bluuebunny/crossref_metadata_2025 huggingface dataset:
Urban Rural Differences on Accessing Patient Centered Medical Home Among Children With Mental/Developmental Health Conditions/Disorders
Authors: Huang Li , Onge Jarron Saint , Lai Sue-Min
Published: March 2024

Introduction:

To address healthcare spending growth and coordinated primary care, most states in the United States have adopted patient-centered medical homes (PCMHs). To evaluate urban rural difference on accessing PCMH among US children, particularly for children with developmental disabilities (DDs) and mental health disorders (MHDs).

Methods:

This cross-sectional study used the 2016–2018 National Survey for Children's Health (NSCH). Multivariable adjusted logistic regression analyses were used to assess the association between accessing PCMHs and rurality and mental/developmental conditions/disorders.

Results:

Children with both DDs and MHDs were statistically significantly higher in rural areas (10.9% rural vs. 8.3% urban, p ≤ .001). Children in rural areas reported higher odds of accessing PCMHs (14%) among all U.S. children, but no differences by subgroups for children with MHDs and/or DDs. Compared with children without DDs/MHDs, the reduction in access to PCMHs varies by children's health status (41% reduction for children both DDs and MHDs, 25% reduction for children with MHDs without DDs) effects. Children with MHDs/DDs were less likely to receive family-centered care, care coordination, and referrals.

Conclusions:

Quality improvements through PCMHs could focus on family-centered care, care coordination, and referrals. Patient-centered medical home performance measurement could be improved to better measure mental health integration and geographical differences.
Single-Leg Heel Raise Capacity is Lower, and Perceived Ankle Instability is Greater, in Dancers and Athletes With Posterior Ankle Impingement Syndrome
Authors: Baillie Peta , Cook Jill , Ferrar Katia , Mayes Susan
Published: March 2024

Objective:

To compare clinical assessment findings between elite athletic populations with and without a clinical diagnosis of posterior ankle impingement syndrome (PAIS).

Design:

Cross-sectional case–control study.

Setting:

Elite ballet and sport.

Participants:

Ten male and female professional ballet dancers and athletes with a clinical diagnosis of PAIS and were matched for age, sex, and activity to 10 professional ballet dancers and athletes without PAIS.

Independent Variables:

Posterior ankle pain on body chart and a positive ankle plantarflexion pain provocation test.

Main Outcome Measures:

Single-leg heel raise (SLHR) endurance test, range of motion testing for weight-bearing ankle dorsiflexion, passive ankle plantarflexion, and first metatarsophalangeal joint dorsiflexion, and Beighton score for generalized joint hypermobility. Participants also completed the Cumberland Ankle Instability Tool (CAIT) questionnaire.

Results:

The group with PAIS achieved significantly fewer repetitions on SLHR capacity testing (P = 0.02) and were more symptomatic for perceived ankle instability according to CAIT scores (P = 0.004).

Conclusions:

Single-leg heel raise endurance capacity was lower, and perceived ankle instability was greater in participants with PAIS. The management of this presentation in elite dancers and athletes should include the assessment and management of functional deficits.
The Kaleidoscope of Midface Management in Apert Syndrome: A 23-Year Single-Institution Experience
Authors: Wu Meagan , Massenburg Benjamin B , Ng Jinggang J , Romeo Dominic J , Swanson Jordan W , Bartlett Scott P , Taylor Jesse A
Published: March 2024

Background:

This study assesses operative trends over time and outcomes of five osteotomy techniques used to treat the Apert midface. Using clinical and photogrammetric data, we present our institution’s selection rationale for correcting specific dysmorphologies of the Apert midface based on the individual phenotype.

Methods:

We retrospectively reviewed patients with Apert syndrome who underwent midface distraction from 2000 to 2023. Patients were temporally divided by the year 2012 to assess differences in surgical approach. Postoperative facial dimension changes, surgical and perioperative characteristics, and complications data were compared across techniques.

Results:

Thirty-nine patients with Apert syndrome underwent 41 midface distraction procedures: 23 (56%) in the early cohort and 18 (44%) in the late cohort. The use of segmental osteotomies for frontofacial advancement increased from 0% before 2012 to 61% from 2012 onwards (p<0.001). Monobloc with bipartition was the only technique that decreased intercanthal distance (p=0.016), and Le Fort II with zygomatic repositioning achieved the greatest median change in bilateral canthal tilt of 8.7° (IQR 1.3°, 8.7°; p=0.068). Monobloc with Le Fort II achieved the greatest median change in facial convexity of -34.9° (IQR -43.3°, -29.2°; p=0.031). Severity of complications, stratified by Clavien-Dindo grade, was greater in transcranial than subcranial procedures but similar between segmental and non-segmental osteotomies (p=0.365).

Conclusions:

In studying the Apert midface and attempting to resolve its varying functional and aesthetic issues, we document an evolution towards multi-piece osteotomies over time. With an appreciation for differential midface hypoplasia, segmentation is associated with more effective normalization of the Apert face.
Pregnancy Termination Policy and Cleft Lip and Palate
Authors: Junn Alexandra , Spoer Daisy L. , Koh Min Jung , Berger Lauren E. , Zuckerman Hannah , Baker Stephen B. , DeLia Derek , Fan Kenneth L.
Published: March 2024

Background:

Restrictive policies on termination of pregnancy (TOP) may lead to more infants with congenital abnormalities. This study aimed to assess the association between statewide enactment of TOP restriction and cleft lip and/or palate (CL/P) incidence, and to identify mediating demographic characteristics.

