bluuebunny/crossref_metadata_2025 huggingface dataset:
A Metabolic Biomarker Panel for Congenital Heart Disease Assessment with Newborn Dried Blood Spots
Authors: Ceresnac Scott R. , Zhang Yaqi , Su Kuo Jung , Tang Qiming , Jin Bo , Schilling James , James Chou C. , Han Zhi , Floyd Brendan J. , Whitin John C. , Sylvester Karl G , Chubb Henry , Luo Ruben Y. , Tian Lu , Cohen Harvey J. , McElhinney Doff B. , Ling Xuefeng B.
Published: August 2023

Background

Congenital heart disease (CHD) represents a significant contributor to both morbidity and mortality in neonates and children. The prompt recognition of CHD can facilitate timely and appropriate intervention, reducing the probability of complications and enhancing the prognosis for impacted newborns. However, unlike other rare conditions routinely identified through federal and state newborn screening (NBS) programs, there’s currently no analogous dried blood spot (DBS) screening for CHD immediately after birth.

Objective

This study was set to identify reliable metabolite biomarkers with clinical relevance, with the aim to assess feasibility of screening and subtype classification of CHD utilizing the DBS newborn screening method.

Methods

We assembled a cohort of DBS datasets from the California Department of Public Health (CDPH) Biobank, encompassing both normal controls and three pre-defined CHD categories (tetralogy of Fallot, inherited arrhythmia syndrome, neonatal cardiomyopathy). A robust, DBS-oriented metabolomic method, employing both global and targeted strategies based on liquid chromatography with tandem mass spectrometry (LC-MS/MS), was developed. To verify the reliability of this metabolic profiling, we conducted a correlation analysis comparing the absolute quantitated metabolite concentration in DBS against the CDPH NBS records. Additionally, for hydrophilic and hydrophobic metabolites, we executed significant pathway and metabolite analyses respectively. Finally, logistic and LightGBM models were established to aid in CHD discrimination and classification.

Results

Our metabolomic workflow demonstrated consistent and reliable quantification of metabolites in DBS samples stored at the California Department of Public Health (CDPH) for up to 15 years. Through this process, we discerned dysregulated metabolic pathways in CHD patients, including deviations in lipid and energy metabolism, as well as oxidative stress pathways. Furthermore, we identified three metabolites as potential biomarkers for CHD assessment, and an additional twelve metabolites as potential markers for classifying different CHD subtypes within DBS samples.

Conclusions

This study represents the first attempt to validate metabolite profiling results using long-term storage DBS samples procured from the high-quality conditions of the CDPH biobank. The results unveil distinct metabolic discrepancies between various CHD subtypes and healthy controls. Furthermore, our findings highlight the potential clinical applications of our DBS-based methods for CHD screening and subtype classification.
Predictors of Population Estimates in a Critically Endangered Species of Black-and-White Colobus Monkeys
Authors: Wikberg Eva C. , Glotfelty Emily , Yeboah Bright Adu , Koranteng Robert , Kodom Charles , Anfwi Bismark Owusu , Boahen Afia
Published: August 2023

Population monitoring can help us determine population status and trajectory, but it is important to assess what factors may influence the number of individuals counted. In this study we conducted a complete count of the Critically EndangeredColobus vellerosusin the forests attached to the Boabeng and Fiema communities in central Ghana. We used 157 repeated counts of the same groups, including both good and unreliable counts to assess what factors predict the number of counted individuals in each group. The number of counted individuals increased with proxies for observation condition, observer experience, and habituation. We therefore recommend observer training and careful planning to increase the chances of having good observation. Then, we used the good counts to calculate the population size and group compositions. The obtained maximum number was 393 individuals in 25 groups. There were no significant differences in group sizes or immature to adult female ratios between groups occupying the older growth forest and groups in other forest types. Although there was still a relatively high immature to adult female ratio indicating that the population size may still increase, it does not appear to grow as rapidly as it used to, based on comparisons with previous population counts. Based on these findings, we recommend priority areas to promote conservation success.
Examining Differences in the Genetic and Functional Architecture of ADHD Diagnosed in Childhood and Adulthood
Authors: Breunig Sophie , Lawrence Jeremy M. , Foote Isabelle F. , Gebhardt Hannah J. , Willcutt Erik G. , Grotzinger Andrew D.
Published: August 2023

Background

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is diagnosed when symptoms onset in childhood. Here we investigate whether individuals who are diagnosed as children differ from those who are diagnosed in adulthood with respect to shared and unique architecture at the genome-wide, functional, and gene expression level of analysis.

Methods

We utilize Genomic SEM to investigate the differences in genetic correlations of childhood and adulthood diagnosed ADHD with 98 behavioral, psychiatric, cognitive, and health outcomes. We go on to apply Stratified Genomic SEM and transcriptome-wide SEM (T-SEM) to identify functional annotations and patterns of gene expression associated with genetic risk sharing or divergence across the ADHD subgroups.

