bluuebunny/crossref_metadata_2025 huggingface dataset:
Are the lipid-lowering effects of incretin-based therapies relevant for cardiovascular benefit?
Authors: Alnima Teba , Smits Mark M. , Hanssen Nordin M.J.
Published: July 2024

Purpose of review

This review examines the impact of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on lipid profiles in individuals with type 2 diabetes mellitus and/or obesity, crucial for optimizing cardiovascular risk management.

Recent findings

GLP-1RAs affect lipid levels by reducing intestinal apolipoprotein B48 production and mesenteric lymph flow, while increasing catabolism of apolipoprotein B100. It remains unknown whether these effects are direct or indirect, but the improvements in lipid levels are strongly correlated to the drug-induced weight loss. Clinical trials demonstrate improvements in lipid profiles, with different effects per agent and dose. We deem it unlikely that improved lipid levels are sufficient to explain the beneficial effects of GLP-1RA on cardiovascular risk, especially given the improvement of many other risk factors (body weight, glycemic control, inflammation) while using these agents. Posthoc mediation analyses of large cardiovascular outcome trials may shed some light on the relative importance of each risk factor.

GLP-1RAs improve lipid profiles in clinical trials, but their complete cardiovascular benefits likely involve multifactorial mechanisms beyond lipid modulation.
Extracorporeal Cardiopulmonary Resuscitation
Authors: Stratton Michael , Edmunds Katherine
Published: July 2024

Extracorporeal cardiopulmonary resuscitation (eCPR) is increasingly being used for refractory cardiac arrest for both in-hospital and out-of-hospital cardiac arrests. The term eCPR refers to cannulating a patient to an extracorporeal membrane oxygenation (ECMO) circuit to provide perfusion after cardiac arrest refractory to standard cardiopulmonary resuscitation. Extracorporeal cardiopulmonary resuscitation has been shown to offer increased survival benefit among a select group of adult and pediatric patients experiencing refractory cardiac arrests, both in hospital and out of hospital. Extracorporeal cardiopulmonary resuscitation should be considered when (1) the cardiac arrest is witnessed, (2) the patient receives high-quality cardiopulmonary resuscitation, (3) the patient is at or in close proximity to an ECMO center, (4) there is a reversible cause for the cardiac arrest where the perfusion from the ECMO circuit serves as a bridge to recovery, and (5) the treating facility has a robust multidisciplinary system in place to facilitate rapidly moving patients from site of arrest to site of cannulation to intensive care unit. To develop an eCPR system of care, a multidisciplinary team consisting of prehospital, emergency medicine, in-hospital, proceduralist, perfusionist, and intensive care medical professionals must be established who support the use of eCPR for refractory cardiac arrest. The future of eCPR is the development of systems of care that use eCPR for a narrow subset of pediatric out-of-hospital cardiac arrests.
Individualized survival predictions using state space model with longitudinal and survival data
Authors: Cauchi Mark , Mills Andrew R. , Lawrie Allan , Kiely David G. , Kadirkamanathan Visakan
Published: July 2024

Monitoring disease progression often involves tracking biomarker measurements over time. Joint models (JMs) for longitudinal and survival data provide a framework to explore the relationship between time-varying biomarkers and patients’ event outcomes, offering the potential for personalized survival predictions. In this article, we introduce the linear state space dynamic survival model for handling longitudinal and survival data. This model enhances the traditional linear Gaussian state space model by including survival data. It differs from the conventional JMs by offering an alternative interpretation via differential or difference equations, eliminating the need for creating a design matrix. To showcase the model’s effectiveness, we conduct a simulation case study, emphasizing its performance under conditions of limited observed measurements. We also apply the proposed model to a dataset of pulmonary arterial hypertension patients, demonstrating its potential for enhanced survival predictions when compared with conventional risk scores.
Physics-informed scaling laws for the performance of pitching foils in schooling configurations
Authors: Gungor Ahmet , Khalid Muhammad Saif Ullah , Hemmati Arman
Published: July 2024

This study introduces novel physics-based scaling laws to estimate the propulsive performance of synchronously pitching foils in various schooling configurations. These relations are derived from quasi-steady lift-based and added mass forces. Hydrodynamic interactions among the schooling foils are considered through vortex-induced velocities imposed on them, constituting the ground effect. Generalized scaling equations are formulated for cycle-averaged coefficients of thrust and power. These equations encompass both the pure-pitching and induced velocity terms, capturing their combined effects. The equations are compared to computational results obtained from two-foil systems, exhibiting foil arrangements over a wide range of parameter space, including Strouhal number (0.15 ≤
St
≤ 0.4), pitching amplitude (

