bluuebunny/crossref_metadata_2025 huggingface dataset:
Activated factor X stimulates atrial endothelial cells and tissues to promote remodelling responses through AT1R/NADPH oxidases/SGLT1/2
Authors: Fakih Walaa , Mroueh Ali , Gong Dal-Seong , Kikuchi Shinnosuke , Pieper Michael Paul , Kindo Michel , Mazzucottelli Jean-Philippe , Mommerot Arnaud , Kanso Mohamad , Ohlmann Patrick , Morel Olivier , Schini-Kerth Valérie , Jesel Laurence
Published: May 2024

Aims

Atrial fibrillation (AF), the most common cardiac arrhythmia favouring ischemic stroke and heart failure involves left atrial remodelling, fibrosis and a complex interplay between cardiovascular risk factors. This study examined whether activated factor X (FXa) induces pro-remodelling and pro-fibrotic responses in atrial endothelial cells (AECs) and human atrial tissues and determined the underlying mechanisms.

Methods and results

AECs collected from porcine hearts and human right atrial appendages (RAA) from patients undergoing heart surgery. Protein expression levels were assessed by Western blot and immunofluorescence staining, mRNA levels by RT-qPCR, formation of reactive oxygen species (ROS) and NO using fluorescent probes, thrombin and angiotensin II generation by specific assays, fibrosis by Sirius red staining and senescence by senescence-associated beta-galactosidase (SA-β-gal) activity. In AECs, FXa increased ROS formation, senescence (SA-β-gal activity, p53, p21), angiotensin II generation and the expression of pro-inflammatory (VCAM-1, MCP-1), pro-thrombotic (tissue factor), pro-fibrotic (TGF-β and collagen-1/3a) and pro-remodelling (MMP-2/9) markers whereas eNOS levels and NO formation were reduced. These effects were prevented by inhibitors of FXa but not thrombin, protease-activated receptors antagonists (PAR-1/2) and inhibitors of NADPH oxidases, ACE, AT1R, SGLT1/SGLT2. FXa also increased expression levels of ACE1, AT1R, SGLT1/2 proteins which were prevented by SGLT1/2 inhibitors. Human RAA showed tissue factor mRNA levels that correlated with markers of endothelial activation, pro-remodelling and pro-fibrotic responses and SGLT1/2 mRNA levels. They also showed protein expression levels of ACE1, AT1R, p22phox, SGLT1/2, and immunofluorescence signals of nitrotyrosine and SGLT1/2 colocalized with those of CD31. FXa increased oxidative stress levels which were prevented by inhibitors of the AT1R/NADPH oxidases/SGLT1/2 pathway.

Conclusion

FXa promotes oxidative stress triggering premature endothelial senescence and dysfunction associated with pro-thrombotic, pro-remodelling and pro-fibrotic responses in AECs and human RAA involving the AT1R/NADPH oxidases/SGLT1/2 pro-oxidant pathway. Targeting this pathway may be of interest to prevent atrial remodelling and the progression of atrial fibrillation substrate.
Current state of rumination syndrome
Authors: Pomenti Sydney , Katzka David A
Published: May 2024

Rumination syndrome (RS) is an underdiagnosed behavioral disorder of recurrent regurgitation. Regurgitation occurs in RS due to increased gastric pressure achieved by subconscious contraction of the abdominal musculature wall, reversing the pressure gradient between the esophagus and the stomach. RS is mainly diagnosed clinically by the Rome Criteria with symptoms of regurgitation without retching of recently ingested food into the mouth and subsequent spitting or re-mastication. When the diagnosis is unable to be made clinically, supportive testing including fed impedance manometry can be considered. RS occurs worldwide, affecting patients of all ages, races, and genders with a prevalence of 3.1–5.8%. There is significant overlap with RS and disorders of a gut–brain interaction and upright gastroesophageal reflux driven by aerophagia and supragastric belching. There is also an association with mood disorder, fibromyalgia, and eating disorders. RS may be misdiagnosed as a variety of other syndromes including gastroesophageal reflux disease, gastroparesis, achalasia, and bulimia nervosa. Once RS is diagnosed, the mainstay of treatment is diaphragmatic breathing to lower the intragastric pressure and increase the lower esophageal pressure. Diaphragmatic breathing can be supported with biofeedback and cognitive behavioral therapy as well as medication options for more refractory cases. Response to therapy overtime and changes in symptoms overtime can now be tracked with a validated questionnaire.
Real-World Comparison of the Effectiveness between Ustekinumab and Vedolizumab in Patients with Ulcerative Colitis Exposed to at least One Anti-TNF Agent
Authors: Fumery Mathurin , Serrero Mélanie , Bouguen Guillaume , Amiot Aurélien , Altwegg Romain , Nachury Maria , Vuitton Lucine , Treton Xavier , Caillo Ludovic , Pereira Bruno , Buisson Antony
Published: May 2024

Background

Both vedolizumab and ustekinumab can be considered for the treatment of ulcerative colitis [UC], but head-to-head trials are lacking.

Aim

We aimed to compare the effectiveness of vedolizumab and ustekinumab after anti-tumour necrosis factor [anti-TNF] failure in UC patients.

Patients and Methods

In this multicentre study, we included consecutive adult patients with UC, with partial Mayo score >2 and prior anti-TNF exposure, treated with vedolizumab or ustekinumab between January 2019 and August 2022. Comparisons were performed using propensity score analyses [inverse probability of treatment weighting].