Results

Relative to the childhood subgroup, adulthood diagnosed ADHD exhibited a significantly larger negativergwith educational attainment, the noncognitive skills of educational attainment, and age at first sexual intercourse. We also observe a larger positivergfor adulthood diagnosed ADHD with major depression, suicidal ideation, loneliness, and a latent internalizing factor. At the functional and gene expression levels, Stratified Genomic SEM and T-SEM analyses revealed three annotations and 22 genes, respectively, that were significantly associated with genetic risk sharing across the subtypes.

Conclusion

This project demonstrates that ADHD diagnosed later in life shows much stronger genetic overlap with internalizing disorders and related traits, indicating the potential clinical relevance of distinguishing these subgroups. Given shared clinical features across internalizing disorders and ADHD (e.g., difficulty concentrating) one interpretation is that the internalizing spectrum is often misdiagnosed as ADHD in adulthood.
Ground level utility of AWaRe Classification: Insights from a Tertiary Care Center In North India
Authors: Negi Gunjita , KB Arjun , Panda Prasan Kumar
Published: August 2023

Background

The overuse and misuse of antimicrobials contribute significantly to antimicrobial resistance (AMR), which is a global public health concern. India has particularly high rates of antimicrobial resistance, posing a threat to effective treatment. The WHO AWaRe classification system was introduced to address this issue and guide appropriate antibiotic prescribing. However, there is a lack of studies examining the prescribing patterns of antimicrobials using the AWaRe classification, especially in North India. Therefore, this study aimed to assess the prescribing patterns of antimicrobials using the WHO AWaRe classification in a tertiary care centre in North India.

Aim

To study the prescribing patterns of antimicrobials using WHO AWaRe classification through a cross-sectional study in AIIMS Rishikesh.

Methods

A descriptive, cross-sectional study was conducted from July 2022 to August 2022 at a tertiary care hospital. Prescriptions containing at least one antimicrobial were included in the study. Data on prescriptions, including patient demographics, departments, types of antimicrobials prescribed, and duration of treatment, were collected. A questionnaire-based survey was also conducted to assess the knowledge and practices of prescribing doctors regarding the utility of AWaRe classification.

Results

A total of 123 patients were included in the study, with antibiotic prescriptions being written for all of them. Most prescriptions were for inpatients, evenly distributed between Medicine and Surgical departments. Metronidazole and Ceftriaxone were the most prescribed antibiotics. According to the AWaRe classification, 57.61% of antibiotics fell under the Access category, 38.27% in Watch, and 4.11% in Reserve. The majority of Access antibiotics were prescribed in the Medicine department, while Watch antibiotics were more common in the Medicine department as well. The questionnaire survey showed that only a third of participants were aware of the AWaRe classification, and there was a lack of knowledge regarding antimicrobial resistance and the potential impact of AWaRe usage.

Conclusion

This study highlights the need for better antimicrobial prescribing practices and increased awareness of the WHO AWaRe classification and antimicrobial resistance (AMR) among healthcare professionals. The findings indicate a high proportion of prescriptions falling under the Access category, suggesting appropriate antibiotic selection. However, there is a significant difference between the WHO DDD and the prescribed daily dose in the analysed prescriptions suggesting overuse and underuse of antibiotics. There is room for improvement and educational interventions and antimicrobial stewardship programs should be implemented to enhance knowledge and adherence to guidelines, ultimately contributing to the containment of antimicrobial resistance.
TikTok is an effective platform for bicycle safety injury prevention education
Authors: Witte Michelina M. , McEvoy Joey M. , Hotz Gillian A.
Published: August 2023

Social media is an efficient way to spread information, given its widespread daily use by the general population. While it has been shown that public health information can be rapidly disseminated, whether the newer social media platform, TikTok, is effective for this purpose has yet to be explored. The goal of this study is to determine the effectiveness of TikTok to educate about bicycle safety. The TikTok account “iBikeSafe” was created to disseminate injury prevention information related to bicycle safety. Data collected was both qualitative (video classification, comment categorization) and quantitative (likes, views, comments). Performance data was compared between TikTok and another video-sharing social media platform (YouTube). Posts that were didactic (or educational) in nature yielded more views, likes, and comments than posts that were fun or casual in nature. Almost half (46%) of comments made by users on iBikeSafe’s TikTok videos were made to constructively further the discussion and to educate others with accurate injury prevention information. Five of the six videos that were adapted from the iBikeSafe YouTube channel for use on TikTok garnered exponentially more views on TikTok (from 118% to 2057%) than on YouTube, despite having less followers/subscribers (759 TikTok vs. 977 YouTube) and being in existence for less time (11 months vs. 8 years). TikTok is an effective platform for injury prevention education. Didactic posts best provide users with the ability to engage with content and to discuss takeaways, while fun posts keep users active within the platform. Both educational and fun types of videos play an integral role in the effective use of this platform for bicycle safety education. Consideration should be taken into account for the appropriate ratio of didactic vs. fun posts for information dissemination in any public health educational campaign making use of this platform.
Trans-ancestry polygenic models for the prediction of LDL blood levels: An analysis of the UK Biobank and Taiwan Biobank
Authors: Hassanin Emadeldin , Lee Ko-Han , Hsieh Tzung-Chien , Aldisi Rana , Lee Yi-Lun , Bobbili Dheeraj , Krawitz Peter , May Patrick , Chen Chien-Yu , Maj Carlo
Published: August 2023