5
∘

≤

θ
0

≤

14
∘

) and phase difference (

0
∘

≤
ϕ
≤

180
∘

) at
Re
= 1000−10 000. The individual contributions of pure-pitching and induced velocity terms to propulsive performance elucidate that solely relying on the pure-pitching terms leads to inadequate estimation, emphasizing the significance of the induced velocity terms. The validity of the approach is further assessed by testing it with three-foil and five-foil configurations, which displays a collapse of estimated and measured results. This indicates that the scaling laws are applicable to multi-foil arrangements.
Sperm performance in the race for fertilization, the influence of female reproductive fluid
Authors: Pinzoni Livia , Rasotto Maria Berica , Gasparini Clelia
Published: July 2024

In studies of sperm competition, particularly in external fertilizers, the importance of the fertilization environment on the paternity share among rival males often goes overlooked. The female reproductive fluid (FRF), produced and released by females, creates the microenvironment that sperm encounter on their quest for fertilization and can generate paternity biases by affecting key traits in sperm competition. Yet, whether there is a direct link between FRF effects on sperm traits and its effect on competitive fertilization dynamics remains to be explored. Here, using the zebrafish
Danio rerio
, we compare within-female paternity share among two competing males and predictors of fertilization success (i.e. sperm traits) in the presence/absence of FRF. Our results unequivocally reveal a direct link between the direction and magnitude of the effect of FRF on sperm traits and the change in the competitive fertilization success of each male. This study demonstrates that the FRF directly mediates post-mating female control through its differential effect on sperm performance and that the FRF's effect on sperm quality alone is sufficient to predict the magnitude of the fitness effects. These findings highlight the need to consider the role of FRF in fertilization, avoiding biases resulting from an exclusive focus on male intrinsic sperm quality.
Enhancing wound healing through deep reinforcement learning for optimal therapeutics
Authors: Lu Fan , Zlobina Ksenia , Rondoni Nicholas A. , Teymoori Sam , Gomez Marcella
Published: July 2024

Finding the optimal treatment strategy to accelerate wound healing is of utmost importance, but it presents a formidable challenge owing to the intrinsic nonlinear nature of the process. We propose an adaptive closed-loop control framework that incorporates deep learning, optimal control and reinforcement learning to accelerate wound healing. By adaptively learning a linear representation of nonlinear wound healing dynamics using deep learning and interactively training a deep reinforcement learning agent for tracking the optimal signal derived from this representation without the need for intricate mathematical modelling, our approach has not only successfully reduced the wound healing time by 45.56% compared to the one without any treatment, but also demonstrates the advantages of offering a safer and more economical treatment strategy. The proposed methodology showcases a significant potential for expediting wound healing by effectively integrating perception, predictive modelling and optimal adaptive control, eliminating the need for intricate mathematical models.
An evolutionary differential game for regulating the role of monoclonal antibodies in treating signalling pathways in oesophageal cancer
Authors: Alajmi Mesfer , Roy Souvik
Published: July 2024

This work presents a new framework for a competitive evolutionary game between monoclonal antibodies and signalling pathways in oesophageal cancer. The framework is based on a novel dynamical model that takes into account the dynamic progression of signalling pathways, resistance mechanisms and monoclonal antibody therapies. This game involves a scenario in which signalling pathways and monoclonal antibodies are the players competing against each other, where monoclonal antibodies use Brentuximab and Pembrolizumab dosages as strategies to counter the evolutionary resistance strategy implemented by the signalling pathways. Their interactions are described by the dynamical model, which serves as the game’s playground. The analysis and computation of two game-theoretic strategies, Stackelberg and Nash equilibria, are conducted within this framework to ascertain the most favourable outcome for the patient. By comparing Stackelberg equilibria with Nash equilibria, numerical experiments show that the Stackelberg equilibria are superior for treating signalling pathways and are critical for the success of monoclonal antibodies in improving oesophageal cancer patient outcomes.
Thomas–Fermi theory of out-of-plane charge screening in graphene
Authors: Moroz Vitaly , Muratov Cyrill B.
Published: July 2024

This paper provides a variational treatment of the effect of external charges on the free charges in an infinite free-standing graphene sheet within the Thomas–Fermi theory. We establish existence, uniqueness and regularity of the energy minimizers corresponding to the free charge densities that screen the effect of an external electrostatic potential at the neutrality point. For the potential due to one or several off-layer point charges, we also prove positivity and a precise universal asymptotic decay rate for the screening charge density, as well as an exact charge cancellation by the graphene sheet. We also treat a simpler case of the non-zero background charge density and establish similar results in that case.
My model, it has three layers: a reduced model of smectic formation in two dimensions
Authors: King David A.
Published: July 2024

My model, it has three layers, 

Three layers is nematic.

And had it just two layers, 

it would be a smectic.

