–8.5. The phylogenetic tree reconstructed using 16S rRNA, gyrB, rpoB and rpoD gene sequences indicated that strain TUM18999T is closely related to

Pseudomonas otitidis

MCC10330T. Although the partial 16S rRNA gene sequence (1412 bp) of TUM18999T exhibits high similarity to those of

Pseudomonas alcaligenes

NBRC 14159T (99.08 %) and

Pseudomonas otitidis

MCC10330T (98.51 %), multi-locus sequence analysis using 16S rRNA, gyrB, rpoB and rpoD genes reveals a clear distinction between TUM18999T and other

Pseudomonas

species. In addition, an average nucleotide identity >90 % was not observed in the

P. aeruginosa

group. Moreover, TUM18999T and

P. otitidis

can be distinguished based on the minimum inhibitory concentration for carbapenem. Meanwhile, the cellular fatty acids are enriched with C18 : 1
 ω7c/C18 : 1
 ω6c (34.35 %), C16 : 1
 ω7c/C16 : 1
 ω6c (24.22 %), C16 : 0 (19.79 %) and C12 : 0 (8.25 %). Based on this evidence, strain TUM18999T can be defined as representing a novel

Pseudomonas

species, with the proposed name Pseudomonas tohonis sp. nov. The type strain is TUM18999T (GTC 22698T=NCTC 14580T).
ICTV Virus Taxonomy Profile: Belpaoviridae 2021
Authors: Soriano Beatriz , Krupovic Mart , Llorens Carlos
Published: November 2021

The family Belpaoviridae comprises metazoan-infecting reverse-transcribing viruses with long terminal repeats, commonly known as Bel/Pao LTR retrotransposons. These viruses share evolutionary history and genes involved in genome replication and virion formation with reverse-transcribing viruses of the families Metaviridae, Pseudoviridae, Retroviridae and Caulimoviridae. These five families form the order Ortervirales. This is a summary of the ICTV Report on the family Belpaoviridae, which is available at ictv.global/report/belpaoviridae.
Mono- and bi-allelic effects of coding variants on disease in 176,899 Finns
Authors: Heyne H. O. , Karjalainen J. , Karczewski K. J. , Lemmelä S. M. , Zhou W. , FinnGen  , Havulinna A. S. , Kurki M. , Rehm H. L. , Palotie A. , Daly M. J.
Published: November 2021

Identifying Mendelian diseases with recessive inheritance is challenging as the majority of cases are caused by compound heterozygous genotypes which require sequencing data in families to definitively identify. Bottleneck events, such as in the Finnish population, enrich specific homozygous variants to higher frequencies and thus facilitate identification of disease associations through easily recognized homozygous genotypes. Here, we study homozygous and heterozygous effects of 82,516 coding variants on 2,444 disease endpoints using nationwide electronic health record (EHR) data of 176,899 Finns. We find known and novel associations to homozygous genotypes across a broad spectrum of phenotypes such as retinal dystrophy, adult-onset cataract and female infertility (13/20 of which would have been missed by the traditional additive GWAS model). With these results, and supporting simulations, we demonstrate the added benefit of homozygous scans in GWAS. We further use these results to explore inheritance patterns of known Mendelian variants. We find many Mendelian variants whose inheritance cannot be adequately described with the traditional definition of dominant or recessive. In particular, we find disease risk in heterozygous carriers of variants known to cause disease with recessive inheritance, as well as for variants labeled benign in ClinVar. Our results demonstrate how biobank efforts, particularly in founder populations, can broaden our understanding of the impact of genetic variants.
Evaluating Digital Device Technology in Alzheimer’s Disease via Artificial Intelligence
Authors: Sood Meemansa , Aborageh Mohamed , Domingo-Fernández Daniel , Harms Robbert , Lordick Thomas , Birkenbihl Colin , Owens Andrew P , Coello Neva , Narayan Vaibhav A. , Aarsland Dag , Bügler Maximilian , Fröhlich Holger ,   for the Alzheimer’s Disease Neuroimaging Initiative,   RADAR-AD Consortium
Published: November 2021

