bluuebunny/crossref_metadata_2025 huggingface dataset:
MALDI-TOF mass spectrometry of saliva samples as a prognostic tool for COVID-19
Authors: Lazari Lucas C. , Zerbinati Rodrigo M. , Rosa-Fernandes Livia , Santiago Veronica Feijoli , Rosa Klaise F. , Angeli Claudia B. , Schwab Gabriela , Palmieri Michelle , Sarmento Dmity J. S. , Marinho Claudio R. F. , Almeida Janete Dias , To Kelvin , Giannecchini Simone , Wrenger Carsten , Sabino Ester C. , Martinho Herculano , Lindoso José A. L. , Durigon Edison L. , Braz-Silva Paulo H. , Palmisano Giuseppe
Published: December 2021

The SARS-CoV-2 infections are still imposing a great public health challenge despite the recent developments in vaccines and therapy. Searching for diagnostic and prognostic methods that are fast, low-cost and accurate is essential for disease control and patient recovery. The MALDI-TOF mass spectrometry technique is rapid, low cost and accurate when compared to other MS methods, thus its use is already reported in the literature for various applications, including microorganism identification, diagnosis and prognosis of diseases. Here we developed a prognostic method for COVID-19 using the proteomic profile of saliva samples submitted to MALDI-TOF and machine learning algorithms to train models for COVID-19 severity assessment. We achieved an accuracy of 88.5%, specificity of 85% and sensitivity of 91.5% for classification between mild/moderate and severe conditions. Then, we tested the model performance in an independent dataset, we achieved an accuracy, sensitivity and specificity of 67.18, 52.17 and 75.60% respectively. Saliva is already reported to have high inter-sample variation; however, our results demonstrates that this approach has the potential to be a prognostic method for COVID-19. Additionally, the technology used is already available in several clinics, facilitating the implementation of the method. Further investigation using a bigger dataset is necessary to consolidate the technique.
Weakening of the cognition and height association from 1957 to 2018: findings from four British birth cohort studies
Authors: Bann David , Wright Liam , Davies Neil M , Moulton Vanessa
Published: December 2021

Background

On average taller individuals have been repeatedly found to have higher scores on cognitive assessments, yet it is unclear whether the magnitude of this association has systematically changed across time. Recent studies have found that this association can be explained by genetic factors, yet this does not preclude the influence of environmental or social factors that affect the genome. We tested whether the association between cognition and height has weakened across time.

Methods

We used four British birth cohorts (born 1946c, 1958c, 1970c, and 2001) with comparable data available at 10/11 and 14/17 years (N = 41,418). Height was measured at each age, and cognition via verbal reasoning (10/11 years) and vocabulary/comprehension scales (14/16 years) and via mathematical tests at both ages. We constructed age-adjusted height and cognition measures and converted cognition measures to ridit scores to aid interpretation. We then used linear and quantile regression to investigate whether cross-sectional associations between cognition and height differed in each cohort, sequentially adjusting for sex, childhood socioeconomic position, and maternal and paternal height.

Results

Taller participants had higher mean cognitive assessment scores in childhood and adolescence, yet the associations were weaker in later (1970c and 2001c) cohorts – after adjustment for sex the mean difference in height comparing the highest with lowest verbal cognition scores at 10/11 years was 0.57 SD (95% CI = 0.44, 0.7) in the 1946c, 0.59 SD (0.52, 0.65) in the 1958c, 0.47 SD (0.41, 0.53) in the 1970c, 0.30 SD (0.23, 0.37) in the 2001c. This pattern of change in association was observed across all specifications (ages 10/11 and 14/16 years, and for each cognition measure used), and was robust to adjustment for social class and parental height, and modelling of plausible missing-not-at-random scenarios. Quantile regression suggested that these average differences were driven by differences in the lower centiles of height. This pattern was most evident in older cohorts – for example, in 1958c, the difference in height was 0.73 SD (0.64, 0.82) at the 10th centile, yet 0.46 SD (0.34, 0.57) at the 90th centile.

Conclusion

Associations between height and cognitive assessment scores in childhood-adolescence weakened by at least half from 1957 to 2018. These results support the notion that environmental and social change can markedly weaken associations between cognition and other traits.
Software Application Profile: SUMnlmr, an R package that facilitates flexible and reproducible non-linear Mendelian randomisation analyses
Authors: Mason Amy M. , Burgess Stephen
Published: December 2021

Motivation

Mendelian randomisation methods that estimate non-linear exposure—outcome relationships typically require individual-level data. This package implements non-linear Mendelian randomisation methods using stratified summarised data, facilitating analyses where individual-level data cannot easily be shared, and additionally increasing reproducibility as summarised data can be reported. Dependence on summarised data means the methods are independent of the form of the individual- level data, increasing flexibility to different outcome types (such as continuous, binary, or time-to- event outcomes).

Implementation

SUMnlmr is available as an R package (version 3.1.0 or higher).

General features

The package implements the previously proposed fractional polynomial and piecewise linear methods on stratified summarised data that can either be estimated from individual-level data using the package or supplied by a collaborator. It constructs plots to visualise the estimated exposure— outcome relationship, and provides statistics to assess preference for a non-linear model over a linear model.