Background

Polygenic risk scores (PRSs) are proposed for use in clinical and research settings for risk stratification. PRS predictions often show bias toward the population of available genome-wide association studies, which is typically of European ancestry. This study aims to assess the performance differences of ancestry-specific PRS and test the implementation of multi-ancestry PRS to enhance the generalizability of low-density lipoprotein (LDL) cholesterol predictions in the East Asian population

Methods

We computed ancestry-specific and multi-ancestry PRS for LDL using data from the global lipid consortium while accounting for population-specific linkage disequilibrium patterns using PRS-CSx method. We first conducted an ancestry-wide analysis using the UK Biobank dataset (n=423,596) and then applied the same models to the Taiwan Biobank dataset (TWB, n=68,978). PRS performances were based on linear regression with adjustment for age, sex, and principal components. PRS strata were considered to assess the extent to which a PRS categorization can stratify individuals for LDL cholesterol levels in East Asian samples.

Results

Population-specific PRS better predicted LDL levels within the target population but multi-ancestry PRS were more generalizable. In the TWB dataset, covariate-adjusted R2values were 9.3% for ancestry-specific PRS, 6.7% for multi-ancestry PRS, and 4.5% for European-specific PRS. Similar trends (8.6%, 7.8%, 6.2%) were observed in the smaller East Asian population of the UK Biobank (n=1,480). Consistent with the R2values, PRS stratification in East Asians (TWB) effectively captured a heterogenous variability in LDL blood cholesterol levels across PRS strata. The mean difference in LDL levels between the lowest and highest East Asian-specific PRS (EAS_PRS) deciles was 0.82, compared to 0.59 for European-specific PRS (EUR_PRS) and 0.76 for multi-ancestry PRS. Notably, the mean LDL values in the top decile of multi-ancestry PRS were comparable to those of EAS_PRS (3.543 vs. 3.541,P=0.86).

Conclusions

Our analysis of the PRS prediction model for LDL cholesterol further supports the issue of PRS generalizability across populations. Our targeted analysis of the East Asian (EAS) population revealed that integrating non-European genotyping data, accounting for population-specific linkage disequilibrium, and considering meta-analyses of non-European-based GWAS alongside powerful European-based GWAS can enhance the generalizability of LDL PRS.
Health Economics Assessment of Statin Therapy Initiation Thresholds for Atherosclerosis Prevention in China: a Cost-Effectiveness Analysis
Authors: Feng Tianyu , Zhang Xiaolin , Xu Jiaying , Gao Shang , Yu Xihe
Published: August 2023

Background

The latest revised Chinese guidelines for the management of dyslipidemia have lowered the 10-year risk threshold for initiating statins for primary prevention of atherosclerotic heart disease. The aim of this study was to examine the negative impact of different statin treatment initiation thresholds on diabetes in a Chinese population and to assess their health economics value.

Methods

In this study, we constructed an event probability-based Microsimulation model to assess the health economics value of statin therapy. The model was based on the Prediction for atherosclerotic cardio-vascular disease (ASCVD) risk in China (China-PAR) and used data from a nationally representative survey and published meta-analysis of the Chinese middle-aged and elderly population as input. We evaluated four different strategies: a 7.5% 10-year risk threshold strategy, a guideline strategy, a 15% 10-year risk threshold strategy, and a 20% 10-year risk threshold strategy. Additionally, we calculated the incremental cost per quality-adjusted life year (QALY) obtained for each strategy to better understand the economics of the various strategies.

Result

The incremental cost per QALY for the 10% 10-year risk threshold strategy, compared to the untreated, was $52,218.75. The incremental cost per QALY for the guideline strategy, compared to the 7.5% 10-year risk threshold strategy, was $464,614.36. These results were robust in most sensitivity analyses.

Conclusion

The current 10-year ASCVD risk thresholds used in China’s dyslipidemia management guidelines are cost-effective in preventing ASCVD events and should be maintained with the current statin initiation thresholds. Relaxing the initiation threshold as willingness to pay increases would be more cost-effective.
COVID-19 among migrants, refugees, and internally displaced persons: systematic review, meta-analysis and qualitative synthesis of the global empirical literature
Authors: Hintermeier Maren , Gottlieb Nora , Rohleder Sven , Oppenberg Jan , Baroudi Mazen , Pernitez-Agan Sweetmavourneen , Lopez Janice , Flores Sergio , Mohsenpour Amir , Wickramage Kolitha , Bozorgmehr Kayvan
Published: August 2023

Background

Pandemic response and preparedness plans aim at mitigating the spread of infectious diseases and protecting public health, but migrants are often side-lined. Evidence amounted early that migrants are disproportionately affected by the COVID-19 pandemic and its consequences. However, synthesised evidence is lacking that quantifies the inequalities in infection risk and disease outcomes, or contextualises the consequences of pandemic measures and their underlying mechanisms.