Results

Among a total of 293 patients included, 151 and 142 received vedolizumab and ustekinumab, respectively. After propensity score analysis, steroid-free clinical remission [SFCR] [partial Mayo score ≤2] was achieved at week 16 in 38.0% and 40.3% of patients treated with vedolizumab and ustekinumab, respectively (adjusted odds ratio [aOR] = 1.11, 95% confidence interval [0.39–3.13], p = 0.85). Rates of SFCR in patients exposed to one, two, and three lines of biologics/small molecules among patients treated with vedolizumab and ustekinumab were respectively 53.3% vs 62.1% [p = 0.52], 44.4% vs 33.8% [p = 0.52], and 2.6% vs 19.1% [p = 0.027]. Endoscopic remission [SFCR and endoscopic Mayo score ≤1] and histological remission [SFCR, endoscopic remission, and Nancy histological index ≤1] at week 16 were achieved in respectively 5.3% vs 17.5% (aOR = 3.77 [1.25–11.36], p = 0.018) and 2.1% vs 11.1% (aOR = 5.85 [1.47–23.30], p = 0.012) in the vedolizumab and ustekinumab groups. No difference regarding the risk of drug discontinuation between the two groups (aHR = 1.03 [0.51–2.08], p = 0.92) was observed. While no factor was identified for vedolizumab, primary failure to at least one biologic/small molecule (OR = 0.31 [0.11–0.82], p = 0.018) was significantly associated with a decreased rate of SFCR among patients treated with ustekinumab.

Conclusion

While no difference in terms of short-term clinical remission was observed, ustekinumab appears to be more effective than vedolizumab in inducing endoscopic and histological remission at week 16 after failure of anti-TNFs in UC.
B-type natriuretic peptide levels predict long-term mortality in a large cohort of adults with congenital heart disease
Authors: Yumita Yusuke , Xu Zhuoyuan , Diller Gerhard-Paul , Kempny Aleksander , Rafiq Isma , Montanaro Claudia , Li Wei , Gu Hong , Dimopoulos Konstantinos , Niwa Koichiro , Gatzoulis Michael A , Brida Margarita
Published: May 2024

Background and Aims

Many adult patients with congenital heart disease (ACHD) are still afflicted by premature death. Previous reports suggested natriuretic peptides may identify ACHD patients with adverse outcome. The study investigated prognostic power of B-type natriuretic peptide (BNP) across the spectrum of ACHD in a large contemporary cohort.

Methods

The cohort included 3392 consecutive ACHD patients under long-term follow-up at a tertiary ACHD centre between 2006 and 2019. The primary study endpoint was all-cause mortality.

Results

A total of 11 974 BNP measurements were analysed. The median BNP at baseline was 47 (24–107) ng/L. During a median follow-up of 8.6 years (29 115 patient-years), 615 (18.1%) patients died. On univariable and multivariable analysis, baseline BNP [hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.15–1.18 and HR 1.13, 95% CI 1.08–1.18, respectively] and temporal changes in BNP levels (HR 1.22, 95% CI 1.19–1.26 and HR 1.19, 95% CI 1.12–1.26, respectively) were predictive of mortality (P < .001 for both) independently of congenital heart disease diagnosis, complexity, anatomic/haemodynamic features, and/or systolic systemic ventricular function. Patients within the highest quartile of baseline BNP (>107 ng/L) and those within the highest quartile of temporal BNP change (>35 ng/L) had significantly increased risk of death (HR 5.8, 95% CI 4.91–6.79, P < .001, and HR 3.6, 95% CI 2.93–4.40, P < .001, respectively).

Conclusions

Baseline BNP and temporal BNP changes are both significantly associated with all-cause mortality in ACHD independent of congenital heart disease diagnosis, complexity, anatomic/haemodynamic features, and/or systolic systemic ventricular function. B-type natriuretic peptide levels represent an easy to obtain and inexpensive marker conveying prognostic information and should be used for the routine surveillance of patients with ACHD.
Application and Comparison of Machine Learning and Database-Based Methods in Taxonomic Classification of High-Throughput Sequencing Data
Authors: Tian Qinzhong , Zhang Pinglu , Zhai Yixiao , Wang Yansu , Zou Quan
Published: May 2024

The advent of high-throughput sequencing technologies has not only revolutionized the field of bioinformatics but has also heightened the demand for efficient taxonomic classification. Despite technological advancements, efficiently processing and analyzing the deluge of sequencing data for precise taxonomic classification remains a formidable challenge. Existing classification approaches primarily fall into two categories, database-based methods and machine learning methods, each presenting its own set of challenges and advantages. On this basis, the aim of our study was to conduct a comparative analysis between these two methods while also investigating the merits of integrating multiple database-based methods. Through an in-depth comparative study, we evaluated the performance of both methodological categories in taxonomic classification by utilizing simulated data sets. Our analysis revealed that database-based methods excel in classification accuracy when backed by a rich and comprehensive reference database. Conversely, while machine learning methods show superior performance in scenarios where reference sequences are sparse or lacking, they generally show inferior performance compared with database methods under most conditions. Moreover, our study confirms that integrating multiple database-based methods does, in fact, enhance classification accuracy. These findings shed new light on the taxonomic classification of high-throughput sequencing data and bear substantial implications for the future development of computational biology. For those interested in further exploring our methods, the source code of this study is publicly available on https://github.com/LoadStar822/Genome-Classifier-Performance-Evaluator. Additionally, a dedicated webpage showcasing our collected database, data sets, and various classification software can be found at http://lab.malab.cn/~tqz/project/taxonomic/.
Differences in Daily Physical Activity by Alzheimer’s Risk Markers Among Older Adults
Authors: Marino Francesca R , Deal Jennifer A , Dougherty Ryan J , Bilgel Murat , Tian Qu , An Yang , Simonsick Eleanor M , Resnick Susan M , Ferrucci Luigi , Spira Adam P , Wanigatunga Amal A , Schrack Jennifer A
Published: May 2024

Background

Daily physical activity patterns differ by Alzheimer’s disease (AD) status and might signal cognitive risk. It is critical to understand whether patterns are disrupted early in the AD pathological process. Yet, whether established AD risk markers (β-amyloid [Aβ] or apolipoprotein E-ε4 [APOE-ε4]) are associated with differences in objectively measured activity patterns among cognitively unimpaired older adults is unclear.