Availability

The package is freely available from GitHub [https://github.com/amymariemason/SUMnlmr].
Genetic Subtypes of Smoldering Multiple Myeloma are associated with Distinct Pathogenic Phenotypes and Clinical Outcomes
Authors: Bustoros Mark , Anand Shankara , Sklavenitis-Pistofidis Romanos , Redd Robert , Boyle Eileen M. , Zhitomirsky Benny , Dunford Andrew J , Tai Yu-Tzu , Chavda Selina J , Boehner Cody , Neuse Carl Jannes , Rahmat Mahshid , Dutta Ankit , Casneuf Tineke , Verona Raluca , Kastritis Efstathis , Trippa Lorenzo , Stewart Chip , Walker Brian A. , Davies Faith E. , Dimopoulos Meletios-Athanasios , Bergsagel Leif , Yong Kwee , Morgan Gareth J. , Aguet François , Getz Gad , Ghobrial Irene M.
Published: December 2021

Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with significant heterogeneity in disease progression. Existing clinical models of progression risk do not fully capture this heterogeneity. Here we integrated 42 genetic alterations from 214 SMM patients using unsupervised binary matrix factorization (BMF) clustering and identified six distinct genetic subtypes. These subtypes were differentially associated with established MM-related RNA signatures, oncogenic and immune transcriptional profiles, and evolving clinical biomarkers. Three subtypes were associated with increased risk of progression to active MM in both the primary and validation cohorts, indicating they can be used to better predict high and low-risk patients within the currently used clinical risk stratification model.
Geometrical frustration of phase-separated domains in Coscinodiscus diatom frustules
Authors: Feofilova Maria , Schüepp Silvan , Schmid Roman , Hacker Florian , Spanke Hendrik T. , Bain Nicolas , Jensen Katharine E. , Dufresne Eric R.
Published: December 2021

Diatoms are single-celled organisms with a cell wall made of silica, called the frustule. Even though their elaborate patterns have fascinated scientists for years, little is known about the biological and physical mechanisms underlying their organization. In this work, we take a top-down approach and examine the micron-scale organization of diatoms from the Coscinodiscus family. We find two competing tendencies of organization, which appear to be controlled by distinct biological pathways. On one hand, micron-scale pores organize locally on a triangular lattice. On the other, lattice vectors tend to point globally toward a center of symmetry. This competition results in a frustrated triangular lattice, populated with geometrically necessary defects whose density increases near the center.
Human pathogenic RNA viruses establish non-competing lineages by occupying independent niches
Authors: Mutz Pascal , Rochman Nash D. , Wolf Yuri I. , Faure Guilhem , Zhang Feng , Koonin Eugene V.
Published: December 2021

Many pathogenic viruses are endemic among human populations and can cause a broad variety of diseases, some potentially leading to devastating pandemics. How virus populations maintain diversity and what selective pressures drive population turnover, is not thoroughly understood. We conducted a large-scale phylodynamic analysis of 27 human pathogenic RNA viruses spanning diverse life history traits in search of unifying trends that shape virus evolution. For most virus species, we identify multiple, co-circulating lineages with low turnover rates. These lineages appear to be largely noncompeting and likely occupy semi-independent epidemiological niches that are not regionally or seasonally defined. Typically, intra-lineage mutational signatures are similar to inter-lineage signatures. The principal exception are members of the familyPicornaviridae, for which mutations in capsid protein genes are primarily lineage-defining. The persistence of virus lineages appears to stem from limited outbreaks within small communities so that only a minor fraction of the global susceptible population is infected at any time. As disparate communities become increasingly connected through globalization, interaction and competition between lineages might increase as well, which could result in changing selective pressures and increased diversification and/or pathogenicity. Thus, in addition to zoonotic events, ongoing surveillance of familiar, endemic viruses appears to merit global attention with respect to the prevention or mitigation of future pandemics.

Significance

Numerous pathogenic viruses are endemic in humans and cause a broad variety of diseases, but what is their potential of causing new pandemics? We show that most human pathogenic RNA viruses form multiple, co-circulating lineages with low turnover rates. These lineages appear to be largely noncompeting and occupy distinct epidemiological niches that are not regionally or seasonally defined, and their persistence appears to stem from limited outbreaks in small communities so that a minor fraction of the global susceptible population is infected at any time. However, due to globalization, interaction and competition between lineages might increase, potentially leading to increased diversification and pathogenicity. Thus, endemic viruses appear to merit global attention with respect to the prevention of future pandemics.
Extend Mixed Models to Multi-layer Neural Networks for Genomic Prediction Including Intermediate Omics Data
Authors: Zhao Tianjing , Zeng Jian , Cheng Hao
Published: December 2021