Methods

Systematic review searching 25 databases and grey literature (12/2019 to 11/2021). We considered empirical articles covering migrants, refugees, asylum-seekers, and internally displaced persons reporting SARS-CoV-2 cases, hospitalisation, ICU admission, mortality, COVID-19 vaccination rates or health consequences of pandemic measures. Random-effects meta-analysis of observational studies and qualitative analysis were performed for evidence synthesis. A Protocol was registered with PROSPERO (CRD42021296952).

Findings

Out of 6956 studies, we included 241 in the review. For the quantitative studies (n=46), meta-analysis with over 40 million study participants showed that compared to non-migrants, migrants have an elevated risk of infection (RR = 2·33; 95%-CI: 1·88-2·89) but similar risk for hospitalisation (RR = 1·05; 0·80-1·37), while the likelihood of ICU admission was higher (RR = 1·36; 1·04-1·78). Among those hospitalised, migrants had a lower risk of mortality (RR = 0·47; 0·30-0·73), while their population-based excess mortality tended to be higher (RR = 1·31; 0·95-1·80). The qualitative synthesis (n=44) highlighted the complex interplay of social and COVID-19-related factors at different levels. This involved increased exposure, risk, and impact of pandemic measures that compromised the health of migrants.

Interpretation

Even in the advanced stages of the pandemic, migrants faced higher infection risks and disproportionately suffered from the consequences of COVID-19 disease, including deaths. Population-level interventions in future health emergencies must better consider socio-economic, structural and community-level exposures to mitigate risks among migrants and enhance health information systems, to close coverage gaps in migrant groups.

Funding

None.
Chloroform associated with bone mineral density and bone mineral content in adults: a population-based cross-sectional research
Authors: Li Lin , Liu XK , Zhang Xia , Zhang Yan , Li Qing , Geng HF , Shi Li , Wang Ben , Qiu QQ , Yu TP , Sang YQ , Wang LY , Xu Wei , Liang Jun
Published: August 2023

Background

According to a recent cross-sectional study, reduced Bone Mineral Density (BMD) in U.S. adults is associated with co-exposure to several Volatile Organic Compounds (VOCs), and contact with VOCs increases the risk of developing osteoporosis. However, the relationship between chloroform (an essential VOC component) and BMD remains unclear. Consequently, we aimed to explore the relationship between chloroform alone and Bone Mineral Density or Bone Mineral Content (BMD or BMC).

Methods

Herein, 2,553 individuals aged 18 and above from the National Health and Nutrition Examination Surveys (NHANES) in 2009-2010, 2013-2014, and 2017-2020, were included. We employed two independent t-tests and multi-linear regression models to statistically assess the relationship between chloroform exposure and BMD/BMC in the spine and femoral area.

Results

A “V”-shaped correlation between chloroform exposure and BMD/BMC was observed in the unadjusted model, particularly in the Ward’s triangle and femoral neck as a whole. A negative correlation was specifically observed for the Ward’s triangle BMD/BMC and L4 BMD/BMC. On the other hand, in the adjusted model, a dominantly negative correlation between the L4 BMC and chloroform exposure was observed over a range of exposure levels. The subgroup analysis revealed a negative correlation between chloroform concentrations and BMC in the femur and spine, especially in women and the 65-80 age population.

Conclusion

Our study revealed a “V” shaped correlation between chloroform and BMD/BMC of the femur and spine in U.S. adults. This finding highlights the fact that prolonged exposure to chloroform may increase the risk of developing osteoporosis.
The Sidelines Effect on Minds: The Impact of Injury on Mental Health in National Collegiate Athletic Association Athletes
Authors: Axton Ruth A. , Crowell Nancy A. , Merenstein Daniel J.
Published: August 2023

Injury and mental health are prevalent topics in among NCAA Division 1 (DI) student-athletes; however, there is limited literature regarding the impact of injury on student-athletes’ mental health. This study examined the impact of injury on social support and self-stigma and the relationship between athletic identity and self-stigma. A convenience sample survey yielded 101 responses from DI student-athletes. The survey was composed of demographic questions, Sarason Social Support Questionnaire, Self-Stigma for Seeking Self-Help Scale, and Athletic Identity Measurement Scale. There was no significant difference between injured and non-injured athletes in the mean scores of social support (t test p= 0.69) or self-stigma (t test p =0.92). There was a nonsignificant weak correlation between athletic identity and self-stigma. The results reveal that self-stigma is prevalent within this community, with an average score of 23.34 for all respondents. These conclusions can aid mental health professionals in providing support and education to student-athletes.
Work Attendance during Acute Respiratory Illness Before and During the COVID-19 Pandemic, United States, 2018–2022
Authors: Ahmed Faruque , Nowalk Mary Patricia , Zimmerman Richard K. , Bear Todd , Grijalva Carlos G. , Talbot H. Keipp , Florea Ana , Tartof Sara Y. , Gaglani Manjusha , Smith Michael , McLean Huong Q. , King Jennifer P. , Martin Emily T. , Monto Arnold S. , Phillips C. Hallie , Wernli Karen J. , Flannery Brendan , Chung Jessie R. , Uzicanin Amra
Published: August 2023

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and influenza viruses can be transmitted by infected persons who are pre-symptomatic or symptomatic. To assess impact of the COVID-19 pandemic on work attendance during illness, we analyzed prospectively collected data from persons with acute respiratory illness (ARI) enrolled in a multi-state study during 2018–2022. Persons with prior experience working from home were significantly less likely than those without this experience to work onsite on the day before illness and during the first 3 days of illness; the effect was more pronounced for the COVID-19 pandemic period than the pre-pandemic influenza seasons. Persons with influenza or COVID-19 were significantly less likely to work onsite than persons with other ARIs. Among persons for whom positive COVID-19 test results were available by the second or third day of illness, few worked onsite. Work-from-home policies may reduce the likelihood of workplace exposures to respiratory viruses.