Methods

Wrist accelerometry, brain Aβ (+/−), and APOE-ε4 genotype were collected in 106 (Aβ) and 472 (APOE-ε4) participants (mean age 76 [standard deviation{SD}: 8.5) or 75 [SD: 9.2] years, 60% or 58% women) in the Baltimore Longitudinal Study of Aging. Adjusted linear and function-on-scalar regression models examined whether Aβ or APOE-ε4 status was cross-sectionally associated with activity patterns (amount, variability, or fragmentation) overall and by time of day, respectively. Differences in activity patterns by combinations of Aβ and APOE-ε4 status were descriptively examined (n = 105).

Results

There were no differences in any activity pattern by Aβ or APOE-ε4 status overall. Aβ+ was associated with lower total amount and lower within-day variability of physical activity overnight and early evening, and APOE-ε4 carriers had higher total amount of activity in the evening and lower within-day variability of activity in the morning. Diurnal curves of activity were blunted among those with Aβ+ regardless of APOE-ε4 status, but only when including older adults with mild cognitive impairment/dementia.

Conclusions

Aβ+ in cognitively unimpaired older adults might manifest as lower amount and variability of daily physical activity, particularly during overnight/evening hours. Future research is needed to examine changes in activity patterns in larger samples and by other AD biomarkers.
Recommendations on Methods for Assessing Multimorbidity Changes Over Time: Aligning the Method to the Purpose
Authors: Nagel Corey L , Bishop Nicholas J , Botoseneanu Anda , Allore Heather G , Newsom Jason T , Dorr David A , Quiñones Ana R
Published: May 2024

Background

The rapidly growing field of multimorbidity research demonstrates that changes in multimorbidity in mid- and late-life have far reaching effects on important person-centered outcomes, such as health-related quality of life. However, there are few organizing frameworks and comparatively little work weighing the merits and limitations of various quantitative methods applied to the longitudinal study of multimorbidity.

Methods

We identify and discuss methods aligned to specific research objectives with the goals of (i) establishing a common language for assessing longitudinal changes in multimorbidity, (ii) illuminating gaps in our knowledge regarding multimorbidity progression and critical periods of change, and (iii) informing research to identify groups that experience different rates and divergent etiological pathways of disease progression linked to deterioration in important health-related outcomes.

Results

We review practical issues in the measurement of multimorbidity, longitudinal analysis of health-related data, operationalizing change over time, and discuss methods that align with 4 general typologies for research objectives in the longitudinal study of multimorbidity: (i) examine individual change in multimorbidity, (ii) identify subgroups that follow similar trajectories of multimorbidity progression, (iii) understand when, how, and why individuals or groups shift to more advanced stages of multimorbidity, and (iv) examine the coprogression of multimorbidity with key health domains.

Conclusions

This work encourages a systematic approach to the quantitative study of change in multimorbidity and provides a valuable resource for researchers working to measure and minimize the deleterious effects of multimorbidity on aging populations.
Historic Cognitive Function Trajectories as Predictors of Sedentary Behavior and Physical Activity in Older Adults
Authors: Rosenberg Dori E , Wu Yinxiang , Idu Abisola , Greenwood-Hickman Mikael Anne , McCurry Susan M , LaCroix Andrea Z , Shaw Pamela A
Published: May 2024

Background

We examined whether trajectories of cognitive function over 10 years predict later-life physical activity (PA), sedentary time (ST), and sleep.

Methods

Participants were from the Adult Changes in Thought (ACT) cohort study. We included 611 ACT participants who wore accelerometers and had 3+ measures of cognition in the 10 years prior to accelerometer wear. The Cognitive Assessment Screening Instrument (CASI) measured cognition and was scored using item-response theory (IRT). activPAL and ActiGraph accelerometers worn over 7 days measured ST and PA outcomes. Self-reported time in bed and sleep quality measured sleep outcomes. Analyses used growth mixture modeling to classify CASI-IRT scores into latent groups and examine associations with PA, ST, and sleep including demographic and health covariates.

Results

Participants (Mean age = 80.3 (6.5) years, 90.3% White, 57.1% female, 29.3% had less than 16 years of education) fell into 3 latent trajectory groups: average stable CASI (56.1%), high stable CASI (34.0%), and declining CASI (9.8%). The declining group had 16 minutes less stepping time (95% confidence interval [95% CI]: 0.6, 31.4), 1 517 fewer steps per day (95% CI: 138, 2 896), and 16.3 minutes per day less moderate-to-vigorous PA (95% CI: 1.3, 31.3) compared to the average stable group. There were no associations between CASI trajectory and sedentary or sleep outcomes.