The use of digital technologies may help to diagnose Alzheimer’s Disease (AD) at the pre-symptomatic stage. However, before implementation into clinical practice, digital measures (DMs) need to be evaluated for their diagnostic benefit compared to established questionnaire-based assessments, such as the Mini-Mental State Examination (MMSE) for cognition and Functional Activity Questionnaire (FAQ) for daily functioning. Moreover, the quantitative and qualitative relationship of DMs to these well understood scores needs to be clarified to aid interpretation. In this work we analyzed data from 148 subjects, 58 cognitively normal and 90 at different stages of the disease, which had performed a smartphone based virtual reality game to assess cognitive function. In addition, we used clinical data from Alzheimer’s Disease Neuroimaging Initiative (ADNI). We employed an Artificial Intelligence (AI) based approach to elucidate the relationship of DMs to questionnaire-based cognition and functional activity scores. In addition, we used Machine Learning (ML) and statistical methods to assess the diagnostic benefit of DMs compared to questionnaire-based scores. We found non-trivial relationships between DMs, MMSE, and FAQ which can be visualized as a complex network. DMs, in particular those reflecting scores of individual tasks in the virtual reality game, showed a better ability to discriminate between different stages of the disease than questionnaire-based methods. Our results indicate that DMs have the potential to act as a crucial measure in the early diagnosis and staging of AD.
cfTrack: Exome-wide mutation analysis of cell-free DNA to simultaneously monitor the full spectrum of cancer treatment outcomes: MRD, recurrence, and evolution
Authors: Li Shuo , Zeng Weihua , Ni Xiaohui , Zhou Yonggang , Stackpole Mary L. , Noor Zorawar S. , Yuan Zuyang , Neal Adam , Memarzadeh Sanaz , Garon Edward B. , Dubinett Steven M. , Li Wenyuan , Zhou Xianghong Jasmine
Published: November 2021

Purpose

Cell-free DNA (cfDNA) offers a non-invasive approach to monitor cancer. Here we develop a method using whole-exome sequencing (WES) of cfDNA for simultaneously monitoring the full spectrum of cancer treatment outcomes, including MRD, recurrence, evolution, and second primary cancer.

Experimental Design

Three simulation datasets were generated from 26 cancer patients to benchmark the detection performance of MRD/recurrence and second primary cancers. For further validation, cfDNA samples (n=76) from cancer patients (n=35) with six different cancer types were used for validating the performance of cancer monitoring during various treatments.

Results

We present a cfDNA-based cancer monitoring method, named cfTrack. Taking advantage of the broad genome coverage of WES data, cfTrack can sensitively detect MRD and cancer recurrence by integrating signals across the known clonal tumor mutations of a patient. In addition, cfTrack detects tumor evolution and second primary cancers by de novo identifying emerging tumor mutations. A series of machine learning and statistical denoising techniques are applied to enhance the detection power. On the simulation data, cfTrack achieved an average AUC of 99% on the validation dataset and 100% on the independent dataset in detecting recurrence in samples with tumor fraction ≥0.05%. In addition, cfTrack yielded an average AUC of 88% in detecting second primary cancers in samples with tumor fraction ≥0.2%. On real data, cfTrack accurately monitors tumor evolution during treatment, which cannot be accomplished by previous methods.

Conclusion

Our results demonstrated that cfTrack can sensitively and specifically monitor the full spectrum of cancer treatment outcomes using exome-wide mutation analysis of cfDNA.

Translational Relevance

Continuous cancer monitoring is clinically necessary for cancer patients to detect minimal residual disease (MRD), recurrence, and progression, allowing for early intervention and therapy adjustment. Cell-free DNA (cfDNA) in blood has become an appealing option due to its non-invasiveness. Until now, cfDNA-based cancer monitoring methods have been focused on deep sequencing at a few known mutations, which are however insufficient when tumors evolve or new tumors emerge. We present the method, cfTrack, which for the first time uses whole-exome sequencing (WES) of cfDNA to track the full range of cancer treatment outcomes, including MRD, recurrence, evolution, and second primary cancer. We demonstrate that, even with very low tumor fractions, cfTrack achieves sensitive and specific monitoring of tumor MRD/recurrence/evolution based on both simulation data and a cohort of cancer patients. These findings demonstrate the clinical utility of cfTrack.
Quantifying changes in vaccine coverage in mainstream media as a result of COVID-19 outbreak
Authors: Christensen Bente , Laydon Daniel J , Chelkowski Tadeusz , Jemielniak Dariusz , Vollmer Michaela , Bhatt Samir , Krawczyk Konrad
Published: November 2021

Background

Achieving vaccine-derived herd immunity depends on public acceptance of vaccination, which in turn relies on people’s understanding of its risks and benefits. The fundamental objective of public health messaging on vaccines is therefore the clear and concise communication of often complex information, and increasingly the countering of misinformation. The primary outlet shaping societal understanding is the mainstream online news media. There was widespread media coverage of the multiple vaccines that were rapidly developed in response to COVID-19. We studied vaccine coverage on the front pages of mainstream online news, using text-mining analysis to quantify the amount of information and sentiment polarization of vaccine coverage delivered to readers.