Article’s summary line

Work-from-home policies may reduce the likelihood of workplace exposures to SARS-CoV-2 and influenza viruses.
An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants
Authors: Nmezi Bruce , Bey Guillermo Rodriguez , Oranburg Talia DeFrancesco , Dudnyk Kseniia , Lardo Santana M. , Herdman Nathan , Jacko Anastasia , Rubio Sandy , Alcocer Emanuel Loeza , Kofler Julia , Kim Dongkyeong , Rankin Julia , Kivuva Emma , Gutowski Nicholas , Schon Katherine , van den Ameele Jelle , Chinnery Patrick F. , Sousa Sérgio B. , Palavra Filipe , Toro Camilo , Pinto e Vairo Filippo , Saute Jonas , Pan Lisa , Alturkustani Murad , Hammond Robert , Gros-Louis Francois , Gold Michael , Park Yungki , Bernard Geneviève , Raininko Raili , Zhou Jian , Hainer Sarah J. , Padiath Quasar S.
Published: August 2023

The role of non-coding regulatory elements and how they might contribute to tissue type specificity of disease phenotypes is poorly understood. Autosomal Dominant Leukodystrophy (ADLD) is a fatal, adult-onset, neurological disorder that is characterized by extensive CNS demyelination. Most cases of ADLD are caused by tandem genomic duplications involving the lamin B1 gene (LMNB1) while a small subset are caused by genomic deletions upstream of the gene. Utilizing data from recently identified families that carryLMNB1gene duplications but do not exhibit demyelination, ADLD patient tissues, CRISPR modified cell lines and mouse models, we have identified a novel silencer element that is lost in ADLD patients and that specifically targets overexpression to oligodendrocytes. This element consists of CTCF binding sites that mediate three-dimensional chromatin looping involving theLMNB1and the recruitment of the PRC2 repressor complex. Loss of the silencer element in ADLD identifies a previously unknown role for silencer elements in tissue specificity and disease causation.
Assay for characterizing adsorption-properties of surfaces (APS) used for sample preparation prior to quantitative omics
Authors: Siebels Bente , Moritz Manuela , Hübler Diana , Gocke Antonia , Voß Hannah , Schlüter Hartmut
Published: August 2023

Analytes during their journey from their natural sources to their identification and quantification are prone to adsorption to surfaces before they enter an analytical instrument, causing false quantities. This problem is especially severe in diverse omics. Here, thousands of analytes with a broad range of chemical properties and thus different affinities to surfaces are quantified within a single analytical run. For quantifying adsorption effects caused by surfaces of sample handling tools, an assay was developed, applying LC-MS/MS-based differential bottom-up proteomics and as probe a reference mixture of thousands of tryptic peptides, covering a broad range of chemical properties. The assay was tested by investigating the adsorption properties of several vials composed of polypropylene, including low-protein-binding polypropylene vials, borosilicate glass vials and low-retention glass vials. In total 3531 different peptides were identified and quantified across all samples and therefore used as probes. A significant number of hydrophobic peptides adsorbed on polypropylene vials. In contrast, only very few peptides adsorbed to low-protein-binding polypropylene vials. The highest number of peptides adsorbed to glass vials, driven by electrostatic as well as hydrophobic interactions. Calculation of the impact of the adsorption of peptides on differential quantitative proteomics showed significant false results. In summary, the new assay is suitable to characterize adsorption properties of surfaces getting into contact with analytes during sample preparation, thereby giving the opportunity to find parameters for minimizing false quantities.

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A robust genome and assembly with transcriptomic data from the striped scorpion,Centruroides vittatus
Authors: Yamashita Tsunemi , Rhoads Douglas D. , Pummill Jeff
Published: August 2023

Scorpions, a seemingly primitive, stinging arthropod taxa, are known to exhibit marked diversity in their venom components. These venoms are known for their human pathology, but also important as models for therapeutic and drug development applications. We report a high quality genome assembly and annotation of the striped bark scorpion,Centruroides vittatus, created with several shotgun libraries. The final assembly is 760 Mb in size, with a BUSCO score of 97.8%, a 30.85% GC, and a N50 of 2.35 Mb. We estimated 36,189 proteins with 37.32% assigned to GO terms in our GOanna analysis. We were able to map 2011 and 60 venom toxin genes to contigs and scaffolds, respectively. We were also able to identify expression differences between venom gland (telson) and body tissue (carapace) with 19 Sodium toxin and 14 Potassium toxin genes to 18 contigs and two scaffolds. This assembly along with our transcriptomic data, provides further data to investigate scorpion venom genomics.
Quantification of biases in predictions of protein-protein binding affinity changes upon mutations
Authors: Tsishyn Matsvei , Pucci Fabrizio , Rooman Marianne
Published: August 2023