Methods:

The authors examined state-specific trends in CL/P incidence in infants before and after implementation of laws restricting TOP in Michigan compared with New York, where no such laws were passed. The percentage change of CL/P incidence per 1000 live births in postpolicy years (2012 to 2015) compared with prepolicy years (2005 to 2011) was compared, with adjustments for confounding factors in multivariate models.

Results:

The incidence of CL/P changed significantly in Michigan (19.1%) compared with New York (−7.31%). Adjusting for sex, race/ethnicity, median household income level, and expected payer, the adjusted percentage difference between Michigan and New York was 53.3% (P < 0.001). Stratification by race/ethnicity and median household income demonstrated that changes were only significant among Black (139%; P < 0.001) and Hispanic (125%; P = 0.045) patients and among those from the lowest (50.3%; P < 0.001) and second lowest (40.1%; P = 0.01) income quartiles.

Conclusion:

The authors’ research, combined with the recent Supreme Court decision in Dobbs v Jackson Women’s Health Organization allowing states to place further restrictions on TOP, suggests that more infants in the future will be born in need of treatment for CL/P.
Regional variation in weight change after the transition to dolutegravir in Uganda and South Africa
Authors: Migisha Richard , Chen Geoffrey , Muyindike Winnie R. , Aung Taing Nandi , Nanfuka Victoria , Komukama Nimusiima , Chandiwana Nomathemba , Shazi Gugulethu , Tien Dessie , Moosa Mahomed-Yunus S. , Gupta Ravindra K. , Pillay Deenan , Marconi Vincent C. , Hedt-Gauthier Bethany , Venter Willem D.F. , Siedner Mark J. , McCluskey Suzanne M. , Manne-Goehler Jennifer
Published: March 2024

Background:

People with HIV (PWH) on integrase inhibitor-based regimens may be at risk of excess weight gain, but it is unclear if this risk is consistent across settings. We assessed weight change over 48 weeks among PWH who were transitioned to tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD).

Design:

We conducted a prospective cohort study at public-sector HIV clinics in Uganda and South Africa.

Methods:

Eligible participants were adults who were transitioned to TLD. Weight was measured at enrollment, 24-, and 48-weeks post TLD transition. Our outcomes were weight change, change in waist circumference, and clinically significant weight gain, defined as ≥10% increase in weight from baseline, over 48 weeks. We used linear mixed-effects regression models, adjusted for demographic factors, to estimate weight gain and identify risk factors.

Results:

Weight data were available for 428 participants in Uganda and 367 in South Africa. The mean weight change was 0.6 kg [95% CI: 0.1–1.0] in Uganda and 2.9 kg [2.3–3.4] in South Africa (P < 0.001). The mean change in waist circumference was 0.8 cm [95% CI: 0.0–1.5]) in Uganda and 2.3 cm [95% CI: 1.4–3.2] in South Africa (P = 0.012). Clinically significant weight gain occurred in 9.8% [7.0–12.6] of participants in Uganda and 18.0% [14.1–21.9] in South Africa (P < 0.001). After adjustment, PWH gained significantly less weight in Uganda than in South Africa.

Conclusions:

PWH in South Africa experienced significantly greater weight gain and increases in waist circumference compared to Uganda. Strategies to address weight gain in PWH should be carefully considered and may vary by region.
Oral hygiene in critically ill patients at a tertiary hospital in São Paulo, Brazil: a best practice implementation project
Authors: Ribeiro Bersaneti Mariana Davies , Lobo Renata Desordi , Brandão Thais Bianca , Silva Souza Regina Claudia , Poveda Vanessa de Brito
Published: March 2024

Objectives:

This project aimed to promote evidence-based practices relat. ed to the oral health of critically ill patients in an intensive care unit in Brazil.

Introduction:

The oral hygiene of patients on mechanical ventilation is an essential component of nursing care quality, and well-defined guidelines ensure appropriate care. Mechanical ventilation is associated with the risk of ventilator-associated pneumonia, which can increase mortality, length of stay, time on mechanical ventilation, and hospital costs.

Methods:

This project was guided by the JBI Evidence Implementation Framework, which consists of seven stages: (1) identification of the area of practice to be changed, (2) involvement of change agents, (3) context assessment and readiness for change, (4) review of practices against evidence-based audit criteria, (5) implementation of practice changes, (6) reassessment of practices using a follow-up audit, and (7) consideration of the sustainability of changes in practice.

Results:

Four audit criteria were developed to evaluate compliance with best practices. In the follow-up audit, Criteria 1, 2, and 3 obtained compliance of ≥ 80%. Thus, for Criterion 1, all the patients on mechanical ventilation for more than 24 hours were evaluated by the oral medicine team, resulting in 100% compliance. For Criterion 2 on appropriate oral hygiene measures, a compliance rate of 80% was achieved. For Criterion 3, 39 professionals (90.7%) participated in educational activities related to the oral health protocol for critically ill patients, obtaining 90.7% compliance. For Criterion 4 regarding patients being evaluated before receiving any oral health care, improvement was low (only 50%), revealing the need for further improvement.

Conclusion:

This best practice project improved the professional practice of nursing staff and increased compliance with best practices for the oral health of critically ill patients.