Conclusions

Declining cognition predicted lower PA providing some evidence of a reverse relationship between PA and cognition in older adults. However, this conclusion is limited by having outcomes at only one time point, a nonrepresentative sample, self-reported sleep outcomes, and using a global cognition measure.
Why More Biologists Must Embrace Quantitative Modeling
Authors: Milligan Brook G , Rohde Ashley T
Published: May 2024

Synopsis

Biology as a field has transformed since the time of its foundation from an organized enterprise cataloging the diversity of the natural world to a quantitatively rigorous science seeking to answer complex questions about the functions of organisms and their interactions with each other and their environments. As the mathematical rigor of biological analyses has improved, quantitative models have been developed to describe multi-mechanistic systems and to test complex hypotheses. However, applications of quantitative models have been uneven across fields, and many biologists lack the foundational training necessary to apply them in their research or to interpret their results to inform biological problem-solving efforts. This gap in scientific training has created a false dichotomy of “biologists” and “modelers” that only exacerbates the barriers to working biologists seeking additional training in quantitative modeling. Here, we make the argument that all biologists are modelers and are capable of using sophisticated quantitative modeling in their work. We highlight four benefits of conducting biological research within the framework of quantitative models, identify the potential producers and consumers of information produced by such models, and make recommendations for strategies to overcome barriers to their widespread implementation. Improved understanding of quantitative modeling could guide the producers of biological information to better apply biological measurements through analyses that evaluate mechanisms, and allow consumers of biological information to better judge the quality and applications of the information they receive. As our explanations of biological phenomena increase in complexity, so too must we embrace modeling as a foundational skill.
Historical climate drivers and species’ ecological niche in the Beaufort Sea food web
Authors: Sora Kristen J , Wabnitz Colette C C , Steiner Nadja S , Sumaila U Rashid , Hoover Carie , Niemi Andrea , Loseto Lisa L , Li Mi-Ling , Giang Amanda , Gillies Emma , Cheung William W L
Published: May 2024

Climate change impacts have been particularly acute and rapid in the Arctic, raising concerns about the conservation of key ecologically and culturally significant species (e.g. beluga whales, Arctic cod), with consequences for the Indigenous community groups in the region. Here, we build on an Ecopath with Ecosim model for the Canadian Beaufort Sea Shelf and Slope to examine historical (1970–2021) changes in the ecological dynamics of the food web and key species under climate change. We compare the individual and cumulative effects of (i) increased sea surface temperature; (ii) reduced sea ice extent; (iii) ocean deoxygenation; and (iv) changing ocean salinity in the ecosystem models. We found that including salinity time series in our ecosystem models reduced the diversity found within the ecosystem, and altered the trophic levels, biomass, and consumption rates of some marine mammal and fish functional groups, including the key species: beluga whales, as well as Arctic and polar cods. Inclusion of the dissolved oxygen time series showed no difference to ecosystem indicators. The model findings reveal valuable insights into the attribution of temperature and salinity on Arctic ecosystems and highlight important factors to be considered to ensure that existing conservation measures can support climate adaptation.
Disavowing an Implied Term of Fairness
Authors: Brodie Douglas
Published: May 2024

In the Court of Appeal decision in Burn v Alder Hey (Burn), there are obiter suggestions that the employment contract contains an implied term that would require the employer to act fairly during a disciplinary process. In an article in this journal, Collins and Golding (the authors) endorse this direction of travel and explore what they see as a number of advantages that would accrue for employees (and other workers) should the courts hold that such a term is indeed part of the law of contract. This article seeks to argue that recognition of the term would be misguided.
The Capsular Polysaccharide Obstructs Wall Teichoic Acid Functions in Staphylococcus aureus
Authors: Lehmann Esther , van Dalen Rob , Gritsch Lisa , Slavetinsky Christoph , Korn Natalya , Rohmer Carina , Krause Daniela , Peschel Andreas , Weidenmaier Christopher , Wolz Christiane
Published: May 2024

Background

The cell envelope of Staphylococcus aureus contains 2 major secondary cell wall glycopolymers: capsular polysaccharide (CP) and wall teichoic acid (WTA). Both CP and WTA are attached to the cell wall and play distinct roles in S. aureus colonization, pathogenesis, and bacterial evasion of host immune defenses. We aimed to investigate whether CP interferes with WTA-mediated properties.

Methods

Strains with natural heterogeneous expression of CP, strains with homogeneous high CP expression, and CP-deficient strains were compared regarding WTA-dependent phage binding, cell adhesion, IgG deposition, and virulence in vivo.

Results

WTA-mediated phage adsorption, specific antibody deposition, and cell adhesion were negatively correlated with CP expression. WTA, but not CP, enhanced the bacterial burden in a mouse abscess model, while CP overexpression resulted in intermediate virulence in vivo.

Conclusions

CP protects the bacteria from WTA-dependent opsonization and phage binding. This protection comes at the cost of diminished adhesion to host cells. The highly complex regulation and mostly heterogeneous expression of CP has probably evolved to ensure the survival and optimal physiological adaptation of the bacterial population as a whole.
Longitudinal Analysis of Nursing Home Residents’ T-Cell Responses After SARS-CoV-2 mRNA Vaccinations Shows Influence of Biological Sex and Infection History
Authors: Smith Carson L , Didion Elise , Aung Htin , Tamilselvan Banumathi , Bej Taissa , Oyebanji Oladayo A , Shive Carey L , Wilson Brigid M , Cameron Mark , Cameron Cheryl , Gravenstein Stefan , Canaday David H
Published: May 2024

Background

Vaccines and vaccine boosting have blunted excess morbidity and mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in older nursing home residents (NHR). However, the impact of repeated vaccination on the T-cell response based on biological sex and prior infection of NHR remain understudied.