Understanding the impact of mutations on protein-protein binding affinity is a key objective for a wide range of biotechnological applications and for shedding light on disease-causing mutations, which are often located at protein-protein interfaces. Over the past decade, many computational methods using physics-based and/or machine learning approaches have been developed to predict how protein binding affinity changes upon mutations. They all claim to achieve astonishing accuracy on both training and test sets, with performances on standard benchmarks such as SKEMPI 2.0 that seem overly optimistic. Here we benchmarked eight well-known and well-used predictors and identified their biases and dataset dependencies, using not only SKEMPI 2.0 as a test set but also deep mutagenesis data on the SARS-CoV-2 spike protein in complex with the human angiotensin-converting enzyme 2. We showed that, even though most of the tested methods reach a significant degree of robustness and accuracy, they suffer from limited generalizability properties and struggle to predict unseen mutations. Interestingly, the generalizability problems are more severe for pure machine learning approaches while physics-based methods are less affected by this issue. Moreover, undesirable prediction biases towards specific mutation properties, the most marked being towards destabilizing mutations, are also observed and should be carefully considered by method developers. We conclude from our analyses that there is room for improvement in the prediction models and suggest ways to check, assess and improve their generalizability and robustness.
Remote ischemic conditioning modulates inflammatory response and metabolic pathways
Authors: Torres-Querol Coral , Pamplona Reinald , Arqué Gloria , Purroy Francisco
Published: August 2023

Remote ischemic conditioning (RIC) is an endogenous procedure that reduces ischemic injury by repeated transient mechanical obstruction of vessels at a remote limb. However, the specific mechanism of this protective phenomenon remains incompletely understood. We aimed to study perturbations in the brain and plasma metabolome following RIC as well as to identify potential novel inflammatory cytoprotective targets.

A mouse model of transient focal cerebral ischemia by compressing the distal middle cerebral artery was used. Multiplex cytokine assay was performed in plasma samples. Blood plasma and brain samples were collected and metabolomes analyzed using non-targeted LC-MS.

The analysis revealed a moderate impact on the brain metabolome compared to circulatory metabolites following RIC intervention. Interestingly, 3 plasma metabolites, Cer(42:3), HexCer(36:1) and TG(28:0), stood out as highly significantly upregulated. Moreover, RIC applied during the ischemia (RIPerC) and after the ischemia (RIPostC) protect against cerebral ischemia-reperfusion injury by modulating the peripheral immunomodulation.

This study indicated that RIC neuroprotection is present in ischemic mice via the inflammatory response and metabolic changes both in the peripheral blood and ischemic brain.
Neural attentional filters and behavioural outcome follow independent individual trajectories over the adult life span
Authors: Tune Sarah , Obleser Jonas
Published: August 2023

Preserved communication abilities promote healthy aging. To this end, the age-typical loss of sensory acuity might in part be compensated for by an individual’s preserved attentional neural filtering. Is such a compensatory brain–behaviour link longitudinally stable? Can it predict individual change in listening behaviour? We here show that individual listening behaviour and neural filtering ability follow largely independent developmental trajectories modelling electroencephalographic and behavioural data of N = 105 aging individuals (39–82 yrs). First, despite the expected decline in hearing- threshold–derived sensory acuity, listening-task performance proved stable over 2 years. Second, neural filtering and behaviour were correlated only within each separate measurement timepoint (T1, T2). Longitudinally, however, our results raise caution on attention-guided neural filtering metrics as predictors of individual trajectories in listening behaviour: Neither neural filtering at T1 nor its two-year change could predict individual two-year behavioural change, under a combination of modelling strategies.
A comparison of clustering models for inference of T cell receptor antigen specificity
Authors: Hudson Dan , Lubbock Alex , Basham Mark , Koohy Hashem
Published: August 2023

The vast potential sequence diversity of TCRs and their ligands has presented an historic barrier to computational prediction of TCR epitope specificity, a holy grail of quantitative immunology. One common approach is to cluster sequences together, on the assumption that similar receptors bind similar epitopes. Here, we provide an independent evaluation of widely used clustering algorithms for TCR specificity inference, observing some variability in predictive performance between models, and marked differences in scalability. Despite these differences, we find that different algorithms produce clusters with high degrees of similarity for receptors recognising the same epitope. Our analysis highlights an unmet need for improvement of complex models over a simple Hamming distance comparator, and strengthens the case for use of clustering models in TCR specificity inference.
MRI-based cell tracking of OATP-expressing cell transplants by pre-labeling with Gd-EOB-DTPA
Authors: Bhattacharyya Tapas , Mallett Christiane L. , Shapiro Erik M.
Published: August 2023

Purpose

To detect cell transplants labeled with a clinical gadolinium-based contrast agent as hyperintense signals using a clinically familiar T1-weighted MRI protocol.