Spanish abstract:

http://links.lww.com/IJEBH/A175
Choice of molecular marker influences spatial patterns of phylogenetic diversity
Authors: Luebert Federico , Scherson Rosa A.
Published: March 2024

Spatial patterns of phylogenetic diversity (PD) are increasingly becoming relevant for conservation decisions. PD measures are based on phylogenies estimated from molecular data. This paper addresses the question of how different molecular markers impact PD spatial patterns. We first conducted a simple simulation to explore the effect of deep and shallow changes in topology (simulating variations in molecular markers), using ultrametric and non-ultrametric trees, and then used a dataset of Chilean flora with four sets of markers to assess potential differences in spatial patterns of PD ranks using different markers and types of trees. The simulation consistently showed that the difference in PD rank was lower for ultrametric trees than for phylograms. A similar trend was observed using the Chilean flora dataset, with among-markers variability in spatial patterns of the PD metrics lower for ultrametric than for non-ultrametric trees, depicted as top 2.5 and 5% hotspots. Frequency distribution of PD values differed among markers as well, with this variation less apparent for ultrametric trees. We conclude that the choice of markers impacts spatial patterns of PD, and these results vary more strongly for phylograms, suggesting that ultrametric trees are more robust to the choice of marker.
Turbulence causes kinematic and behavioural adjustments in a flapping flier
Authors: Lempidakis Emmanouil , Ross Andrew N. , Quetting Michael , Krishnan Krishnamoorthy , Garde Baptiste , Wikelski Martin , Shepard Emily L. C.
Published: March 2024

Turbulence is a widespread phenomenon in the natural world, but its influence on flapping fliers remains little studied. We assessed how freestream turbulence affected the kinematics, flight effort and track properties of homing pigeons (
Columba livia
), using the fine-scale variations in flight height as a proxy for turbulence levels. Birds showed a small increase in their wingbeat amplitude with increasing turbulence (similar to laboratory studies), but this was accompanied by a reduction in mean wingbeat frequency, such that their flapping wing speed remained the same. Mean kinematic responses to turbulence may therefore enable birds to increase their stability without a reduction in propulsive efficiency. Nonetheless, the most marked response to turbulence was an increase in the variability of wingbeat frequency and amplitude. These stroke-to-stroke changes in kinematics provide instantaneous compensation for turbulence. They will also increase flight costs. Yet pigeons only made small adjustments to their flight altitude, likely resulting in little change in exposure to strong convective turbulence. Responses to turbulence were therefore distinct from responses to wind, with the costs of high turbulence being levied through an increase in the variability of their kinematics and airspeed. This highlights the value of investigating the variability in flight parameters in free-living animals.
Latent evolutionary signatures: a general framework for analysing music and cultural evolution
Authors: Warrell Jonathan , Salichos Leonidas , Gancz Michael , Gerstein Mark B.
Published: March 2024

Cultural processes of change bear many resemblances to biological evolution. The underlying units of non-biological evolution have, however, remained elusive, especially in the domain of music. Here, we introduce a general framework to jointly identify underlying units and their associated evolutionary processes. We model musical styles and principles of organization in dimensions such as harmony and form as following an evolutionary process. Furthermore, we propose that such processes can be identified by extracting latent evolutionary signatures from musical corpora, analogously to identifying mutational signatures in genomics. These signatures provide a latent embedding for each song or musical piece. We develop a deep generative architecture for our model, which can be viewed as a type of variational autoencoder with an evolutionary prior constraining the latent space; specifically, the embeddings for each song are tied together via an energy-based prior, which encourages songs close in evolutionary space to share similar representations. As illustration, we analyse songs from the McGill Billboard dataset. We find frequent chord transitions and formal repetition schemes and identify latent evolutionary signatures related to these features. Finally, we show that the latent evolutionary representations learned by our model outperform non-evolutionary representations in such tasks as period and genre prediction.
The influence of aortic stiffness on carotid stiffness: computational simulations using a human aorta carotid model
Authors: Petrova Marjana , Li Yujie , Gholipour Alireza , Kiat Hosen , McLachlan Craig S.
Published: March 2024

Increased aortic and carotid stiffness are independent predictors of adverse cardiovascular events. Arterial stiffness is not uniform across the arterial tree and its accurate assessment is challenging. The complex interactions and influence of aortic stiffness on carotid stiffness have not been investigated. The aim of this study was to evaluate the effect of aortic stiffness on carotid stiffness under physiological pressure conditions. A realistic patient-specific geometry was used based on magnetic resonance images obtained from the OsiriX library. The luminal aortic–carotid model was reconstructed from magnetic resonance images using 3D Slicer. A series of aortic stiffness simulations were performed at different regional aortic areas (levels). By applying variable Young's modulus to the aortic wall under two pulse pressure conditions, one could examine the deformation, compliance and von Mises stress between the aorta and carotid arteries. An increase of Young's modulus in an aortic area resulted in a notable difference in the mechanical properties of the aortic tree. Regional deformation, compliance and von Mises stress changes across the aorta and carotid arteries were noted with an increase of the aortic Young's modulus. Our results indicate that increased carotid stiffness may be associated with increased aortic stiffness. Large-scale clinical validation is warranted to examine the influence of aortic stiffness on carotid stiffness.
New insight into the global record of the Ediacaran tubular morphotype: a common solution to early multicellularity
Authors: Surprenant Rachel L. , Droser Mary L.
Published: March 2024