Methods

We examined T-cell responses to SARS-CoV-2 mRNA vaccines in a cohort of NHR and healthcare workers (HCW) over 2 years. We used interferon-γ ELIspot and flow cytometry to assess T-cell response before, 2 weeks, and 6 months after the initial series and each of 2 booster vaccines. We analyzed these data longitudinally with mixed-effect modeling and also examined subsets of our cohorts for additional changes in T-cell effector function.

Results

Prior SARS-CoV-2 infection and female sex contributed to higher T-cell response in NHR but not HCW. When looking across time points, NHR but not HCW with prior infection had significantly higher T-cell responses than infection-naive subjects. These patterns of response were maintained across multiple booster vaccinations.

Conclusions

These results suggest that the age, multimorbidity, and/or frailty of the NHR cohort may accentuate sex and infection status differences in T-cell response to mRNA vaccination.
The Effect of Gastrointestinal Graft-Versus-Host Disease and Diarrhea on the Pharmacokinetic Profile of Sotrovimab in Hematopoietic Stem Cell Transplant Recipients
Authors: Boonyaratanakornkit Jim , Wang Qianwen , Nader Ahmed , Kimball Louise , Stevens-Ayers Terry , Levkova Marta , Blazevic Rachel , Nguyen Jeanette , Wright Jennifer , Castor Jared , Greninger Alexander L , Ford Emily , Mielcarek Marco , Fordred Shelley , Han Jennifer , Boeckh Michael , Waghmare Alpana
Published: May 2024

Background

Monoclonal antibodies (mAbs) are utilized broadly to treat cancer and infectious diseases, and mAb exposure (serum concentration over time) is one predictor of overall treatment efficacy. Herein, we present findings from a clinical trial evaluating the pharmacokinetics of the long-acting mAb sotrovimab targeting severe acute respiratory syndrome coronavirus 2 in hematopoietic cell transplant (HCT) recipients.

Methods

All participants received an intravenous infusion of sotrovimab within 1 week prior to initiating the pretransplant preparative regimen. The serum concentration of sotrovimab was measured longitudinally for up to 24 weeks posttransplant.

Results

Compared to non-HCT participants, we found that mAb clearance was 10% and 26% higher in autologous and allogeneic HCT recipients, respectively. Overall sotrovimab exposure was approximately 15% lower in HCT recipients compared to non-HCT recipients. Exposure was significantly reduced in HCT recipients who developed diarrhea and lower gastrointestinal graft-versus-host disease (GVHD) posttransplant.

Conclusions

These data show that sotrovimab exposure may be reduced in HCT recipients, possibly related to increased gastrointestinal clearance in patients with GVHD. This phenomenon has implications for dose selection and duration of efficacy with sotrovimab and potentially other mAbs in this vulnerable patient population. Thus, mAb dose regimens developed in non-HCT populations may have to be optimized when applied to HCT populations.
Metabolic potential of Nitrososphaera-associated clades
Authors: Bei Qicheng , Reitz Thomas , Schädler Martin , Hodgskiss Logan H , Peng Jingjing , Schnabel Beatrix , Buscot François , Eisenhauer Nico , Schleper Christa , Heintz-Buschart Anna
Published: May 2024

Soil ammonia-oxidizing archaea (AOA) play a crucial role in converting ammonia to nitrite, thereby mobilizing reactive nitrogen species into their soluble form, with a significant impact on nitrogen losses from terrestrial soils. Yet, our knowledge regarding their diversity and functions remains limited. In this study, we reconstructed 97 high-quality AOA metagenome-assembled genomes (MAGs) from 180 soil samples collected in Central Germany during 2014–2019 summers. These MAGs were affiliated with the order Nitrososphaerales and clustered into four family-level clades (NS-α/γ/δ/ε). Among these MAGs, 75 belonged to the most abundant but least understood δ-clade. Within the δ-clade, the amoA genes in three MAGs from neutral soils showed a 99.5% similarity to the fosmid clone 54d9, which has served as representative of the δ-clade for the past two decades since even today no cultivated representatives are available. Seventy-two MAGs constituted a distinct δ sub-clade, and their abundance and expression activity were more than twice that of other MAGs in slightly acidic soils. Unlike the less abundant clades (α, γ, and ε), the δ-MAGs possessed multiple highly expressed intracellular and extracellular carbohydrate-active enzymes responsible for carbohydrate binding (CBM32) and degradation (GH5), along with highly expressed genes involved in ammonia oxidation. Together, these results suggest metabolic versatility of uncultured soil AOA and a potential mixotrophic or chemolithoheterotrophic lifestyle among 54d9-like AOA.
Narratives of Blended Experience
Authors: Flint Tom , O’Keefe Brian , Mastermaker Mike , Sturdee Miriam , Benyon David
Published: May 2024

This paper focuses on interaction across and between the physical/digital divide. We use blending theory to design for these situations, otherwise known as conceptual integration. Initially, this paper offers a discussion of the literature around blends. From this literature, we applied Benyon’s (Benyon, 2014) proposition of conceptual integration in mixed reality spaces (Blended Spaces) to consider interactions with the digital that complement the physical. We investigated blended spaces in partnership with undergraduate students during a live theatre festival. Our collaborators designed applications that applied blending principles, employing techniques drawn from speculative design. Outputs consist of speculative, narrative storyboards that use data gathered directly from stakeholder interviews and over 380 festival visitors. Our work led us to propose reworking Blended Spaces into a model that novice designers could easily conceive and apply. The work we conducted highlighted the need to consider user transitions from physical to digital and back again and highlighted the experiential nature of this type of interaction.
A general framework for developing computable clinical phenotype algorithms
Authors: Carrell David S , Floyd James S , Gruber Susan , Hazlehurst Brian L , Heagerty Patrick J , Nelson Jennifer C , Williamson Brian D , Ball Robert
Published: May 2024

Objective

To present a general framework providing high-level guidance to developers of computable algorithms for identifying patients with specific clinical conditions (phenotypes) through a variety of approaches, including but not limited to machine learning and natural language processing methods to incorporate rich electronic health record data.