We study a reduced model of smectic formation in two dimensions where the particles occupy three equally spaced layers. The role of particle geometry comes in through the interactions between particles on the central layer and those above and below. The system is understood to be a perfect smectic when the central layer is empty, and nematic when all three are equally occupied. It is possible to compute the free energies of these states exactly. We find that the free energy of the nematic can only exceed that of the perfect smectic if the particle tips are sufficiently wide. While not an indication of a true smectic transition, this mirrors the fact that ellipsoids do not make a smectic but sphero-cylinders do.
Haplotype Analysis Reveals Pleiotropic Disease Associations in the HLA Region
Authors: Smith Courtney J. , Strausz Satu ,   FinnGen, Spence Jeffrey P. , Ollila Hanna M. , Pritchard Jonathan K.
Published: July 2024

The human leukocyte antigen (HLA) region plays an important role in human health through involvement in immune cell recognition and maturation. While genetic variation in the HLA region is associated with many diseases, the pleiotropic patterns of these associations have not been systematically investigated. Here, we developed a haplotype approach to investigate disease associations phenome-wide for 412,181 Finnish individuals and 2,459 traits. Across the 1,035 diseases with a GWAS association, we found a 17-fold average per-SNP enrichment of hits in the HLA region. Altogether, we identified 7,649 HLA associations across 647 traits, including 1,750 associations uncovered by haplotype analysis. We find some haplotypes show trade-offs between diseases, while others consistently increase risk across traits, indicating a complex pleiotropic landscape involving a range of diseases. This study highlights the extensive impact of HLA variation on disease risk, and underscores the importance of classical and non-classical genes, as well as non-coding variation.
Associations of circulating T-cell subsets in carotid artery stiffness: the Multi-Ethnic Study of Atherosclerosis
Authors: DeConne Theodore M. , Buzkova Petra , Pewowaruk Ryan , Delaney Joseph A. , Psaty Bruce M. , Tracy Russell P. , Doyle Margaret F. , Sitlani Colleen M. , Landay Alan L. , Huber Sally A. , Hughes Timothy M. , Bertoni Alain G. , Gepner Adam D. , Olson Nels C. , Ding Jingzhong
Published: July 2024

Background

Arterial stiffness measured by total pulse wave velocity (T-PWV) is associated with increased risk of multiple age-related diseases. T-PWV can be described by structural (S-PWV) and load-dependent (LD-PWV) arterial stiffening. T-cells have been associated with arterial remodeling, blood pressure, and arterial stiffness in humans and animals; however, it is unknown whether T-cells are related to S-PWV or LD-PWV. Therefore, we evaluated the cross-sectional associations of peripheral T-cell subpopulations with T-PWV, S-PWV, and LD-PWV stiffness.

Methods

Peripheral blood T-cells were characterized using flow cytometry and the carotid artery was measured using B-mode ultrasound to calculate T-PWV at the baseline examination in a subset of the Multi-Ethnic Study of Atherosclerosis (MESA, n=1,984). A participant-specific exponential model was used to calculate S-PWV and LD-PWV based on elastic modulus and blood pressure gradients. The associations between five primary (p-significance<0.01) and twenty-five exploratory (p-significance<0.05) immune cell subpopulations, per 1-SD increment, and arterial stiffness measures were assessed using adjusted, linear regressions.

Results

For the primary analysis, higher CD4+CD28-CD57+T-cells were associated with higher LD-PWV (β=0.04 m/s, p<0.01) after adjusting for co-variates. For the exploratory analysis, T-cell subpopulations that commonly shift with aging towards memory and differentiated/immunosenescent phenotypes were associated with greater T-PWV, S-PWV, and LD-PWV after adjusting for co-variates.

Conclusions

In this cross-sectional study, several T-cell subpopulations commonly associated with aging were related with measures of arterial stiffness. Longitudinal studies that examine changes in T-cell subpopulations and measures of arterial stiffness are warranted.
Immunological presentations and clinical features associated with Thymic Malignancies: The potential role of histological classifications and tumour grading on the future recurrence of opportunistic infections and paraneoplastic autoimmune conditions
Authors: Abikenari Matthew A , Delgado Sofia , Ashraghi Mohammad , Greco Giacomo , Tucker Andrew , Taberham Rhona , Quirke Mary , Stavroulias Dionisios , Yancheva Slaveya , Mccole Mark , Buckley Camilla , Leite Maria Isabel
Published: July 2024