The tubular morphogroup is a common component of Earth’s first complex, multicellular communities—the Ediacaran biota—and offers valuable insight into biological traits that are fundamental to animal life because they have intriguing links to metazoan phyla and are highly abundant in Ediacaran ecosystems. Biomineral tubes (e.g.
Cloudina
) are well described from the Nama assemblage (~550–538 Myr), yielding a relatively detailed understanding of this subset of the morphogroup. Conversely, the non-biomineral tubular taxa of the Nama assemblage, as well as of the older White Sea assemblage (~560–550 Myr), are poorly understood. As a result, the variability of characters that define non-biomineral tubular organisms is unknown and their diversity dynamics throughout the terminal Ediacaran are unconstrained. To test hypotheses related to the diversity, morphological variability and temporal distribution of non-biomineral tubes, a comprehensive database of non-biomineral Ediacaran tubular taxa was compiled. Results demonstrate previously unrecognized morphological disparity in the non-biomineral tubular morphogroup and reveal that it comprises a higher number of genera than all other non-tubular morphogroups in the White Sea and the Nama. Thus, it illustrates that a tubular form dominated Ediacaran ecosystems for considerably longer than previously appreciated and, importantly, was the most common solution to early multicellularity.
Consistent seasonal flexibility of the gut and its regions across wild populations of a winter-quiescent fish
Authors: Fernandes Timothy J. , Li Hugo , Shuter Brian J. , McMeans Bailey C.
Published: March 2024

Seasonality in north-temperate environments imposes drastic temperature and resource variations that shape the seasonal ecophysiology of resident organisms. A better understanding of an organism’s capacity to flexibly respond to this drastic seasonal variation may reveal important mechanisms for tolerating or responding to environmental variation introduced by global change. In fishes, the digestive system is both the interface between resource and energy acquisition and one of the most expensive organ systems to maintain. However, little evidence describing the capacity for seasonal flexibility in the digestive tract of wild northern fishes exists. Here, we investigated phenotypic flexibility in the size of the gastrointestinal (GI) tract across three northern populations of a winter-dormant warm-water fish, pumpkinseed sunfish (
Lepomis gibbosus
). In all populations, pumpkinseed exhibited pronounced structural flexibility in the GI tract, aligned with winter and the timing of reproduction. The dry mass of the GI increased by 1.3- to nearly 2.5-fold in the early spring. The pyloric caeca demonstrated the greatest capacity for flexibility, increasing by up to 3.7-fold prior to reproduction. In all populations, minimum dry GI mass was consistently achieved during winter and mid-summer. This capacity for gut flexibility may represent a novel mechanism for facilitating rapid adaptive responses (e.g. metabolic plasticity) to future environmental change.
No evidence for a role of MHC class II genotype in the chemical encoding of heterozygosity and relatedness in Antarctic fur seals
Authors: Tebbe Jonas , Havenstein Katja , Forcada Jaume , Tiedemann Ralph , Caspers Barbara , Hoffman Joseph I.
Published: March 2024

Despite decades of research, surprisingly little is known about the mechanism(s) by which an individual's genotype is encoded in odour. Many studies have focused on the role of the major histocompatibility complex (MHC) owing to its importance for survival and mate choice. However, the salience of MHC-mediated odours compared to chemicals influenced by the rest of the genome remains unclear, especially in wild populations where it is challenging to quantify and control for the effects of the genomic background. We addressed this issue in Antarctic fur seals by analysing skin swabs together with full-length MHC DQB II exon 2 sequences and data from 41 genome-wide distributed microsatellites. We did not find any effects of MHC relatedness on chemical similarity and there was also no relationship between MHC heterozygosity and chemical diversity. However, multilocus heterozygosity showed a significant positive association with chemical diversity, even after controlling for MHC heterozygosity. Our results appear to rule out a dominant role of the MHC in the chemical encoding of genetic information in a wild vertebrate population and highlight the need for genome-wide approaches to elucidate the mechanism(s) and specific genes underlying genotype-odour associations.
Biomechanical adaptations enable phoretic mite species to occupy distinct spatial niches on host burying beetles
Authors: Sun Syuan-Jyun , Chen Simon , Federle Walter , Kilner Rebecca M.
Published: March 2024

Niche theory predicts that ecologically similar species coexist by minimizing interspecific competition through niche partitioning. Therefore, understanding the mechanisms of niche partitioning is essential for predicting interactions and coexistence between competing organisms. Here, we study two phoretic mite species,Poecilochirus carabiandMacrocheles nataliaethat coexist on the same host burying beetleNicrophorus vespilloidesand use it to ‘hitchhike’ between reproductive sites. Field observations revealed clear spatial partitioning between species in distinct host body parts.Poecilochirus carabipreferred the ventral side of the thorax, whereasM. nataliaewere exclusively found ventrally at the hairy base of the abdomen. Experimental manipulations of mite density showed that each species preferred these body parts, largely regardless of the density of the other mite species on the host beetle. Force measurements indicated that this spatial distribution is mediated by biomechanical adaptations, because each mite species required more force to be removed from their preferred location on the beetle. WhileP. carabiattached with large adhesive pads to the smooth thorax cuticle,M. nataliaegripped abdominal setae with their chelicerae. Our results show that specialist biomechanical adaptations for attachment can mediate spatial niche partitioning among species sharing the same host.
Subclinical variations on ECG and their associations with structural brain aging networks
Authors: Haddad Elizabeth , Matloff William , Park Gilsoon , Liu Mengting , Jahanshad Neda , Kim Ho Sung
Published: March 2024