With the growing amount and diversity of intermediate omics data complementary to genomics (e.g., DNA methylation, gene expression, and protein abundance), there is a need to develop methods to incorporate intermediate omics data into conventional genomic evaluation. The omics data helps decode the multiple layers of regulation from genotypes to phenotypes, thus forms a connected multi-layer network naturally. We developed a new method named NN-LMM to model the multiple layers of regulation from genotypes to intermediate omics features, then to phenotypes, by extending conventional linear mixed models (“LMM”) to multi-layer artificial neural networks (“NN”). NN-LMM incorporates intermediate omics features by adding middle layers between genotypes and phenotypes. Linear mixed models (e.g., pedigree-based BLUP, GBLUP, Bayesian Alphabet, single-step GBLUP, or single-step Bayesian Alphabet) can be used to sample marker effects or genetic values on intermediate omics features, and activation functions in neural networks are used to capture the nonlinear relationships between intermediate omics features and phenotypes. NN-LMM had significantly better prediction performance than the recently proposed single-step approach for genomic prediction with intermediate omics data. Compared to the single-step approach, NN-LMM can handle various patterns of missing omics measures, and allows nonlinear relationships between intermediate omics features and phenotypes. NN-LMM has been implemented in an open-source package called “JWAS”.
Novel Multiple Sclerosis Agents-Induced Cardiotoxicity
Authors: Al-Yafeai Zaki , Abduljabbar Hamzah , Carvajal-González Alexander , Arvas Muhammed , Patel Shaun , Patel Neev
Published: December 2021

Background

Emerging novel therapeutics have been developed to hamper the progression of multiple sclerosis. However, the adverse events related to these new agents remain largely unknown. Therefore, we sought to investigate the cardiovascular complications of these drugs.

Methods

Utilizing data from the U.S. Food and Drug Administration Adverse Events Reporting System, we comprehensively evaluated the cardiovascular complications of the newly FDA approved anti-multiple sclerosis agents. Disproportionality signal analysis was conducted by measuring reporting odds ratio (ROR) with 95% confidence interval of all the cardiovascular adverse events adverse events since approval till 2021.

Results

After vetting the newly approved agents for multiple sclerosis, CD20 and CD25 inhibitors and sphingosine-1-phosphate receptors agonists were the latest approved medications for multiple sclerosis since 2015. Two CD20 (ocrelizumab, ofatumumab) and one CD25 inhibitors (daclizumab) were significantly associated with multiple cardiovascular adverse events. Among all the cardiotoxic events; coronary artery disease, cardiac failure and atrial fibrillation were the most predominant among CD20 or CD25 blockers. Interestingly, Sphingosine-1-phosphate receptors agonists showed much fewer reported cardiac adverse events. However, fingolimod and siponimod were associated with significant bradycardia.

Conclusions

Our data revealed the new agents prescribed for multiple sclerosis have cardiotoxic effects, including not only the known adverse effects observed effects for S1P receptor modulators but also undefined cardiovascular complications associated with CD20 and CD25 inhibitors. These findings potentially instigate further studies to personalize prescribing these agents for multiple sclerosis based on patient’s cardiovascular profile.
A quantitative evaluation of aerosol generation from upper airway suctioning during tracheal intubation and extubation sequences
Authors: Shrimpton AJ , Brown JM , Cook TM , Penfold CM , Reid JP , Pickering AEP
Published: December 2021

Background

Open respiratory suctioning is considered to be an aerosol generating procedure (AGP) and laryngopharyngeal suction, used to clear secretions during anaesthesia, is widely managed as an AGP. It is uncertain whether such upper airway suctioning should be designated an aerosol generating procedure (AGP) because of a lack of both aerosol and epidemiological evidence of risk.

Aim

To assess the relative risk of aerosol generation by upper airway suction during tracheal intubation and extubation in anaesthetised patients.

Methods

Prospective environmental monitoring study in ultraclean operating theatres to assay aerosol concentration during intubation and extubation sequences including upper airway suctioning for patients undergoing surgery (n=19 patients). An Optical Particle Sizer (particle size 300nm-10μm) was used to sample aerosol from 20cm above the patient’s mouth. Baseline recordings (background, tidal breathing and volitional coughs) were followed by intravenous induction of anaesthesia with neuromuscular blockade. Four periods of oropharyngeal suction were performed with a Yankauer sucker: pre-laryngoscopy, post-intubation and pre- and post-extubation.

Findings

Aerosol from breathing was reliably detected (65[39-259] particles.L−1 (median[IQR])) above background (4.8[1-7] particles.L−1, p<0.0001 Friedman). The procedure of upper airway suction was associated with much lower average concentrations of aerosol than breathing (6.0[0-12] particles.L−1, P=0.0007) and was indistinguishable from background (P>0.99). The peak aerosol concentration recorded during suctioning (45[30-75] particles.L−1) was much lower than both volitional coughs (1520[600-4363] particles.L−1, p<0.0001, Friedman) and tidal breathing (540[300-1826] particles.L−1, p<0.0001, Friedman).

Conclusion

The procedure of upper airway suction during airway management is associated with no higher concentration of aerosol than background and much lower than breathing and coughing. Upper airway suction should not be designated as a high risk AGP.
Diagnostic Strategies to Identify Patients with Genetic Salt-Losing Tubulopathies
Authors: Wan Elizabeth , Iancu Daniela , Ashton Emma , Siew Keith , Mohidin Barian , Sung Chih-Chien , Nagano China , Bockenhauer Detlef , Lin Shih-Hua , Nozu Kandai , Walsh Stephen B
Published: December 2021

Background

Distinguishing patients with the inherited salt-losing tubulopathies (SLT), Gitelman or Bartter syndrome (GS or BS) from wildtype (WT) patients who purge is difficult. We decided to identify clinical/biochemical characteristics which correctly classify SLT.