Materials and Methods

Drawing on extensive prior phenotyping experiences and insights derived from 3 algorithm development projects conducted specifically for this purpose, our team with expertise in clinical medicine, statistics, informatics, pharmacoepidemiology, and healthcare data science methods conceptualized stages of development and corresponding sets of principles, strategies, and practical guidelines for improving the algorithm development process.

Results

We propose 5 stages of algorithm development and corresponding principles, strategies, and guidelines: (1) assessing fitness-for-purpose, (2) creating gold standard data, (3) feature engineering, (4) model development, and (5) model evaluation.

Discussion and Conclusion

This framework is intended to provide practical guidance and serve as a basis for future elaboration and extension.
JWST MIRI and NIRCam unveil previously unseen infrared stellar populations in NGC 6822
Authors: Nally Conor , Jones Olivia C , Lenkić Laura , Habel Nolan , Hirschauer Alec S , Meixner Margaret , Kavanagh P J , Boyer Martha L , Ferguson Annette M N , Sargent B A , Nayak Omnarayani , Temim Tea
Published: May 2024

NGC 6822 is a nearby (∼490 kpc) non-interacting low-metallicity (0.2 Z⊙) dwarf galaxy which hosts several prominent H ii regions, including sites of highly embedded active star formation. In this work, we present an imaging survey of NGC 6822 conducted with the Near Infrared Camera (NIRCam) and Mid-Infrared Instrument (MIRI) onboard JWST. We describe the data reduction, source extraction, and stellar population identifications from combined near- and mid-infrared (IR) photometry. Our NIRCam observations reach 7 mag deeper than previous JHKs surveys of this galaxy, which were sensitive to just below the tip of the red giant branch (TRGB). These JWST observations thus reveal for the first time in the near-IR the red clump stellar population and extend nearly 3 mag deeper. In the mid-IR, we observe roughly 2 mag below the TRGB with the MIRI F770W and F1000W filters. With these improvements in sensitivity, we produce a catalogue of ∼900 000 point sources over an area of ∼6.0 × 4.3 arcmin2. We present several NIRCam and MIRI colour–magnitude diagrams and discuss which colour combinations provide useful separations of various stellar populations to aid in future JWST observation planning. Finally, we find populations of carbon- and oxygen-rich asymptotic giant branch stars which will assist in improving our understanding of dust production in low-metallicity, early Universe analogue galaxies.
Does the fundamental metallicity relation evolve with redshift? I: the correlation between offsets from the mass-metallicity relation and star formation rate
Authors: Garcia Alex M , Torrey Paul , Ellison Sara , Grasha Kathryn , Hernquist Lars , Zovaro Henry R M , Chen Qian-Hui , Hemler Z S , Kewley Lisa J , Nelson Erica J , Wright Ruby J
Published: May 2024

The scatter about the mass-metallicity relation (MZR) has a correlation with the star formation rate (SFR) of galaxies. The lack of evidence of evolution in correlated scatter at z ≲ 2.5 leads many to refer to the relationship between mass, metallicity, and SFR as the Fundamental Metallicity Relation (FMR). Yet, recent high-redshift (z > 3) JWST observations have challenged the fundamental (i.e. redshift-invariant) nature of the FMR. In this work, we show that the cosmological simulations Illustris, IllustrisTNG, and Evolution and Assembly of GaLaxies and their Environment (EAGLE) all predict MZRs that exhibit scatter with a secondary dependence on SFR up to z = 8. We introduce the concept of a ‘strong’ FMR, where the strength of correlated scatter does not evolve with time, and a ‘weak’ FMR, where there is some time evolution. We find that each simulation analysed has a statistically significant weak FMR – there is non-negligible evolution in the strength of the correlation with SFR. Furthermore, we show that the scatter is reduced an additional ∼10–40 per cent at z ≳ 3 when using a weak FMR, compared to assuming a strong FMR. These results highlight the importance of avoiding coarse redshift binning when assessing the FMR.
The oldest stars with low neutron-capture element abundances and origins in ancient dwarf galaxies
Authors: Andales Hillary Diane , Santos Figueiredo Ananda , Fienberg Casey Gordon , Mardini Mohammad K , Frebel Anna
Published: May 2024

We present a detailed chemical abundance and kinematic analysis of six extremely metal-poor (−4.2 ≤ [Fe/H] ≤−2.9) halo stars with very low neutron-capture abundances ([Sr/H] and [Ba/H]) based on high-resolution Magellan/MIKE spectra. Three of our stars have [Sr/Ba] and [Sr/H] ratios that resemble those of metal-poor stars in ultra-faint dwarf galaxies (UFDs). Since early UFDs may be the building blocks of the Milky Way, extremely metal-poor halo stars with low, UFD-like Sr and Ba abundances may thus be ancient stars from the earliest small galactic systems that were accreted by the proto-Milky Way. We label these objects as Small Accreted Stellar System (SASS) stars, and we find an additional 61 similar ones in the literature. A kinematic analysis of our sample and literature stars reveals them to be fast-moving halo objects, all with retrograde motion, indicating an accretion origin. Because SASS stars are much brighter than typical UFD stars, identifying them offers promising ways towards detailed studies of early star formation environments. From the chemical abundances of SASS stars, it appears that the earliest accreted systems were likely enriched by a few supernovae whose light element yields varied from system to system. Neutron-capture elements were sparsely produced and/or diluted, with r-process nucleosynthesis playing a role. These insights offer a glimpse into the early formation of the Galaxy. Using neutron-capture elements as a distinguishing criterion for early formation, we have access to a unique metal-poor population that consists of the oldest stars in the universe.
The mutation R107Q alters mtSSB ssDNA compaction ability and binding dynamics
Authors: Martucci Martial , Moretton Amandine , Tarrés-Solé Aleix , Ropars Virginie , Lambert Louise , Vernet Patrick , Solà Maria , Falkenberg Maria , Farge Geraldine , van den Wildenberg Siet
Published: May 2024