Impaired cardiac function is associated with cognitive impairment and brain imaging features of aging. Cardiac arrhythmias, including atrial fibrillation, are implicated in clinical and subclinical brain injuries. Even in the absence of a clinical diagnosis, subclinical or prodromal substrates of arrhythmias, including an abnormally long or short P-wave duration (PWD), a measure associated with atrial abnormalities, have been associated with stroke and cognitive decline. However, the extent to which PWD has subclinical influences on overall aging patterns of the brain is not clearly understood. Here, using neuroimaging and ECG data from the UK Biobank, we use a novel regional “brain age” method to identify the brain aging networks associated with abnormal PWD. We find that PWD is inversely associated with accelerated brain aging in the sensorimotor, frontoparietal, ventral attention, and dorsal attention networks, even in the absence of overt cardiac diseases. These findings suggest that detrimental aging outcomes may result from subclinically abnormal PWD.
The landscape of coagulation cascade in pulmonary arterial hypertension
Authors: Xiao Genfa , Lian Guili , Liu Xiaoli , Xie Liangdi
Published: March 2024

Background

Both the thrombotic and bleeding events were frequently complicated in pulmonary arterial hypertension (PAH), making recommendations regarding anticoagulation difficult.

Methods

The histopathological examination was performed on the lungs of two PAH models and global coagulation cascade alteration in lung tissue and peripheral venous blood was assessed by RNA sequencing and immunoassay, respectively. The clinical data and plasma samples were collected from PAH patients and controls and plasma coagulation cascade in subject was quantified by both immunoassay and proteomic approach.

Results

RNA sequencing analysis of lung tissues in two PAH models showed the reduced anticoagulants and intrinsic clotting factors and increased tissue factor (TF) expression. The immunoassay assessment of coagulation cascade in PAH models revealed increased TF expression, reduced intrinsic and common clotting factors and decreased anticoagulants antithrombin (AT)-Ⅲ in the peripheral circulation. Additionally, clinical evaluation of hemostatic parameters in PAH patients demonstrated hemostatic deficiency and lower AT-Ⅲ activity. Consistently, proteomic and immunoassay analysis of coagulation cascade in PAH patients revealed the increased extrinsic clotting factors, impairment of intrinsic and common pathways and impairment of AT-Ⅲ anticoagulant pathway.

Conclusions

The activation of extrinsic pathway and impairment of heparin/AT-Ⅲ anticoagulant system are conserved mechanisms for thrombosis across rat and human PAH, restoring its function with heparin supplementation may be a better option for future anticoagulant therapy.

Clinical Perspective

What Is New?

The activation of extrinsic pathway and impairment of heparin/AT-Ⅲ system were responsible for thrombosis in pulmonary arterial hypertension.

Impairment of intrinsic and common pathways, due to reduced plasma levels of clotting factors F10, F11, F2 and vWF, contributed to hemorrhagic complications, such as hemoptysis in PAH patients.

What Are the Clinical Implications?

Increased risk of bleeding for anticoagulation with warfarin and novel oral anticoagulants may be attributed to further impairment of intrinsic and common pathways in PAH.

Restoring function of heparin/ AT-Ⅲ anticoagulant system with heparin supplementation may be a better option for future anticoagulant therapy.
Mathematical Modelling of Oxygenation Dynamics using High-Resolution Perfusion Data – Part 1: Statistical Framework
Authors: Sharabiani Mansour T. A. , Mahani Alireza S. , Issitt Richard W. , Srinivasan Yadav , Bottle Alex , Stoica Serban
Published: March 2024

Background

Balancing oxygen supply and demand during cardiopulmonary bypass (CPB) is crucial to minimise adverse outcomes. This is managed by adjusting oxygen delivery components – cardiac index (CI), haemoglobin concentration (Hb), arterial oxygen saturation (SaO2) – and metabolic demand through temperature (Temp) changes. The oxygen extraction ratio (OER) responds to these adjustments, affecting oxygen consumption, but this response is not well understood. We aimed to develop a mathematical model to capture OER dynamics during CPB and quantify oxygen demand’s dependence on temperature.

Methods

We developed GARIX, a time-series model predicting minute-by-minute OER changes during CPB, incorporating exogenous variables (CI, Hb, SaO2, Temp) and an equilibrium term representing the difference between oxygen consumption and temperature-dependent oxygen demand, modelled linearly per the van’t Hoff specification (constant Q10). The model was trained on data from 343 CPB operations (20,000 minutes) in 334 paediatric patients at a UK centre (2019–2021). We used variable importance analysis and simulations to study the model’s properties.

Results

The model shows OER adapts to align oxygen consumption with demand. The adaptive response has a rapid phase (<10 minutes) and a slower phase extending up to several hours. Equilibrium analysis yields Q10= 2.25, indicating oxygen demand doubles with every 8.5°C increase in temperature during CPB.