Methods

We analyzed 28 million articles from 172 major news sources, across 11 countries between July 2015 and April 2021. We employed keyword-based frequency analysis to estimate the proportion of coverage given to vaccines in our dataset. We performed topic detection using BERTopic and Named Entity Recognition to identify the leading subjects and actors mentioned in the context of vaccines. We used the Vader Python module to perform sentiment polarization quantification of all our English-language articles.

Results

We find that the proportion of headlines mentioning vaccines on the front pages of international major news sites increased from 0.1% to 3.8% with the outbreak of COVID-19. The absolute number of negatively polarized articles increased from a total of 6,698 before the COVID-19 outbreak 2015-2019 compared to 28,552 in 2020-2021. Overall, however, before the COVID-19 pandemic, vaccine coverage was slightly negatively polarized (57% negative) whereas with the outbreak, the coverage was primarily positively polarized (38% negative).

Conclusions

Because of COVID-19, vaccines have risen from a marginal topic to a widely discussed topic on the front pages of major news outlets. Despite a perceived rise in hesitancy, the mainstream online media, i.e. the primary information source to most individuals, has been strongly positive compared to pre-pandemic vaccine news, which was mainly negative. However, the pandemic was accompanied with an order of magnitude increase in vaccine news volume that due to pre-pandemic low frequency sampling bias may contribute to a perceived negative sentiment. These results highlight the important interactions between the volume of news and overall polarisation. To the best of our knowledge, our work is the first systematic text mining study of vaccines in the context of COVID-19.
Plasma Soluble Tumor Necrosis Factor Receptor Concentrations and Clinical Events after Hospitalization: Findings from ASSESS-AKI and ARID studies
Authors: Coca Steven G. , Vasquez-Rios George , Mansour Sherry G. , Moledina Dennis G. , Thiessen-Philbrook Heather , Wurfel Mark M. , Himmelfarb Jonathan , Siew Eddie , Garg Amit X. , Hsu Chi-yuan , Liu Kathleen D. , Kimmel Paul L. , Chinchilli Vernon M. , Kaufman James S. , Wilson Michelle , Banks Rosamonde E , Packington Rebecca , McCole Eibhlin , Kurth Mary Jo , Richardson Ciaran , Go Alan S. , Selby Nicholas M , Parikh Chirag R.
Published: November 2021

Background

The role of plasma soluble tumor necrosis factor receptor (sTNFR)1 and sTNFR2 in the prognosis of clinical events after hospitalization with or without acute kidney injury (AKI) is unknown.

Methods

We measured sTNFR1 and sTNFR2 obtained 3 months post-discharge using samples from Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) and AKI Risk in Derby (ARID) that enrolled patients with and without AKI. The associations between biomarkers with longitudinal kidney disease incidence and progression, heart failure and death were evaluated. Analyses were adjusted for demographics and key covariates at the 3-month visit.

Results

Among 1474 participants with plasma biomarker measurements, 19% developed kidney disease progression, 14% had later heart failure, and 21% died over a median follow-up of 4.4 years. For the kidney outcome, the adjusted HRs per doubling in concentration were 2.9 (2.2-3.9) for sTNFR1 and 1.9 (1.5-2.5) for sTNFR2. AKI during the index hospitalization did not modify the association between biomarkers and kidney events. For heart failure, the adjusted HRs per doubling in concentration were 1.9 (1.4-2.5) for sTNFR1 and 1.5 (1.2-2.0) for sTNFR2. For mortality, the adjusted HRs were 3.3 (2.5-4.3) for sTNFR1 and 2.5 (2.0-3.1) for sTNFR2. The findings in ARID were qualitatively similar for the magnitude of association between biomarkers and outcomes.

Conclusion

Plasma sTNFR1 and sTNFR2 measured 3 months after discharge were independently associated with clinical events, regardless of AKI status during the index admission. sTNFR1 and sTNFR2 may assist with the risk stratification of patients during follow-up.