Mitochondrial single-stranded DNA-binding protein (mtSSB) is essential for mitochondrial DNA (mtDNA) replication. Recently, several mtSSB variants have been associated with autosomal dominant mitochondrial optic atrophy and retinal dystrophy. Here, we have studied at the molecular level the functional consequences of one of the most severe mtSSB variants, R107Q. We first studied the oligomeric state of this variant and observed that the mtSSBR107Q mutant forms stable tetramers in vitro. On the other hand, we showed, using complementary single-molecule approaches, that mtSSBR107Q displays a lower intramolecular ssDNA compaction ability and a higher ssDNA dissociation rate than the WT protein. Real-time competition experiments for ssDNA-binding showed a marked advantage of mtSSBWT over mtSSBR107Q. Combined, these results show that the R107Q mutation significantly impaired the ssDNA-binding and compacting ability of mtSSB, likely by weakening mtSSB ssDNA wrapping efficiency. These features are in line with our molecular modeling of ssDNA on mtSSB showing that the R107Q mutation may destabilize local interactions and results in an electronegative spot that interrupts an ssDNA-interacting-electropositive patch, thus reducing the potential mtSSB-ssDNA interaction sites.
Stress-induced nucleoid remodeling in Deinococcus radiodurans is associated with major changes in Heat Unstable (HU) protein dynamics
Authors: Vauclare Pierre , Wulffelé Jip , Lacroix Françoise , Servant Pascale , Confalonieri Fabrice , Kleman Jean-Philippe , Bourgeois Dominique , Timmins Joanna
Published: May 2024

Bacteria have developed a wide range of strategies to respond to stress, one of which is the rapid large-scale reorganization of their nucleoid. Nucleoid associated proteins (NAPs) are believed to be major actors in nucleoid remodeling, but the details of this process remain poorly understood. Here, using the radiation resistant bacterium D. radiodurans as a model, and advanced fluorescence microscopy, we examined the changes in nucleoid morphology and volume induced by either entry into stationary phase or exposure to UV-C light, and characterized the associated changes in mobility of the major NAP in D. radiodurans, the heat-unstable (HU) protein. While both types of stress induced nucleoid compaction, HU diffusion was reduced in stationary phase cells, but was instead increased following exposure to UV-C, suggesting distinct underlying mechanisms. Furthermore, we show that UV-C-induced nucleoid remodeling involves a rapid nucleoid condensation step associated with increased HU diffusion, followed by a slower decompaction phase to restore normal nucleoid morphology and HU dynamics, before cell division can resume. These findings shed light on the diversity of nucleoid remodeling processes in bacteria and underline the key role of HU in regulating this process through changes in its mode of assembly on DNA.
SEMA 2.0: web-platform for B-cell conformational epitopes prediction using artificial intelligence
Authors: Ivanisenko Nikita V , Shashkova Tatiana I , Shevtsov Andrey , Sindeeva Maria , Umerenkov Dmitriy , Kardymon Olga
Published: May 2024

Prediction of conformational B-cell epitopes is a crucial task in vaccine design and development. In this work, we have developed SEMA 2.0, a user-friendly web platform that enables the research community to tackle the B-cell epitopes prediction problem using state-of-the-art protein language models. SEMA 2.0 offers comprehensive research tools for sequence- and structure-based conformational B-cell epitopes prediction, accurate identification of N-glycosylation sites, and a distinctive module for comparing the structures of antigen B-cell epitopes enhancing our ability to analyze and understand its immunogenic properties. SEMA 2.0 website https://sema.airi.net is free and open to all users and there is no login requirement. Source code is available at https://github.com/AIRI-Institute/SEMAi
Earth's core–mantle boundary shaped by the crystallization of a hydrous terrestrial magma ocean
Authors: Hu Qingyang , Deng Jie , Zhuang Yukai , Yang Zhenzhong , Huang Rong
Published: May 2024

Enigmatic anomalous structures of Earth's lowermost mantle may have been incubated at the hydrous magma ocean of the Hadean eon.
Clinical Spectrum and Epidemiology of Human Parechovirus Infections in Infants: A Retrospective Study in the Western Part of Sweden
Authors: Rembeck Karolina , Elfving Kristina , Patzi Churqui Marianela , Saguti Fredy , Studahl Marie , Norder Heléne
Published: May 2024

Background

Human parechovirus (HPeV) infections can cause sepsis and meningoencephalitis in infants. To improve our knowledge of the consequences of HPeV infections in young children, the incidence, clinical spectrum, and short-term outcome among infants infected with HPeV were investigated retrospectively.