Methods

66 patients with possible SLT were recruited to a prospective observational cohort study at the UCL Renal Tubular Clinic (London). 31 datapoints were recorded on each patient. All patients were genotyped for pathogenic mutations in genes which cause SLT; 39 patients had pathogenic variants in genes causing SLT. We obtained similar datasets from cohorts in Taipei and Kobe; the combined dataset comprised 419 patients, 291 had genetically confirmed SLT. London and Taipei datasets were combined to train machine learning (ML) algorithms. These were then tested on the Kobe dataset to determine the best biochemical predictors of genetic confirmation of SLT.

Results

Single biochemical variables (e.g. plasma renin) were significantly, but inconsistently different between SLT and WT, in the London and combined cohorts.

A decision table algorithm using serum bicarbonate and urinary sodium excretion (FENa) achieved a classification accuracy of 74%. A simpler algorithm based on the FECl achieved a classification accuracy of 61%. This was superior to all of the single biochemical variables identified previously.
SARS-CoV-2 T cell responses are expected to remain robust against Omicron
Authors: Ahmed Syed Faraz , Quadeer Ahmed Abdul , McKay Matthew R.
Published: December 2021

Omicron, the most recent SARS-CoV-2 variant of concern (VOC), harbours multiple mutations in the spike protein that were not observed in previous VOCs. Initial studies suggest Omicron to substantially reduce the neutralizing capability of antibodies induced from vaccines and previous infection. However, its effect on T cell responses remains to be determined. Here, we assess the effect of Omicron mutations on known T cell epitopes and report data suggesting T cell responses to remain broadly robust against this new variant.
Microarray-based detection of antibodies against SARS-CoV-2 proteins, common respiratory viruses and type I interferons
Authors: Savvateeva Elena , Filippova Marina , Valuev-Elliston Vladimir , Nuralieva Nurana , Yukina Marina , Troshina Ekaterina , Baklaushev Vladimir , Ivanov Alexander , Gryadunov Dmitry
Published: December 2021

A microarray-based assay to detect IgG and IgM antibodies against betacoronaviruses (SARS-CoV-2, SARS, MERS, OC43, and HKU1), other respiratory viruses and type I interferons (IFN-Is) was developed. This multiplex assay was applied to track antibody cross-reactivity due to previous contact with similar viruses and to identify antibodies against IFN-Is as the markers for severe COVID-19. In total, 278 serum samples from convalescent plasma donors, COVID-19 patients in the intensive care unit (ICU) and patients who recovered from mild/moderate COVID-19, vaccine recipients, prepandemic and pandemic patients with autoimmune endocrine disorders, and a heterogeneous prepandemic cohort including healthy individuals and chronically ill patients were analyzed. The anti-SARS-CoV-2 microarray results agreed well with the ELISA results. Regarding ICU patients, autoantibodies against IFN-Is were detected in 10.5% of samples, and 10.5% of samples were found to simultaneously contain IgM antibodies against more than two different viruses. Cross-reactivity between IgG against the SARS-CoV-2 nucleocapsid and IgG against the OC43 and HKU1 spike proteins was observed, resulting in positive signals for the SARS-CoV-2 nucleocapsid in prepandemic samples from patients with autoimmune endocrine disorders. The presence of IgG against the SARS-CoV-2 nucleocapsid in the absence of IgG against the SARS-CoV-2 spike RBD should be interpreted with caution.
Identification of Genetic Loci Simultaneously Associated with Multiple Cardiometabolic Traits
Authors: Wood Alexis C. , Arora Amit , Newell Michelle , Bland Victoria L. , Zhou Jin , Pirastu Nicola , Ordovas Jose M. , Klimentidis Yann C.
Published: December 2021

Background and Aims

Cardiometabolic disorders (CMD) arise from a constellation of features such as increased adiposity, hyperlipidemia, hypertension and compromised glucose control. Many genetic loci have shown associations with individual CMD-related traits, but no investigations have focused on simultaneously identifying loci showing associations across all domains. We therefore sought to identify loci associated with risk across seven continuous CMD-related traits.

Methods and Results

We conducted separate genome-wide association studies (GWAS) for systolic and diastolic blood pressure (SBP/DBP), hemoglobin A1c (HbA1c), low- and high-density lipoprotein cholesterol (LDL-C/HDL-C), waist-to-hip-ratio (WHR), and triglycerides (TGs) in the UK Biobank (N=356,574–456,823). Multiple loci reached genome-wide levels of significance (N=145-333) for each trait, but only four loci (in/nearVEGFA, GRB14-COBLL1, KLF14, andRGS19-OPRL1)were associated with risk across all seven traits (P<5×10−8). We sought replication of these four loci in an independent set of seven trait-specific GWAS meta-analyses.GRB14-COBLL1showed the most consistent replication, revealing nominally significant associations (P<0.05) with all traits except DBP.