Significance Statement

Soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 associate with kidney outcomes in patients with chronic kidney disease with and without diabetes mellitus. However, their role in the post-hospitalization stage is unknown. High sTNFR1 and sTNFR2 obtained 3 months after discharge associate with kidney events, heart failure hospitalizations, and death among patients who did and did not have acute kidney injury (AKI). Furthermore, sTNFRs provide discriminative value at the time of predicting kidney events. These findings were demonstrated in two large independent prospective cohorts. sTNFR1 and sTNFR2 may detect patients at risk of future adverse events even when patients do not meet the clinical criteria for AKI or exhibit biochemical abnormalities.
Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson’s disease cohort
Authors: Loesch Douglas , Horimoto Andrea R. V. R. , Sarihan Elif Irem , Inca-Martinez Miguel , Mason Emily , Cornejo-Olivas Mario , Torres Luis , Mazzetti Pilar , Cosentino Carlos , Sarapura-Castro Elison , Rivera-Valdivia Andrea , Medina Angel C. , Dieguez Elena , Raggio Victor , Lescano Andres , Tumas Vitor , Borges Vanderci , Ferraz Henrique B. , Rieder Carlos R. , Schumacher-Schuh Artur , Santos-Lobato Bruno L. , Velez-Pardo Carlos , Jimenez-Del-Rio Marlene , Lopera Francisco , Moreno Sonia , Chana-Cuevas Pedro , Fernandez William , Arboleda Gonzalo , Arboleda Humberto , Arboleda-Bustos Carlos E. , Yearout Dora , Zabetian Cyrus P. ,   International Parkinson Disease Genomics Consortium (IPDGC), Thornton Timothy A. , Mata Ignacio F. , O’Connor Timothy D.
Published: November 2021

Background

Large-scale Parkinson’s disease (PD) genome-wide association studies (GWAS) and meta-analyses have, until recently, only been conducted on subjects with European-ancestry. Consequently, polygenic risk scores (PRS) constructed using PD GWAS data are likely to be less predictive when applied to non-European cohorts.

Methods

Using GWAS data from Nalls et al. 2019, we constructed a PD PRS for a Latino PD cohort (LARGE-PD) and tested it for association with PD status. We validated the PRS performance through testing the PD PRS in an independent cohort of Latino PD patients and by repeating the PRS analysis in LARGE-PD with the addition of 440 external Peruvian controls. To explore the global distribution of PD PRS, we utilized 1000 Genomes Project (1KGP) and Peruvian Genome Project (PGP) data to estimate PD risk allele frequencies. We also tested SNCA haplotypes for association with PD risk using logistic regression in LARGE-PD and a European-ancestry PD cohort from the International Parkinson Disease Genomics Consortium (IPDGC).

Results

The GWAS-significant PD PRS had an area under the receiver-operator curve (AUC) of 0.668 (95% CI: 0.640-0.695) and explained 2.2% of the phenotypic variance on the liability scale in LARGE-PD. The inclusion of external Peruvian data as controls mitigated this result, dropping the AUC 0.632 (95% CI: 0.607-0.657). In 1KGP Latinos, we found the PD PRS to exhibit a bias by ancestry. At the SNCA locus, haplotypes differ by ancestry. Ancestry-specific SNCA haplotypes were associated with PD status in both LARGE-PD and the IPDGC cohort (p-value < 0.05). Apart from rs356182, these haplotypes share as little as 14% of their variants.

Conclusion

The PD PRS has potential for PD risk prediction in Latinos, but variability caused by admixture patterns and bias in the PD PRS calculated using only European-ancestry data limits its utility. The inclusion of diverse subjects can help elucidate PD risk loci and improve risk prediction in non-European cohorts. In the case of the SNCA locus, by leveraging a Latino cohort, we provide orthogonal evidence for rs356182 causality.
Ultrafast RNA extraction-free SARS-CoV-2 detection by direct RT-PCR using a rapid thermal cycling approach
Authors: Struijk Robin , van den Ouden Anton , McNally Brian , de Groot Theun , Mulder Bert , de Vos Gert
Published: November 2021