Methods

HEK293 cells were stably transduced to express human OATP1B3, a hepatic transporter that transport Gd-EOB-DTPA into cells that express the transporters, the intracellular accumulation of which cells causes signal enhancement on T1-weighted MRI. Cells were labeled in media containing Gd-EOB-DTPA for MRI evaluation and indocyanine green for cryofluorescence tomography validation. Labeled cells were injected into chicken hearts, in vitro, after which MRI and cryofluorescence tomography were performed in tandem.

Results

OATP1B3-expressing cells had substantially reduced T1 following labeling with Gd-EOB-DTPA in culture. Following their implantation into chicken heart, these cells were easily identified in T1-weighted MRI. Cryofluorescence tomography validated that the areas of signal enhancement in MRI overlapped with areas of indocyanine green signal, indicating that signal enhancement was due to the transplanted cells.

Conclusion

OATP1B3-expressing cells can be pre-labeled with Gd-EOB-DTPA prior to injection into tissue, affording the use of clinically familiar T1-weighted MRI to robustly detect cell transplants.
Periods of environmental sensitivity couple larval behavior and development
Authors: Faerberg Denis F. , Aprison Erin Z. , Ruvinsky Ilya
Published: August 2023

Summary

The typical life cycle in most animal phyla includes a larval period that bridges embryogenesis and adulthood1. Despite the great diversity of larval forms, all larvae grow, acquire adult morphology and function, while navigating their habitats to obtain resources necessary for development. How larval development is coordinated with behavior remains substantially unclear. Here, we describe features of the iterative organization of larval stages that serve to assess the environment and procure resources prior to costly developmental commitments. We found that male-excreted pheromones accelerate2-4the onset of adulthood inC. eleganshermaphrodites by coordinately advancing multiple developmental events and growth during the last larval stage. The larvae are sensitive to the accelerating male pheromones only at the end of the penultimate larval stage, just before the acceleration begins. Other larval stages also contain windows of sensitivity to environmental inputs. Importantly, behaviors associated with search and consumption of food are distinct between early and late portions of larval stages. We infer that each larval stage inC. elegansis subdivided into two epochs: A) global assessment of the environment to identify the most suitable patch and B) consumption of sufficient food and acquisition of salient information for developmental events in the next stage. We predict that in larvae of other species behavior is also divided into distinct epochs optimized either for assessing the habitat or obtaining the resources. Thus, a major role of larval behavior is to coordinate the orderly progression of development in variable environments.

“Life is what happens to you when you’re busy making other plans.”

Allen Saunders (popularized by John Lennon)
Ontogeny of the organized nasopharynx-associated lymphoid tissue in rainbow trout
Authors: Garcia Benjamin J , Reyes Alexis , Martinez Chrysler , Serra dos Santos Yago , Salinas Irene
Published: August 2023

Understanding the ontogeny of teleost mucosa-associated lymphoid tissues (MALT) is critical for determining the earliest timepoint for effective mucosal vaccination of young fish. Here, we describe the developmental sequence that leads to the formation of an organized MALT structure in rainbow trout, the organized nasopharynx-associated lymphoid tissue (O-NALT). Control rainbow trout were sampled between 340 and 1860 degree days (DD) and routine histology and immunofluorescence staining were used to determine cellular changes in immune cells in the nasal cavity as well as O-NALT formation. We identified that O-NALT is first seeded by CD8α+T cells at 700DD followed by IgM+B cells and CD4-2b+T cells at 1000DD. Histomorphologically, trout O-NALT is fully formed at 1400DD when it is composed of 67% CD4-2b+cells, 20% IgM+cells, 13% CD8α+T cells, and no IgT+B cells. Whole body gene expression analyses uncovered waves ofigmh,cd4-2b, andcd8aexpression that recapitulate the cellular seeding sequence of O-NALT by specific lymphocyte subsets. Our results indicate that 1) O-NALT formation results from a specific sequence of lymphocyte subset colonization pioneered by CD8α+T cells and 2) the presence of the full O-NALT structure at 1400DD may mark this timepoint as the earliest developmental stage at which mucosal vaccines can induce long lasting, specific immune responses.
Antigen Geometry Tunes Mast Cell Signaling Through Distinct FcεRI Aggregation and Structural Changes
Authors: Rinaldi Derek A. , Kanagy William K. , Kaye Hannah C. , Grattan Rachel M. , Lucero Shayna R. , Pérez Marelessis Palomino , Wester Michael J. , Lidke Keith A. , Wilson Bridget S. , Lidke Diane S.
Published: August 2023