Conclusions

Our analyses suggest that very few loci are associated in the same direction of risk with traits representing the full spectrum of CMD features. We identified four such loci, and an understanding of the pathways between these loci and CMD risk may eventually identify factors that can be used to identify pathologic disturbances that represent broadly beneficial therapeutic targets.
Simple decision rules to predict local surges in COVID-19 hospitalizations during the winter and spring of 2022
Authors: Yaesoubi Reza , You Shiying , Xi Qin , Menzies Nicolas A. , Tuite Ashleigh , Grad Yonatan H. , Salomon Joshua A.
Published: December 2021

Low rates of vaccination, emergence of novel variants of SARS-CoV-2, and increasing transmission relating to seasonal changes leave many U.S. communities at risk for surges of COVID-19 during the winter and spring of 2022 that might strain hospital capacity, as in previous waves. The trajectories of COVID-19 hospitalizations during this period are expected to differ across communities depending on their age distributions, vaccination coverage, cumulative incidence, and adoption of risk mitigating behaviors. Yet, existing predictive models of COVID-19 hospitalizations are almost exclusively focused on national- and state-level predictions. This leaves local policymakers in urgent need of tools that can provide early warnings about the possibility that COVID-19 hospitalizations may rise to levels that exceed local capacity. In this work, we develop simple decision rules to predict whether COVID-19 hospitalization will exceed the local hospitalization capacity within a 4- or 8-week period if no additional mitigating strategies are implemented during this time. These decision rules use real-time data related to hospital occupancy and new hospitalizations associated with COVID-19, and when available, genomic surveillance of SARS-CoV-2. We showed that these decision rules present reasonable accuracy, sensitivity, and specificity (all ≥80%) in predicting local surges in hospitalizations under numerous simulated scenarios, which capture substantial uncertainties over the future trajectories of COVID-19 during the winter and spring of 2022. Our proposed decision rules are simple, visual, and straightforward to use in practice by local decision makers without the need to perform numerical computations.

Significance Statement

In many U.S. communities, the risk of exceeding local healthcare capacity during the winter and spring of 2022 remains substantial since COVID-19 hospitalizations may rise due to seasonal changes, low vaccination coverage, and the emergence of new variants of SARS-CoV-2, such as the omicron variant. Here, we provide simple and easy-to-communicate decision rules to predict whether local hospital occupancy is expected to exceed capacity within a 4- or 8-week period if no additional mitigating measures are implemented. These decision rules can serve as an alert system for local policymakers to respond proactively to mitigate future surges in the COVID-19 hospitalization and minimize risk of overwhelming local healthcare capacity.
Modifiable traits, healthy behaviours, and leucocyte telomere length
Authors: Bountziouka Vasiliki , Musicha Crispin , Allara Elias , Kaptoge Stephen , Wang Qingning , Di Angelantonio Emanuele , Butterworth Adam S , Thompson John R , Danesh John N , Wood Angela M , Nelson Christopher P , Codd Veryan , Samani Nilesh J
Published: December 2021

Background

Telomere length is associated with risk of several age–related diseases and cancers. The extent to which telomere length may be modifiable through lifestyle and behaviour and whether this has any clinical consequences is unknown.

Methods

In up to 422,797 participants in UK Biobank, we investigated associations of leucocyte telomere length (LTL) with 117 potentially modifiable traits, as well as two indices of healthy behaviours incorporating smoking, physical activity, diet, maintenance of a healthy body weight and alcohol intake. Associations were interpreted as age–related change in LTL by dividing the trait beta coefficients with the age–coefficient. We used Mendelian Randomisation (MR) to test causality of the observed associations of educational attainment and smoking behaviour with LTL. We investigated whether the associations of LTL with 22 diseases were modified by the number of healthy behaviours and the extent to which the associations of more healthy behaviours with greater life expectancy and lower risk of coronary artery disease (CAD) may be mediated through LTL.

Results

71 traits showed significant associations with LTL but most were modest, equivalent to <1 year of age–related change in LTL. In multivariable analyses of 17 traits with stronger associations (equivalent to ≥2 years of age–related change in LTL), five traits – oily fish intake, educational attainment, general health status, walking pace and current smoking – remained significant. MR analysis suggested that educational attainment and smoking behaviour causally affect LTL. Both indices of healthy behaviour were positively and linearly associated with LTL, with those with the healthiest behaviour having longer LTL equivalent to ∼3·5 years of age–related change in LTL when compared with those with the least heathy behaviours (P<0·001). However, healthy behaviours only explained <0·2% of the total variation in LTL and did not significantly modify the association of LTL with risk of any of the diseases studied. Neither the association of more healthy behaviours on greater life expectancy or lower risk of CAD were substantially mediated through LTL.

Conclusions

Several potentially modifiable traits and healthy behaviours have a quantifiable association with LTL, at least some of which are likely to be causal. However, these effects are not of a sufficient magnitude to substantially alter the association between LTL and various diseases or life expectancy.
Quality Assurance Assessment of Intra-Acquisition Diffusion-Weighted and T2-Weighted Magnetic Resonance Imaging Registration and Contour Propagation for Head and Neck Cancer Radiotherapy
Authors: Naser Mohamed A. , Wahid Kareem A. , Ahmed Sara , Salama Vivian , Dede Cem , Edwards Benjamin W. , Lin Ruitao , McDonald Brigid , Salzillo Travis C. , He Renjie , Ding Yao , Abdelaal Moamen Abobakr , Thill Daniel , O’Connell Nicolette , Willcut Virgil , Christodouleas John P. , Lai Stephen Y , Fuller Clifton D. , Mohamed Abdallah S. R.
Published: December 2021

Background/Purpose

Adequate image registration of anatomic and functional MRI scans is necessary for MR-guided head and neck cancer (HNC) adaptive radiotherapy planning. Despite the quantitative capabilities of diffusion-weighted imaging (DWI) MRI for treatment plan adaptation, geometric distortion remains a considerable limitation. Therefore, we systematically investigated various deformable image registration (DIR) methods to co-register DWI and T2-weighted (T2W) images.