The surging COVID19 pandemic has underlined the need for quick, sensitive, and high-throughput SARS-CoV-2 detection assays. Although many different methods to detect SARS-CoV-2 particles in clinical material have been developed, none of these assays are successful in combining all three of the above characteristics into a single, easy-to-use method that is suitable for large-scale use. Here we report the development of a direct RT-PCR SARS-CoV-2 detection method that can reliably detect minute quantities of SARS-CoV-2 gRNA in nasopharyngeal swab samples as well as the presence of human genomic DNA. An extraction-less validation protocol was carried out to determine performance characteristics of the assay in both synthetic SARS-CoV-2 RNA as well as clinical specimens. Feasibility of the assay and analytical sensitivity was first determined by testing a dilution series of synthetic SARS-CoV-2 RNA in two different solvents (water and AMIES VTM), revealing a high degree of linearity and robustness in fluorescence readouts. Following analytical performance using synthetic RNA, the limit of detection was determined at equal to or less than 1 SARS-CoV-2 copy/ul of sample in a commercially available sample panel that contains surrogate clinical samples with varying SARS-CoV-2 viral load. Lastly, we benchmarked our method against a reference qPCR method by testing 87 nasopharyngeal swab samples. The direct endpoint ultra-fast RT-PCR method exhibited a positive percent agreement score of 98.5% and a negative percent agreement score of 100% as compared to the reference method, while RT-PCR cycling was completed in 27 minutes/sample as opposed to 60 minutes/sample in the reference qPCR method. In summary, we describe a rapid direct RT-PCR method to detect SARS-CoV-2 material in clinical specimens which can be completed in significantly less time as compared to conventional RT-PCR methods, making it an attractive option for large-scale SARS-CoV-2 screening applications.
Cerebellar and Prefrontal Structures Associated with Executive Functioning in Pediatric Patients with Congenital Heart Defects
Authors: Badaly Daryaneh , Beers Sue R. , Ceschin Rafael , Lee Vincent K. , Sulaiman Shahida , Zahner Alexandria , Wallace Julia , Berdaa-Sahel Aurélia , Burns Cheryl , Lo Cecilia W. , Panigrahy Ashok
Published: November 2021

Objective

Children, adolescents, and young adults with congenital heart defects (CHD) often display cognitive and behavioral manifestations of executive dysfunction. We consider the prefrontal and cerebellar brain structures as mechanisms for executive dysfunction among those with CHD.

Method

55 participants with CHD (M age = 13.93) and 95 healthy controls (M age = 13.13) completed magnetic resonance imaging (MRI) of the brain, from which we extracted volumetric data on prefrontal and cerebellar regions. Participants also completed neuropsychological tests of executive functioning; their parents completed behavioral ratings of their executive functions.

Results

Compared to healthy controls, those with CHD had smaller cerebellums and lateral, medial, and orbital prefrontal regions, they performed more poorly on tests of working memory, inhibitory control, and mental flexibility, and their parents rated them as having poorer executive functions across several indices. Across both groups, there were significant correlations for cerebellar and/or prefrontal volumes with cognitive assessments of working memory, mental flexibility, and inhibitory control and with behavioral ratings of working memory, task initiation, and emotional control. Greater prefrontal volumes were associated with better working memory, among those with larger cerebellums (with group differences based on the measure and the prefrontal region). Greater prefrontal volumes were related to better emotional regulation only among participants with CHD with smaller cerebellar volumes, and with poorer inhibition and emotional regulation only among healthy controls with larger cerebellar volumes.

Conclusion

The cerebellum modulates the relationships between prefrontal regions and executive functioning differently for pediatric patients with CHD versus health controls.
Projecting vaccine demand and impact for emerging zoonotic pathogens
Authors: Lerch A , ten Bosch QA , L’Azou Jackson M , Bettis AA , Bernuzzi M , Murphy GAV , Tran QM , Huber JH , Siraj AS , Bron GM , Elliott M , Hartlage CS , Koh K , Strimbu K , Walters M , Perkins TA , Moore SM
Published: November 2021

Despite large outbreaks in humans seeming improbable for a number of zoonotic pathogens, several pose a concern due to their epidemiological characteristics and evolutionary potential. To enable effective responses to these pathogens in the event that they undergo future emergence, the Coalition for Epidemic Preparedness Innovations is advancing the development of vaccines for several pathogens prioritized by the World Health Organization. A major challenge in this pursuit is anticipating demand for a vaccine stockpile to support outbreak response. We developed a modeling framework for outbreak response for emerging zoonoses under three reactive vaccination strategies. Annual vaccine regimen requirements for a population-wide strategy ranged from >670,000 (95% prediction interval: 0-3,630,000) regimens for Lassa virus to 1,190,000 (95% PrI: 0-8,480,000) regimens for Rift Valley fever virus, while the regimens required for ring vaccination or targeting healthcare workers (HCWs) were several orders of magnitude lower (between 1/25 and 1/700) than those required by a population-wide strategy. For each pathogen and vaccination strategy, reactive vaccination typically prevented fewer than 10% of cases, because of their presently low R0 values. Targeting HCWs had a higher per-regimen impact than population-wide vaccination. Our framework provides a flexible methodology for estimating vaccine stockpile needs and the geographic distribution of demand under a range of outbreak response scenarios.
Attractor Landscapes as a Model Selection Criterion in Data Poor Environments
Authors: Lyman Cole A. , Richman Spencer , Morris Matthew C. , Cao Hongbao , Scerri Antony , Cheadle Chris , Broderick Gordon
Published: November 2021