Conclusions

Our model provides a physiologically plausible framework for explaining OER changes during CPB, capturing dynamic adjustments and steady-state oxygen consumption. These findings highlight the value of mathematical modelling in estimating key oxygenation parameters like Q10, given limitations on clinical experimentation.
Following The Evolutionary Paths Of Highly Specific Homophilic Adhesion Proteins
Authors: Wiseglass Gil , Rubinstein Rotem
Published: March 2024

Many adhesion proteins, evolutionarily related through gene duplication, exhibit distinct and precise interaction preferences and affinities crucial for cell patterning. Yet, the evolutionary path by which these proteins, which are highly similar in structure and sequence, acquire new specificity and prevent cross-interactions within their family members remains unknown. To bridge this gap, this study focuses on Drosophila Down syndrome cell adhesion molecule-1 (Dscam1) proteins, which are cell adhesion proteins that have undergone extensive gene duplication. Dscam1 evolved under strong selective pressure to achieve strict homophilic recognition, essential for neuronal self-avoidance and patterning. Through a combination of phylogenetic analysis, ancestral sequence reconstruction, and cell aggregation assays, we studied the evolutionary trajectory of Dscam1 exon 4 across various insect lineages. We demonstrated that recent Dscam1 duplications in the mosquito lineage bind with strict homophilic specificities without any cross-interactions. We found that ancestral and intermediate Dscam1 isoforms were able to maintain their homophilic bindings capabilities, with some intermediate isoforms also engaging in promiscuous interactions with other paralogs. Our results highlight the robust selective pressure for homophilic specificity integral to Dscam1 function within the process of neuronal self-avoidance. Importantly, our study suggests that the path to achieving such selective specificity does not introduce disruptive mutations that prevent self-binding but includes an evolutionary intermediate that demonstrates promiscuous heterophilic interactions. Overall, these results offer insights into evolutionary strategies that underlie adhesion protein interaction specificity.
Exploring structural diversity across the protein universe with The Encyclopedia of Domains
Authors: Lau A. M. , Bordin N. , Kandathil S. M. , Sillitoe I. , Waman V. P. , Wells J. , Orengo C. A. , Jones D. T.
Published: March 2024

The AlphaFold Protein Structure Database (AFDB) contains full-length predictions of the three-dimensional structures of almost every protein in UniProt. Because protein function is closely linked to structure, the AFDB is poised to revolutionise our understanding of biology, evolution and more. Protein structures are composed of domains, independently folding units that can be found in multiple structural contexts and functional roles. The AFDB’s potential remains untapped due to the difficulty of characterising 200 million structures. Here we present The Encyclopedia of Domains or TED, which combines state-of-the-art deep learning-based domain parsing and structure comparison algorithms to segment and classify domains across the whole AFDB. TED describes over 370 million domains, over 100 million more than detectable by sequence-based methods. Nearly 80% of TED domains share similarities to known superfamilies in CATH, greatly expanding the set of known protein structural domains. We uncover over 10,000 previously unseen structural interactions between superfamilies, expand domain coverage to over 1 million taxa, and unveil thousands of architectures and folds across the unexplored continuum of protein fold space. We expect TED to be a valuable resource that provides a functional interface to the AFDB, empowering it to be useful for a multitude of downstream analyses.
The Genomic portrait of the Picene culture: new insights into the Italic Iron Age and the legacy of the Roman expansion in Central Italy
Authors: Ravasini Francesco , Niinemäe Helja , Solnik Anu , de Gennaro Luciana , Montinaro Francesco , Hui Ruoyun , Delpino Chiara , Finocchi Stefano , Giroldini Pierluigi , Mei Oscar , Cilli Elisabetta , Hajiesmaeil Mogge , Pistacchia Letizia , Risi Flavia , Giacometti Chiara , Scheib Christiana Lyn , Tambets Kristiina , Metspalu Mait , Cruciani Fulvio , D’Atanasio Eugenia , Trombetta Beniamino
Published: March 2024

Background

The Italic Iron Age was characterized by the presence of various ethnic groups partially examined from a genomic perspective. To explore the evolution of Iron Age Italic populations and the genetic impact of Romanization, we focused on the Picenes, one of the most fascinating pre-Roman civilizations, who flourished on the Middle Adriatic side of Central Italy between the 9thand the 3rdcentury BCE, until the Roman colonization.

Results

We analyzed more than 50 samples, spanning more than 1,000 years of history from the Iron Age to Late Antiquity. Despite cultural diversity, our analysis reveals no major differences between the Picenes and other coeval populations, suggesting a shared genetic history of the Central Italian Iron Age ethnic groups. Nevertheless, a slight genetic differentiation between populations along the Adriatic and Tyrrhenian coasts can be observed, possibly due to genetic contacts between populations residing on the Italian and Balkan shores of the Adriatic Sea. Additionally, we found several individuals with ancestries deviating from their general population. Lastly, In the Late Antiquity period, the genetic landscape of the Middle Adriatic region drastically changed, indicating a relevant influx from the Near East.

Conclusions

Our findings, consistently with archeological hypotheses, suggest genetic interactions across the Adriatic Sea during the Bronze/Iron Age and a high level of individual mobility typical of cosmopolitan societies. Finally, we highlighted the role of the Roman Empire in shaping genetic and phenotypic changes that greatly impacted the Italian peninsula.
Intricate interactions between antiviral immunity and transposable element control inDrosophila
Authors: Mayeux Camille A , Larue Anaïs , Oliveira Daniel S. , Varoqui Marion , Henri Hélène , Rebollo Rita , Kremer Natacha , Chambeyron Séverine , Fablet Marie
Published: March 2024

Transposable elements (TEs) are parasite DNA sequences that are controlled by RNA interference pathways in many organisms. In insects, antiviral immunity is also achieved by the action of small RNAs. In the present study, we analyzed the impacts of an infection with Drosophila C Virus (DCV) and found that TEs are involved in a dual response: on the one hand TE control is released upon DCV infection, and on the other hand TE transcripts help the host reduce viral replication. This discovery highlights the intricate interactions in the arms race between host, genomic parasites, and viral pathogens.