Materials/Methods

We compared three commercial (ADMIRE, Velocity, Raystation) and three open-source (Elastix with default settings [Elastix Default], Elastix with parameter set 23 [Elastix 23], Demons) post-acquisition DIR methods applied to T2W and DWI MRI images acquired during the same imaging session in twenty immobilized HNC patients. In addition, we used the non-registered images (None) as a control comparator. Ground truth segmentations of radiotherapy structures (tumor and organs at risk) were generated by a physician expert on both image sequences. For each registration approach, structures were propagated from T2W to DWI images. These propagated structures were then compared with ground truth DWI structures using the Dice similarity coefficient and mean surface distance.

Results

19 left submandibular glands, 18 right submandibular glands, 20 left parotid glands, 20 right parotid glands, 20 spinal cords, and 12 tumors were delineated. Most DIR methods took < 30 seconds to execute per case, with the exception of Elastix 23 which took ∼458 seconds to execute per case. ADMIRE and Elastix 23 demonstrated improved performance over None for all metrics and structures (Bonferroni-corrected p < 0.05), while the other methods did not. Moreover, ADMIRE and Elastix 23 significantly improved performance in individual and pooled analysis compared to all other methods.

Conclusions

The ADMIRE DIR method offers improved geometric performance with reasonable execution time so should be favored for registering T2W and DWI images acquired during the same scan session in HNC patients. These results are important to ensure the appropriate selection of registration strategies for MR-guided radiotherapy.
Ferritin trajectories over repeated whole blood donations: results from the FIND+ study
Authors: Moazzen Sara , Sweegers Maike G , Janssen Mart , Hogema Boris M , Hoekstra Trynke , van den Hurk Katja
Published: December 2021

Background

Whole blood donors lose approximately 200-250 mg of iron per donation. Depending on post-donation erythropoiesis, available iron stores, and iron absorption rates, optimal donation intervals may differ between donors. This project aims to define subpopulations of donors with different ferritin trajectories over repeated donations.

Methods

Ferritin levels of 300 new whole blood donors were measured from stored (lookback) samples from each donation over a two-year period in an observational cohort study. Latent classes of ferritin level trajectories were investigated using growth mixture models for male and female donors, separately. Associations of ferritin levels with subsequent iron deficiency and/or low haemoglobin were assessed with generalized linear mixed models.

Results

In both genders two groups of donors were identified using group-based trajectory modelling. Ferritin levels showed rather linear reductions among 42.9% of male donors and 87.7% of female donors. For the remaining groups of donors, steeper declines in ferritin levels were observed. Ferritin levels at baseline and the end of follow-up varied greatly between groups.

Conclusion

Repeated ferritin measurements show depleting iron stores in all new whole blood donors, the level at which mainly depends on baseline ferritin levels. Tailored, less intensive donation strategies might help to prevent low iron in donors, and could be supported with ferritin monitoring and/or iron supplementation.
The salivary microbiome shows a high prevalence of core bacterial members yet variability across human populations
Authors: Ruan Xinwei , Luo Jiaqiang , Zhang Pangzhen , Howell Kate
Published: December 2021

Human saliva contains diverse bacterial communities, reflecting human health status, dietary patterns and contributing to variability in the sensory perception of food. Many descriptions of salivary microbiome diversity compare commonalities and differences with reference to a diseased state, but the composition of healthy saliva has not been described. Here, we use a meta-analysis approach to define and explore the core membership of the human salivary microbial community by collecting and re-analysing raw 16S rRNA amplicon sequencing data from 47 studies with 2206 saliva samples. We found 68 core bacterial taxa that were consistently detected. Differences induced by various host intrinsic and behaviour factors, including gender, age, geographic location, tobacco usage, and alcohol consumption, were evident. The core of the salivary microbiome was verified by collecting and analysing saliva in an independent study. These results suggest that the methods used can effectively define a core microbial community in human saliva with high prevalence. The core salivary microbiome demonstrated both stability and variability among populations. Geographic location was identified as the host factor with the largest effect in shaping salivary microbiota. The independent analysis underlined that the impact of geographic variation is likely due to diet.
Landscape dynamics promoted the evolution of mega-diversity in South American freshwater fishes
Authors: Cassemiro Fernanda A. S. , Albert James S. , Antonelli Alexandre , Menegotto André , Wüest Rafael O. , Coelho Marco Túlio P. , Bailly Dayani , da Silva Valéria F. B. , Frota Augusto , da Graça Weferson J. , Ré Reginaldo , Ramos Telton , de Oliveira Anielly Galego , Dias Murilo S. , Colwell Robert K. , Rangel Thiago F. , Graham Catherine H.
Published: December 2021