Modeling of systems for which data is limited often leads to underdetermined model identification problems, where multiple candidate models are equally adherent to data. In such situations additional optimality criteria are useful in model selection apart from the conventional minimization of error and model complexity. This work presents the attractor landscape as a domain for novel model selection criteria, where the number and location of attractors impact desirability. A set of candidate models describing immune response dynamics to SARS-CoV infection is used as an example for model selection based on features of the attractor landscape. Using this selection criteria, the initial set of 18 models is ranked and reduced to 7 models that have a composite objective value with a p-value < 0.05. Additionally, the impact of pharmacologically induced remolding of the attractor landscape is presented.
Fascicles Split or Merge Every ~560 Microns Within the Human Cervical Vagus Nerve
Authors: Upadhye Aniruddha R. , Kolluru Chaitanya , Druschel Lindsey , Lababidi Luna Al , Ahmad Sami S. , Menendez Dhariyat M. , Buyukcelik Ozge N. , Settell Megan L. , Blanz Stephan L. , Jenkins Michael W. , Wilson David L. , Zhang Jing , Tatsuoka Curtis , Grill Warren M. , Pelot Nicole A. , Ludwig Kip A. , Gustafson Kenneth J. , Shoffstall Andrew J.
Published: November 2021

1

Vagus nerve stimulation (VNS) is FDA approved for stroke rehabilitation, epilepsy, and depression; however, the vagus functional anatomy underlying the implant is poorly understood. We used microCT to quantify fascicular structure and neuroanatomy within human cervical vagus nerves. Fascicles split or merged every ~560 μm (17.8 ± 6.1 events/cm). The high degree of fascicular splitting and merging in humans may explain the clinical heterogeneity in patient responses.
Gender Imbalance in the Editorial Activities of a Researcher-led Journal
Authors: Malkinson Tal Seidel , Terhune Devin B. , Kollamkulam Mathew , Guerreiro Maria J. , Bassett Dani S. , Makin Tamar R.
Published: November 2021

Editorial decision-making is a fundamental element of the scientific enterprise. We examined whether contributions to editorial decisions at various stages of the publication process is subject to gender disparity, based on analytics collected by the biomedical researcher-led journal eLife. Despite efforts to increase women representation, the board of reviewing editors (BRE) was men-dominant (69%). Moreover, authors suggested more men from the BRE pool, even after correcting for men’s numerical over-representation. Although women editors were proportionally involved in the initial editorial process, they were under-engaged in editorial activities involving reviewers and authors. Additionally, converging evidence showed gender homophily in manuscripts assignment, such that men Senior Editors over-engaged men Reviewing Editors. This tendency was stronger in more gender-balanced scientific disciplines. Together, our findings confirm that gender disparities exist along the editorial process and suggest that merely increasing the proportion of women might not be sufficient to eliminate this bias.
Quantitative isotope-labeled crosslinker proteomics reveals developmental variation in protein interactions and posttranslational modifications in Diaphorina citri, the citrus greening insect vector
Authors: Ramsey John S. , Zhong Xuefei , Saha Surya , Chavez Juan D. , Johnson Richard , Mahoney Jaclyn E. , Keller Andrew , Moulton Kathy , Mueller Lukas A. , Hall David G. , MacCoss Michael J. , Bruce James E. , Heck Michelle
Published: November 2021

Acquisition of the citrus greening bacterial pathogen, ‘Candidatus Liberibacter asiaticus’ (CLas) by Asian citrus psyllid (Diaphorina citri) nymphs is required efficient tree-to-tree transmission during the adult stage. Quantitative isotope-labeled protein interaction reporter (PIR) cross-linkers were used in parallel with protein quantification using spectral counting to quantify protein interactions within microbe-enriched cellular fractions of nymph and adult D. citri. Over 100 unique crosslinks were found between five insect histone proteins, and over 30% of these were more abundant in nymph compared to adult insects. Strikingly, some cross-links detected in D. citri proteins are conserved in cross-linking studies on human cells, suggesting these protein interaction topologies were present in the common ancestor (∼750MYA) or are subject to convergent evolution. Analysis of posttranslational modifications of crosslinked histones revealed the presence of acetylated and methylated lysine residues, which may impact psyllid chromatin structure and gene expression. Histone H3 peptides acetylated in the N terminal tail region were found to be more abundant in nymph compared to adult insects in two orthogonal proteomics methods. The insect life stage-specific histone posttranslational modifications and protein interactions represent physical evidence that metamorphosis is associated with changes in chromatin structure that regulate genome-wide transcriptional reprogramming.
Measuring the invisible – The sequences causal of genome size differences in eyebrights (Euphrasia) revealed by k-mers
Authors: Becher Hannes , Sampson Jacob , Twyford Alex D.
Published: November 2021

Genome size variation within plant (and other) taxa may be due to presence/absence variation in low-copy sequences or copy number variation in genomic repeats of various frequency classes. However, identifying the sequences underpinning genome size variation has been challenging because genome assemblies commonly contain collapsed representations of repetitive sequences and because genome skimming studies miss low-copy number sequences.