Significance statement

Transposable elements (TEs) are widespread components of all genomes. They were long considered as mere DNA parasites but are now acknowledged as major sources of genetic diversity and phenotypic innovations. UsingDrosophilaC virus, here we show that TEs are at the center of defense and counter-attack between host and virus. On the one hand, TE control is released upon viral infection, and on the other hand, TE transcripts help the host reduce viral replication. To our knowledge, this is the first time such a complex host-pathogen interaction involving TEs is shown.
Machine learning methods applied to classify complex diseases using genomic data
Authors: Segura Magdalena Arnal , Bini Giorgio , Krithara Anastasia , Paliouras George , Tartaglia Gian Gaetano
Published: March 2024

Complex diseases pose challenges in disease prediction due to their multifactorial and polygenic nature. In this work, we explored the prediction of two complex diseases, multiple sclerosis (MS) and Alzheimer’s disease (AD), using machine learning (ML) methods and genomic data from UK Biobank. Different ML methods were applied, including logistic regressions (LR), gradient boosting decision trees (GB), extremely randomized trees (ET), random forest (RF), feedforward networks (FFN), and convolutional neural networks (CNN). The primary goal of this research was to investigate the variability of ML models in classifying complex diseases based on genomic risk. LR was the most robust method across folds and diseases, whereas deep learning methods (FFN and CNN) exhibited high variability. When comparing the performance of polygenic risk scores (PRS) with ML methods, PRS consistently performed at an average level. However, PRS still offers several practical advantages over ML methods. Despite implementing feature selection techniques to exclude non-informative and correlated predictors, the performance of ML models did not improve significantly, underscoring the ability of ML methods to achieve optimal performance even in the presence of correlated features due to linkage disequilibrium. Upon applying explainability tools to extract information about the genomic features contributing most to the classification task, the results confirmed the polygenicity of MS. The prevalence of HLA gene annotations among the top genomic features on chromosome 6 aligns with their significance in the context of MS. Overall, the highest-prioritized genomic variants were identified as expression or splicing quantitative trait loci (eQTL or sQTL) located in non-coding regions within or near genes associated with the immune response and MS. In summary, this research offers deeper insights into how ML models discern genomic patterns related to complex diseases.
Structural and genetic diversity in the secreted mucins,MUC5ACandMUC5B
Authors: Plender Elizabeth G. , Prodanov Timofey , Hsieh PingHsun , Nizamis Evangelos , Harvey William T. , Sulovari Arvis , Munson Katherine M. , Kaufman Eli J. , O’Neal Wanda K. , Valdmanis Paul N. , Marschall Tobias , Bloom Jesse D. , Eichler Evan E.
Published: March 2024

The secreted mucins MUC5AC and MUC5B play critical defensive roles in airway pathogen entrapment and mucociliary clearance by encoding large glycoproteins with variable number tandem repeats (VNTRs). These polymorphic and degenerate protein coding VNTRs make the loci difficult to investigate with short reads. We characterize the structural diversity ofMUC5ACandMUC5Bby long-read sequencing and assembly of 206 human and 20 nonhuman primate (NHP) haplotypes. We find that humanMUC5Bis largely invariant (5761-5762aa); however, seven haplotypes have expanded VNTRs (6291-7019aa). In contrast, 30 allelic variants ofMUC5ACencode 16 distinct proteins (5249-6325aa) with cysteine-rich domain and VNTR copy number variation. We groupedMUC5ACalleles into three phylogenetic clades: H1 (46%, ∼5654aa), H2 (33%, ∼5742aa), and H3 (7%, ∼6325aa). The two most common humanMUC5ACvariants are smaller than NHP gene models, suggesting a reduction in protein length during recent human evolution. Linkage disequilibrium (LD) and Tajima’s D analyses reveal that East Asians carry exceptionally largeMUC5ACLD blocks with an excess of rare variation (p<0.05). To validate this result, we used Locityper for genotypingMUC5AChaplogroups in 2,600 unrelated samples from the 1000 Genomes Project. We observed signatures of positive selection in H1 and H2 among East Asians and a depletion of the likely ancestral haplogroup (H3). In Africans and Europeans, H3 alleles show an excess of common variation and deviate from Hardy-Weinberg equilibrium, consistent with heterozygote advantage and balancing selection. This study provides a generalizable strategy to characterize complex protein coding VNTRs for improved disease associations.
NONEXPRESSOR OF PATHOGENESIS-RELATED GENEScontrol Huanglongbing tolerance by regulating immune balance in citrus plants
Authors: Sarkar Poulami , El-Mohtar Choaa , Turner Donielle , Welker Stacy , Robertson Cecile J. , Orbovic Vladimir , Mou Zhonglin , Levy Amit
Published: March 2024