Landscape dynamics and river network rearrangements are widely thought to shape the diversity of Neotropical freshwater fishes, the most species-rich continental vertebrate fauna on Earth. Yet the effects of hydrogeographic changes on fish dispersal and diversification remain poorly understood. Here we integrate an unprecedented occurrence dataset of 4,967 South American freshwater fish species with a species-dense phylogeny to track the evolutionary processes associated with hydrogeographic events over 100 Ma. Net lineage diversification was heterogeneous through time, across space, and among clades. Three abrupt shifts in diversification rates occurred during the Paleogene (between 63 and 23 Ma) in association with major landscape evolution events, and net diversification accelerated from the Miocene to the Recent (c. 20 – 0 Ma). The Western Amazon exhibited the highest rates of in situ diversification and was also the most important source of species dispersing to other regions. All regional biotic interchanges were associated with documented hydrogeographic events and the formation of biogeographic corridors, including Early Miocene (c. 20 Ma) uplift of the Serra do Mar, and Late Miocene (c. 10 Ma) uplift of the Northern Andes and formation of the modern transcontinental Amazon River. Reciprocal mass dispersal of fishes between the Western and Eastern Amazon coincided with this phase of Andean uplift. The Western Amazon has the highest contemporary levels of species richness and phylogenetic endemism. Our results support the hypothesis that landscape dynamics were constrained by the history of drainage basin connections, strongly affecting the assembly and diversification of basin-wide fish faunas.

Significance Statement

Despite progress in mapping geographic distributions and genealogical relationships, scientists have few clear answers about the origins of South American freshwater fishes, the most diverse vertebrate fauna on Earth. Here we used the most complete dataset of geographic distributions and evolutionary relationships of South American fishes to track how the geological history of river dynamics influenced the origin, extinction, and interchange of species over the past 100 Ma. We found abrupt increases of species origination between 66 and 23 Ma, coinciding with repeated uplifts of the Andes. The Western Amazon region served as source of freshwater fishes to other regions, as a place where species tended to persist over longer historical periods, and where species originations occurred with higher frequency.
Combining δ13C and δ15N from bone and dentine in marine mammal palaeoecological research: insights from toothed whales
Authors: Rey-Iglesia Alba , Wilson Tess , Routledge Jennifer , Skovrind Mikkel , Garde Eva , Heide-Jørgensen Mads Peter , Szpak Paul , Lorenzen Eline D.
Published: December 2021

Stable carbon (δ13C) and nitrogen (δ15N) isotope compositions of bone and dentine collagen extracted from museum specimens have been widely used to study the paleoecology of past populations. Due to possible systematic differences in stable isotope values between bone and dentine, dentine values need to be transformed into bone-collagen equivalent using a correction factor to allow comparisons between the two collagen sources. Here, we provide correction factors to transform dentine δ13C and δ15N values into bone-collagen equivalent for two toothed whales: narwhal and beluga.

We sampled bone and tooth dentine from the skulls of 11 narwhals and 26 belugas. In narwhals, dentine was sampled from tusk and embedded tooth; in beluga, dentine was sampled from tooth. δ13C and δ15N were measured and intraindividual bone and dentine isotopic compositions were used to calculate correction factors for each species.

We detected differences in δ13C and δ15N. In narwhals, we found (i) lower average δ13C and δ15N in bone compared with dentine; (ii) no difference in dentine δ13C between tusk and embedded tooth. For belugas, we also detected lower δ13C and δ15N in bone compared with tooth dentine. The correction factors provided by the study enable the combined analysis of stable isotope data from bone and dentine in these species.
Mechanistic insights of radiation-induced endothelial senescence impelling glioblastoma genomic instability at relapse
Authors: Degorre Charlotte , Renoult Ophélie , Parplys Ann Christin , Awada Hala , Clavreul Anne , Pietri Manon , Oliver Lisa , Joalland Noemie , Ricoul Michelle , Gratas Catherine , Vallette François , Borgmann Kirsten , Sabatier Laure , Pecqueur Claire , Paris François
Published: December 2021

Despite aggressive clinical protocol, all glioblastoma (GBM) recur at the initial site within the irradiated peritumoral microenvironment. Whereas irradiated microenvironment has been recently proposed to accelerate GBM relapse, molecular and cellular mechanisms remain unknown. Here, using relevant in vitro and in vivo models, we decipher how radiation-induced endothelial senescence drives the emergence of aggressive GBM cells. Secretome (SASP) of radiation-induced senescent (RIS) endothelium enhances genomic instability and intratumoral heterogeneity in irradiated GBM cells. In-depth molecular studies revealed that CXCL5 and CXCL8, from the SASP, activate CXCR2 receptor on tumor cells leading to increased DNA hyper-replication, micronuclei formation and aneuploidy. Importantly, through CXCL5/8-CXCR2 axis activation, this SASP increases GBM aggressiveness in vivo. Both chemokines were detected in relapsing, but not primary, GBM biopsies and positively correlated with worst patient outcome. In conclusion, we identify new molecular and preclinical insights of relapsing GBM aggressiveness where RIS vascular niches fuel aggressive tumor emergence.
Acute and chronic physical activity improve spatial pattern separation in humans
Authors: Butavand Daniela Ramirez , Rodríguez María F. , Cifuentes María V. , Miranda Magdalena , Bauza Cristian García , Bekinschtein Pedro , Ballarini Fabricio
Published: December 2021