Here, we take a novel approach based on k-mers, short sub-sequences of equal lengthk, generated from whole genome sequencing data of diploid eyebrights (Euphrasia), a group of plants which have considerable genome size variation within a ploidy level. We compare k-mer inventories within and between closely related species, and quantify the contribution of different copy number classes to genome size differences. We further assign high-copy number k-mers to specific repeat types as retrieved from the RepeatExplorer2 pipeline.

We find complex patterns of k-mer differences between samples. While all copy number classes contributed to genome size variation, the largest contribution came from repeats with 1000-10,000 genomic copies including the 45S rDNA satellite DNA and, unexpectedly, a repeat associated with an Angela transposable element. We also find size differences in the low-copy number class, likely indicating differences in gene space between our samples.

In this study, we demonstrate that it is possible to pinpoint the sequences causing genome size variation within species without use of a reference genome. Such sequences can serve as targets for future cytogenetic studies. We also show that studies of genome size variation should go beyond repeats and consider the whole genome. To allow future work with other taxonomic groups, we share our analysis pipeline, which is straightforward to run, relying largely on standard GNU command line tools.
Generation of a single-cell B cell atlas of antibody repertoires and transcriptomes to identify signatures associated with antigen-specificity
Authors: Agrafiotis Andreas , Neumeier Daniel , Hong Kai-Lin , Chowdhury Tasnia , Ehling Roy , Kuhn Raphael , Sandu Ioana , Kreiner Victor , Cotet Tudor-Stefan , Laslo Daria , Anzböck Stine , Starkie Dale , Lightwood Daniel J. , Oxenius Annette , Reddy Sai T. , Yermanos Alexander
Published: November 2021

Murine models of immunization have played a major role in discovering antibody candidates against therapeutic targets. It nevertheless remains time-consuming and expensive to identify antibodies with diverse binding modalities against druggable candidate molecules. Although new genomics-based pipelines have potential to augment antibody discovery, these methods remain in their infancy due to an incomplete understanding of the selection process that governs B cell clonal selection, expansion and antigen specificity. Furthermore, it remains unknown how factors such as aging and reduction of tolerance influence B cell selection in murine models of immunization. Here we perform single-cell sequencing of antibody repertoires and transcriptomes of B cells following immunizations with a model therapeutic antigen target (human Tumor necrosis factor receptor 2, TNFR2). We determine the relationship between antibody repertoires, gene expression signatures and antigen specificity across 100,000 B cells. Recombinant expression and characterization of 227 monoclonal antibodies revealed the existence of clonally expanded and class-switched antigen-specific B cells that were more frequent in young mice. Although integrating multiple repertoire features such as germline gene usage, somatic hypermutation, and transcriptional signatures failed to distinguish antigen-specific from non-specific B cells, other features such as IgG-subtype and sequence composition correlated with antigen-specificity. This work provides a single-cell resource for B cells relating antibody repertoires, transcriptomes and antigen specificity.
In vivo label-free observation of tumor-related blood vessels in small animals using a newly designed photoacoustic 3D imaging system
Authors: Asao Yasufumi , Nagae Kenichi , Miyasaka Koichi , Sekiguchi Hiroyuki , Aiso Sadakazu , Watanabe Shigeaki , Sato Marika , Kizaka-Kondoh Shinae , Nakajima Yukari , Kishi Kazuo , Yagi Takayuki
Published: November 2021

Introduction

Photoacoustic technology can be used for non-invasive imaging of blood vessels. In this paper, we report on our prototype photoacoustic imaging system with a newly designed ultrasound sensor and its visualization performance of microvascular in animal.

Methods

We fabricated an experimental system for animals using a high-frequency sensor. The system has two modes: still image mode by wide scanning and moving image mode by small rotation of sensor array. Optical test target, euthanized mice and rats, and live mice were used as objects.