Methods

The presence of HPeV RNA was investigated by polymerase chain reaction in cerebrospinal fluid from 327 children aged 0 to 12 months sampled between 2014 and 2017. Eighty-one were infected with HPeV and included in the study. These infants were divided into 3 groups based on clinical assessment: HPeV was the presumed cause of disease (n = 35); HPeV could have contributed to or been considered the cause of disease (n = 24); and HPeV was not considered the cause of disease (n = 22).

Results

Infection with HPeV type 3 was common in all groups (n = 54), and most children were younger than 3 months (n = 63). The children in the first group (HPeV as presumed cause) had meningoencephalitis (n = 20), viral sepsis (n = 9), or non-severe viral infection (n = 6). The youngest were more prone to develop meningoencephalitis, while the slightly older children had symptoms of viral sepsis or nonsevere viral infection (P < .05). Eleven had symptom onset within 2 days after birth. Two infants diagnosed with sudden infant death syndrome were HPeV infected when tested postmortem.

Conclusions

HPeV infections were identified in 25% of children with suspected central nervous system infection. The clinical presentation of those infected with HPeV varied with age. HPeV infections may be associated with sudden infant death syndrome, although this is not well studied. The results suggest that HPeV infections may be underdiagnosed in young infants.
Redistribution of nitrogen to feed the people on a safer planet
Authors: Kahiluoto Helena , Sakieh Yousef , Kaseva Janne , Kersebaum Kurt-Christian , Minoli Sara , Franke James , Rötter Reimund P , Müller Christoph
Published: May 2024

Lack of nitrogen limits food production in poor countries while excessive nitrogen use in industrial countries has led to transgression of the planetary boundary. However, the potential of spatial redistribution of nitrogen input for food security when returning to the safe boundary has not been quantified in a robust manner. Using an emulator of a global gridded crop model ensemble, we found that redistribution of current nitrogen input to major cereals among countries can double production in the most food-insecure countries, while increasing global production of these crops by 12% with no notable regional loss or reducing the nitrogen input to the current production by one-third. Redistribution of the input within the boundary increased production by 6–8% compared to the current relative distribution, increasing production in the food-insecure countries by two-thirds. Our findings provide georeferenced guidelines for redistributing nitrogen use to enhance food security while safeguarding the planet.
Politics Rules Everything Around Me? A Review of Pandemic Politics
Authors: Stecuła Dominik A
Published: May 2024

Although COVID-19 is still very much around, we have reached the stage of the pandemic where we begin to look back and analyze our response to this crisis. It is, however, a monumental task to piece information together from thousands upon thousands of published articles about the pandemic from different academic disciplines. Gadarian, Goodman, and Pepinsky's book, Pandemic Politics, is an authoritative guide that walks us through the American pandemic response, using state-of-the-art multiwave panel data. The argument of the book tells a compelling, coherent, and, ultimately, depressing story about how America's four “preexisting conditions”—political polarization, Donald Trump, a troubled health care system, and systemic inequalities—set the stage for a perfect storm in which the politics dominated public health, culminating in a disastrous pandemic response. In this review article, I situate the book's argument in a broader literature on politicization of science, the importance of populism and anti-intellectualism, misinformation, and trust, filling in some of the considerations the authors omitted from their analyses.
Search Complementarities, Aggregate Fluctuations, and Fiscal Policy
Authors: Fernández-Villaverde Jesús , Mandelman Federico , Yu Yang , Zanetti Francesco
Published: May 2024

We document five novel facts about the role of search effort in forming trading relationships among firms by combining a variety of micro and macro datasets. These facts strongly suggest the presence of search complementarities. To study the implications of these facts for aggregate fluctuations, we build a dynamic general equilibrium model, disciplined by our new firm-level evidence on search effort. The model matches key aspects of the macro and micro data that have remained unaccounted for by standard models, including the time-varying bimodal distribution of output and the strong, nonlinear propagation of shocks. Also, changes to the volatility of shocks have nonlinear effects on macroeconomic fluctuations that advance a novel interpretation of the Great Moderation. Finally, we provide a new account of the state-dependent effects of fiscal policy.
Single nucleus and spatial transcriptomic profiling of healthy human hamstring tendon
Authors: Mimpen Jolet Y. , Ramos‐Mucci Lorenzo , Paul Claudia , Kurjan Alina , Hulley Philippa A. , Ikwuanusi Chinemerem T. , Cohen Carla J. , Gwilym Stephen E. , Baldwin Mathew J. , Cribbs Adam P. , Snelling Sarah J. B.
Published: May 2024

The molecular and cellular basis of health in human tendons remains poorly understood. Among human tendons, hamstring tendon has markedly low pathology and can provide a prototypic healthy tendon reference. The aim of this study was to determine the transcriptomes and location of all cell types in healthy hamstring tendon. Using single nucleus RNA sequencing, we profiled the transcriptomes of 10 533 nuclei from four healthy donors and identified 12 distinct cell types. We confirmed the presence of two fibroblast cell types, endothelial cells, mural cells, and immune cells, and identified cell types previously unreported in tendons, including different skeletal muscle cell types, satellite cells, adipocytes, and undefined nervous system cells. The location of these cell types within tendon was defined using spatial transcriptomics and imaging, and potential transcriptional networks and cell–cell interactions were analyzed. We demonstrate that fibroblasts have the highest number of potential cell–cell interactions in our dataset, are present throughout the tendon, and play an important role in the production and organization of extracellular matrix, thus confirming their role as key regulators of hamstring tendon homeostasis. Overall, our findings underscore the complexity of the cellular networks that underpin healthy human tendon function and the central role of fibroblasts as key regulators of hamstring tendon tissue homeostasis.