Huanglongbing (HLB) is a devastating citrus disease caused by the phloem-resident bacterial pathogenCandidatusliberibacter asiaticus (CLas).CLas infection of susceptible varieties triggers unbalanced immune responses, leading to overaccumulation of callose and reactive oxygen species (ROS), which in turn causes phloem plugging and HLB symptom development. Interestingly, some citrus relatives exhibit little or no symptoms in the presence ofCLas, a phenomenon termed HLB tolerance. Moreover, overexpression of theArabidopsis thaliana NPR1(AtNPR1) gene in susceptible varieties has been shown to confer robust HLB tolerance. However, the mechanisms underlying HLB tolerance remain enigmatic. Here, we show that overexpression ofAtNPR1suppressesCLas- andPseudomonas syringaepv.maculicolaES4326 (Psm)-induced overaccumulation of callose and ROS in citrus andArabidopsis, respectively. Importantly, we found that knocking out of theArabidopsisnegative immune regulators,AtNPR3andAtNPR4, and silencing of theirCitrus sinensisorthologCsNPR3, similarly suppressPsm- andCLas-induced callose and ROS overaccumulation, respectively, and that silencing ofCsNPR3also enhances HLB tolerance. These results reveal a conserved role of theNPR1/NPR3/NPR4-mediated signaling pathway in regulating plant immune balances and provide mechanistic support for overexpression ofAtNPR1or silencing ofAtNPR3/AtNPR4orthologs in citrus as a long-term solution to the HLB disease.
Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in pancreatic cancer
Authors: Cheng Caleb , Hu Jing , Mannan Rahul , Bhattacharyya Rupam , Rossiter Nicholas J. , Magnuson Brian , Wisniewski Jasmine P. , Zheng Yang , Xiao Lanbo , Li Chungen , Awad Dominik , He Tongchen , Bao Yi , Zhang Yuping , Cao Xuhong , Wang Zhen , Mehra Rohit , Morlacchi Pietro , Sahai Vaibhav , Pasca di Magliano Marina , Shah Yatrik M. , Ding Ke , Qiao Yuanyuan , Lyssiotis Costas A. , Chinnaiyan Arul M.
Published: March 2024

Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism12. For example, PDAC utilizes and is dependent on high levels of autophagy and other lysosomal processes3-5. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the challenge of identifying and characterizing favorable targets for drug development6. Here, we characterize PIKfyve, a lipid kinase integral to lysosomal functioning7, as a novel and targetable vulnerability in PDAC. In human patient and murine PDAC samples, we discovered thatPIKFYVEis overexpressed in PDAC cells compared to adjacent normal cells. Employing a genetically engineered mouse model, we established the essential role of PIKfyve in PDAC progression. Further, through comprehensive metabolic analyses, we found that PIKfyve inhibition obligated PDAC to upregulatede novolipid synthesis, a relationship previously undescribed. PIKfyve inhibition triggered a distinct lipogenic gene expression and metabolic program, creating a dependency onde novolipid metabolism pathways, by upregulating genes such asFASNandACACA. In PDAC, the KRAS-MAPK signaling pathway is a primary driver ofde novolipid synthesis, specifically enhancingFASNandACACAlevels. Accordingly, the simultaneous targeting of PIKfyve and KRAS-MAPK resulted in the elimination of tumor burden in a syngeneic orthotopic model and tumor regression in a xenograft model of PDAC. Taken together, these studies suggest that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS-MAPK-directed therapies for PDAC.
A Genome-wide Association Study Identifies Novel Genetic Variants Associated with Neck or Shoulder Pain in the UK Biobank (N = 441,757)
Authors: Tao Yiwen , Pan Qi , Cai Tengda , Lu Zen Haut , Haque Mainul , Dottorini Tania , Colvin Lesley A , Smith Blair H , Meng Weihua
Published: March 2024

Neck and shoulder pain are prevalent musculoskeletal disorders that significantly impact the quality of life for a substantial portion of the global population. Studies have shown that women are more susceptible than men. This study aims to discover genetic variants associated with neck or shoulder pain through a genome-wide association study (GWAS), using data from 441,757 participants in the UK Biobank. The primary GWAS revealed five significant genetic loci (including two novel) associated with neck or shoulder pain, with the most significant single nucleotide polymorphism (SNP) being rs9889282 (p= 2.63 x 10-12) nearCA10on chromosome 17. Two novel significant associations were detected on chromosomes 18 and 14, with the top SNPs being rs4608411 (p= 8.20 x 10-9) nearTCF4and rs370565192 (p= 3.80 x 10-8) inDCAF5, respectively. The female-specific GWAS identified two significant loci including one nearCA10and one nearLINC02770on chromosome 1 with the top SNP being rs5779595 (p= 3.57 x 10-8). The male-specific GWAS identified one locus inSLC24A3on chromosome 20 with the top SNP being rs16980973 (p= 6.52 x 10-9). The tissue expression analysis revealed a significant association between brain tissues and neck or shoulder pain. In summary, this study has identified novel genetic variants for neck or shoulder pain. Sex stratified GWAS also suggested that gender played a role in the occurrence of the phenotype.
Cell type profile variation in menstrual effluent by sample collection method identified using methylation cytometry
Authors: Vlasac Irma M. , Stolrow Hannah G. , Thayer Zaneta M. , Christensen Brock C. , Rivera Luisa
Published: March 2024

Menstrual effluent cell profiles have potential as noninvasive biomarkers of female reproductive and gynecological health and disease. We used DNA methylation-based cell type deconvolution (methylation cytometry) to identify cell type profiles in self-collected menstrual effluent. During the second day of their menstrual cycle healthy participants collected menstrual effluent using a vaginal swab, menstrual cup, and pad. Immune cell proportions were highest in menstrual cup samples, and epithelial cells were highest in swab samples. Our work demonstrates the feasibility and utility of menstrual effluent cell profiling in population-level research using remotely collected samples and DNA methylation.