Results

The results of optical test target showed that the spatial resolution was about 2 times higher than that of our conventional prototype. The image performance in vivo was evaluated in euthanized healthy mice and rats, allowing visualization of detailed blood vessels in the liver and kidneys. In tumor-bearing mice, different results of vascular induction were shown depending on the type of tumor and the method of transplantation. By utilizing the video imaging function, we were able to observe the movement of blood vessels around the tumor.

Conclusion

We have demonstrated the feasibility of the system as a less invasive animal experimental device, as it can acquire vascular images in animals in a non-contrast and non-invasive manner.
Quantifying how post-transcriptional noise and gene copy number variation bias transcriptional parameter inference from mRNA distributions
Authors: Fu Xiaoming , Patel Heta P. , Coppola Stefano , Xu Libin , Cao Zhixing , Lenstra Tineke L. , Grima Ramon
Published: November 2021

Transcriptional rates are often estimated by fitting the distribution of mature mRNA numbers measured using smFISH (single molecule fluorescence in situ hybridization) with the distribution predicted by the telegraph model of gene expression, which defines two promoter states of activity and inactivity. However, fluctuations in mature mRNA numbers are strongly affected by processes downstream of transcription. In addition, the telegraph model assumes one gene copy, but in experiments cells may have two gene copies as cells replicate their genome during the cell cycle. Whilst it is often presumed that post-transcriptional noise and gene copy number variation affect transcriptional parameter estimation, the size of the error introduced remains unclear. To address this issue, here we measure both mature and nascent mRNA distributions of GAL10 in yeast cells using smFISH and classify each cell according to its cell cycle phase. We infer transcriptional parameters from mature and nascent mRNA distributions, with and without accounting for cell cycle phase and compare the results to live-cell transcription measurements of the same gene. We find that: (i) correcting for cell cycle dynamics decreases the promoter switching rates and the initiation rate, and increases the fraction of time spent in the active state, as well as the burst size; (ii) additional correction for post-transcriptional noise leads to further increases in the burst size and to a large reduction in the errors in parameter estimation. Furthermore, we outline how to correctly adjust for measurement noise in smFISH due to uncertainty in transcription site localisation when introns cannot be labelled. Simulations with parameters estimated from nascent smFISH data, which is corrected for cell cycle phases and measurement noise, leads to autocorrelation functions that agree with those obtained from live-cell imaging.
Maf1, a repressor of RNA polymerase III-dependent transcription, regulates bone mass
Authors: Busschers Ellen , Ahmad Naseer , Sun Li , Iben James , Walkey Christopher J. , Rusin Aleksandra , Yuen Tony , Rosen Clifford J. , Willis Ian M. , Zaidi Mone , Johnson Deborah L.
Published: November 2021

Maf1, a key repressor of RNA polymerase III-mediated transcription, has been shown to promote mesoderm formation in vitro. Here, we show, for the first time, that Maf1 plays a critical role in the regulation of osteoblast differentiation and bone mass. A high bone mass phenotype was noted in mice with global deletion of Maf1 (Maf1-/- mice), as well as paradoxically, in mice that overexpressed MAF1 in cells of the osteoblast lineage (Prx1-Cre;LSL-Maf1 mice). Osteoblasts isolated from Maf1-/- mice showed reduced osteoblastogenesis ex vivo. Prx1-Cre;LSL-MAF1 mice showed enhanced osteoblastogenesis concordant with their high bone mass phenotype. Thus, the high bone mass phenotype in Maf1-/- mice is likely due to the confounding effects of the global absence of Maf1 in Maf1-/- mice. Expectedly, MAF1 overexpression promoted osteoblast differentiation and shRNA-mediated Maf1 downregulation inhibited differentiation of ST2 cells, overall indicating Maf1 enhances osteoblast formation. We also found that, in contrast to MAF1 overexpression, other perturbations that repress RNA pol III transcription, including Brf1 knockdown and the chemical inhibition of RNA pol III by ML-60218, inhibited osteoblast differentiation. All perturbations that decrease RNA pol III transcription, however, enhanced adipogenesis in ST2 cell cultures. RNA-seq was used to determine the basis for these opposing actions on osteoblast differentiation. The modalities used to alter RNA pol III transcription resulted in distinct changes gene expression, indicating that this transcription process is highly sensitive to perturbations and triggers diverse gene expression programs and phenotypic outcomes. Specifically, Maf1 induced genes in ST2 cells known to promote osteoblast differentiation. Furthermore, genes that are induced during osteoblast differentiation displayed codon bias. Together, these results reveal a novel role for Maf1 and RNA pol III-mediated transcription in osteoblast fate determination and differentiation and bone mass regulation.