Physical activity benefits both fitness and cognition. However, its effect on long-term memory is unclear. Successful memory involves not only remembering information over time but also keeping memories distinct and less confusing. The ability to separate similar experiences into distinct memories is one of the main features of episodic memory. In this work, we evaluated the effect of acute and chronic physical activity on a new task to assess spatial pattern separation in a 3D virtual reality environment. We manipulated the load of memory similarity and found that 25 minutes of cycling after encoding - but not before retrieval - was sufficient to improve similar, but not dissimilar memories, 24 hours after encoding. Furthermore, we found that participants who engaged in regular physical activity, but not sedentary subjects, showed memory for the similar condition the next day. Thus, physical activity could be a simple way to improve discrimination of spatial memories in humans.
CRCM5484: A BET- BDII Selective Compound With Differential Anti-Leukemic Drug Modulation
Authors: Carrasco Kendall , Montersino Camille , Derviaux Carine , Saez-Ayala Magali , Hoffer Laurent , Restouin Audrey , Castellano Rémy , Casassa Justine , Roche Philippe , Pasquier Eddy , Combes Sébastien , Morelli Xavier , Collette Yves , Betzi Stéphane
Published: December 2021

Differentially screening the Fr-PPIChem chemical library on the BET BRD4-BDII versus -BDI bromodomains led to the discovery of a BDII selective tetrahydropyridothienopyrimidinone (THPTP)-based compound. Structure-activity relationship (SAR) and hit-to-lead approaches allowed us to develop CRCM5484, a potent inhibitor of BET proteins with a preferential and 475-fold selectivity for the second bromodomain of the BRD3 protein (BRD3-BDII) over its first bromodomain (BRD3-BDI). Its very low activity was demonstrated in various cell-based assays, corresponding with recent data describing other selective BDII compounds. However, screening on a drug sensitivity and resistance-profiling platform revealed its ability to modulate the anti-leukemic activity in combination with various FDA-approved and/or in-development drugs in a cell- and context-dependent differential manner. Altogether, the results confirm the originality of the THPTP molecular mode of action in the BD cavity and its potential as starting scaffold for the development of potent and selective bromodomain inhibitors.
BRG1 defines a genomic subset of inflammatory genes transcriptionally controlled by the glucocorticoid receptor
Authors: Mechtidou Aikaterini , Greulich Franziska , Strickland Benjamin A. , Jouffe Céline , Cernilogar Filippo M. , Schotta Gunnar , Uhlenhaut N. Henriette
Published: December 2021

Glucocorticoids (such as Dexamethasone) are commonly used immunomodulatory drugs with potent anti-inflammatory effects, whose mechanisms of action remain incompletely understood. They bind to the Glucocorticoid Receptor (GR), a nuclear hormone receptor that acts as a transcription factor to directly control the expression of inflammatory genes. To elucidate the complex molecular mechanisms employed by GR during the suppression of innate immune responses, we have performed proteomics, ChIP-seq, ATAC-seq, RNA-seq and bioinformatics together with genetic and pharmacological loss of function studies in primary mouse macrophages. We found that GR interacts with the ATP-dependent SWI/SNF chromatin remodeling complex to regulate a specific subset of target genes. Here we show that the central catalytic subunit BRG1 is required not only for the transcriptional activation of classical GR target genes such as Fkbp5 or Klf9, but also for the transcriptional repression of cytokines and chemokines such as Ccl2, Cxcl10 or Il1a. We demonstrate that loss of BRG1 activity leads to reduced histone deacetylase (HDAC) function, and consequently increased histone acetylation, at these repressive GR binding sites. Altogether, our findings suggest that GR interacts with BRG1 to assemble a functional co-repressor complex at a defined fraction of macrophage cis-regulatory elements. These results may indicate additional non-classical, remodeling-independent functions of the SWI/SNF complex and may have implications for the development of future immunomodulatory therapies.

GRAPHICAL ABSTRACT

Graphical Abstract.

In macrophages (mΦ) responding to bacterial LPS and Dexamethasone, the Glucocorticoid Receptor (GR) activates target genes like Klf9 or Fkbp5 via interaction with the BRG1-containing SWI/SNF complex, chromatin remodeling and Mediator recruitment. At the same time, GR represses the expression of inflammatory cytokines and chemokines such as Ccl2, Cxcl10, Il1a etc. by assembling a BRG1-containing co-repressor complex and de-acetylating surrounding histone tails. Loss of BRG1 activity affects both the transcriptional activation and repression of a subset of myeloid GR target genes via distinct mechanisms. (iTF: inflammatory transcription factor; Ac: histone acetylation) (Created with BioRender.com.)
Generative language modeling for antibody design
Authors: Shuai Richard W. , Ruffolo Jeffrey A. , Gray Jeffrey J.
Published: December 2021

Discovery and optimization of monoclonal antibodies for therapeutic applications relies on large sequence libraries, but is hindered by developability issues such as low solubility, low thermal stability, high aggregation, and high immunogenicity. Generative language models, trained on millions of protein sequences, are a powerful tool for on-demand generation of realistic, diverse sequences. We present Immunoglobulin Language Model (IgLM), a deep generative language model for creating synthetic libraries by re-designing variable-length spans of antibody sequences. IgLM formulates antibody design as an autoregressive sequence generation task based on text-infilling in natural language. We trained IgLM on 558M antibody heavy- and light-chain variable sequences, conditioning on each sequence’s chain type and species-of-origin. We demonstrate that IgLM can generate full-length heavy and light chain sequences from a variety of species, as well as infilled CDR loop libraries with improved developability profiles. IgLM is a powerful tool for antibody design and should be useful in a variety of applications.