Immunoreceptor tyrosine-based activation motif (ITAM)-containing Fc receptors are critical components of the innate and adaptive immune systems. FcεRI mediates the allergic response via crosslinking of IgE-bound receptors by multivalent antigens. Yet, the underlying molecular mechanisms that govern the response of FcεRI to specific antigens remain poorly understood. We compared responses induced by two antigens with distinct geometries, high valency DNP-BSA and trivalent DF3, and found unique secretion and receptor phosphorylation profiles that are due to differential recruitment of Lyn and SHIP1. To understand how these two antigens can cause such markedly different outcomes, we used direct stochastic optical reconstruction microscopy (dSTORM) super-resolution imaging combined with Bayesian Grouping of Localizations (BaGoL) analysis to compare the nanoscale characteristics of FcεRI aggregates. DF3 aggregates were found to be smaller and more densely packed than DNP-BSA aggregates. Using lifetime-based Förster resonance energy transfer (FRET) measurements, we discovered that FcεRI subunits undergo structural rearrangements upon crosslinking with either antigen, and in response to interaction with monovalent antigen presented on a supported lipid bilayer. The extent of conformational change is positively correlated with signaling efficiency. Finally, we provide evidence for forces in optimizing FcεRI signaling, such that immobilizing DF3 on a rigid surface promoted degranulation while increasing DNP-BSA flexibility lowered degranulation. These results provide a link between the physical attributes of allergens, including size, shape, valency, and flexibility, and FcεRI signaling strength. Thus, the antigen modulates mast cell outcomes by creating unique aggregate geometries that tune FcεRI conformation, phosphorylation and signaling partner recruitment.

Statement of Significance

This work elucidates the molecular mechanisms underlying differential FcεRI signaling responses induced by antigens of distinct geometries. By combining super-resolution imaging and biophysical techniques, we demonstrate that the physical attributes of allergens, including shape, flexibility, and valency, modulate mast cell signaling outcomes by altering FcεRI aggregate organization and conformational states. This provides novel insights into the structure-function relationships governing FcεRI signal transduction and its role in mast cell activation. Overall, this work establishes a link between allergen physical properties and immune receptor signaling at the molecular level, with important implications for understanding and regulating allergic responses.
singletCode: synthetic barcodes identify singlets in scRNA-seq datasets and evaluate doublet algorithms
Authors: Zhang Ziyang , Melzer Madeline E. , Kiani Karun , Goyal Yogesh
Published: August 2023

Single-cell RNA sequencing datasets comprise true single cells, or singlets, in addition to cells that coalesce during the protocol, or doublets. Identifying singlets with high fidelity in single-cell RNA sequencing is necessary to avoid false negative and false positive discoveries. Although several methodologies have been proposed to infer true singlets and doublets, they typically rely on datasets being highly heterogeneous. Here we develop and apply singletCode, a computational framework that leverages datasets with synthetically introduced DNA barcodes for a hitherto unexplored application: to extract ground truth singlets. We demonstrate the feasibility of singlets extracted via singletCode to evaluate the performance and robustness of existing doublet detection methods. We find that existing doublet detection methods are not as sensitive as expected when tested on doublets simulated from experimentally realistic ground truth singlets. As DNA barcoded datasets are being increasingly reported, singletCode can identify singlets and inform rational choice of doublet detecting algorithms and their associated limitations.
A pro-inflammatory stem cell niche drives myelofibrosis through a targetable galectin 1 axis
Authors: Li Rong , Colombo Michela , Wang Guanlin , Rodriguez-Romera Antonio , O’Sullivan Jennifer , Clark Sally-Ann , Pérez Sáez Juan M. , Meng Yiran , Khan Abdullah O. , Wen Sean , Dong Pengwei , Zhou Wenjiang , Sousos Nikolaos , Murphy Lauren , Clarke Matthew , Jooss Natalie J. , Olijnik Aude-Anais , Wong Zoë C. , Karali Christina Simoglou , Sirinukunwattana Korsuk , Ryou Hosuk , Norfo Ruggiero , Cheng Qian , Brierley Charlotte K. , Carrelha Joana , Ren Zemin , Thongjuea Supat , Rathinam Vijay A , Krishnan Anandi , Royston Daniel , Rabinovich Gabriel A. , Mead Adam J , Psaila Bethan
Published: August 2023

Myeloproliferative neoplasms are stem cell-driven cancers associated with a large burden of morbidity and mortality. The majority of patients present with early-stage disease, but a substantial proportion progress to myelofibrosis and/or secondary leukemia, advanced cancers with a poor prognosis and high symptom burden. Currently, it remains difficult to predict progression, and we lack therapies that reliably prevent or reverse fibrosis development. A major bottleneck to the discovery of disease-modifying therapies has been an incomplete understanding of the interplay between perturbed cellular and molecular states. Several cell types have individually been implicated, but a comprehensive analysis of myelofibrotic bone marrow is lacking. We therefore mapped the crosstalk between bone marrow cell types in myelofibrotic bone marrow. We found that inflammation and fibrosis are orchestrated by a ‘quartet’ of immune and stromal cell lineages – with basophils and mast cells creating a TNF signaling hub, communicating with megakaryocytes, mesenchymal stromal cells and pro-inflammatory fibroblasts. We identified the ý-galactoside binding protein galectin 1 as a striking biomarker of progression to myelofibrosis and poor survival in multiple patient cohorts, and as a promising therapeutic target, with reduced myeloproliferation and fibrosisin vitroandin vivoand improved survival following galectin 1 inhibition. In human bone marrow organoids, TNF increased galectin 1 expression, suggesting a feedback loop wherein the pro-inflammatory MPN clone creates a self-reinforcing niche, fueling progression to advanced disease. This study provides a valuable resource for studying hematopoietic cell-niche interactions, with broad relevance for cancer-associated inflammation and disorders of tissue fibrosis.