Thymic malignancies are rare cancer tumours of the thymus arising from thymic epithelial cells and are characterized by a highly diversified clinical phenotype, substantial histologic and morphologic heterogeneity, and frequent presentations of associated paraneoplastic autoimmune syndromes. Myasthenia Gravis (MG) is the most prevalent of such autoimmune conditions, presenting in roughly half of thymoma patients, and is associated with substantial hyperactivation of T lymphocytes, highly dysregulated negative and positive T lymphocyte selection, leading to a systemic imbalance of the immune system, and consequently aiding and abetting the manifestation of severe opportunistic infections and multiple autoimmune comorbidities such as Pure Red Cell Aplasia and Good’s syndrome. Although the clinical, immunological and cytoarchitectural changes associated with thymomas have been increasingly elucidated in the contemporary literature, very few studies have interrogated the direct role of tumour staging and histological gradings on the occurrence and recurrence of infections and multiple autoimmune comorbidities. The current study aimed to interrogate the role of WHO thymoma classification criteria and Masaoka staging on the recurrence of severe opportunistic infections and the presentation of multiple paraneoplastic autoimmune syndromes post-thymectomy. The current study collected clinical and immunological data from 109 patients suffering from both MG and a pathologically proven thymoma. Statistical analysis of the collected data yielded significant associations between different stages of Masaoka grading and WHO classification on the number of autoimmune comorbidity and presence of severe recurrent infections, leading to the conclusion that early histological gradings and tumour infiltration patterns play a significant role in predicting future immunological behaviour, clinical outcomes, and susceptibility to recurrent infections. Future studies must further investigate the role of autoimmunity, its associated antibody expression profiles and thymic tissue pathology. Furthermore, novel therapeutics must further explore the role of emergent immunotherapeutics, such as adoptive cell therapies, as a viable patient-stratified treatment strategy for thymic malignancies.
Mapping protein conformational landscapes from crystallographic drug fragment screens
Authors: Saeed Ammaar A. , Klureza Margaret A. , Hekstra Doeke R.
Published: July 2024

Proteins are dynamic macromolecules. Knowledge of a protein’s thermally accessible conformations is critical to determining important transitions and designing therapeutics. Accessible conformations are highly constrained by a protein’s structure such that concerted structural changes due to external perturbations likely track intrinsic conformational transitions. These transitions can be thought of as paths through a conformational landscape. Crystallographic drug fragment screens are high-throughput perturbation experiments, in which thousands of crystals of a drug target are soaked with small-molecule drug precursors (fragments) and examined for fragment binding, mapping potential drug binding sites on the target protein. Here, we describe an open-source Python package, COLAV (COnformational LAndscape Visualization), to infer conformational landscapes from such large-scale crystallographic perturbation studies. We apply COLAV to drug fragment screens of two medically important systems: protein tyrosine phosphatase 1B (PTP-1B), which regulates insulin signaling, and the SARS CoV-2 Main Protease (MPro). With enough fragment-bound structures, we find that such drug screens also enable detailed mapping of proteins’ conformational landscapes.
Lesion location changes the association between brain excitability and motor skill acquisition post-stroke
Authors: De Las Heras Bernat , Rodrigues Lynden , Cristini Jacopo , Moncion Kevin , Dancause Numa , Thiel Alexander , Edwards Jodi D. , Eng Janice J. , Tang Ada , Roig Marc
Published: July 2024

Background

The capacity to reacquire motor skills lost after a stroke is crucial to promote upper-limb motor recovery but the impact of lesion location on motor skill acquisition and the underlying neurophysiological mechanisms remain uncertain.

Methods

We used transcranial magnetic stimulation to investigate associations between excitatory and inhibitory cortico-spinal excitability measures and the capacity to acquire a novel motor skill with the most affected hand in 103 individuals with cortical (n=34) or subcortical (n=69) lesions.

Results

Both groups showed similar motor skill acquisition, but subcortical lesions exhibited more impairment in the most affected hand and lower excitability in the ipsilesional hemisphere. In cortical lesions, motor skill acquisition was associated with lower motor thresholds (β=-0.25, 95% CI [−0.47,-0.03]; p=0.024) and higher intracortical inhibition (β=-3.93, 95% CI [−6.89,-0.98]; p=0.011) in the ipsilesional hemisphere. In contrast, in subcortical lesions motor skill acquisition was associated with smaller motor evoked potentials (β=-4.46, 95% CI [−8.54,-0.38]; p=0.033), less intracortical inhibition (β=3.45, 95% CI [0.34,6.56]; p=0.030) and higher facilitation (β=1.34,95% CI [0.15,2.54]; p= 0.028) ipsilesionally. Sensitivity analyses revealed that associations with intracortical inhibition and facilitation in the subcortical group were driven by lesions affecting the corticospinal tract. No associations were found in the contralesional hemisphere.

Conclusions

Reinforcing the existence of lesion-specific neurophysiological patterns, individuals with cortical and subcortical lesions show divergent associations between cortico-spinal excitability and motor skill acquisition. The use of cortico-spinal excitability as a biomarker to predict upper-limb recovery post-stroke or guide motor recovery interventions such as non-invasive brain stimulation should consider lesion location.
Deciphering autoantibody landscape of systemic sclerosis through systems-based approach: insights from a B-cell depletion clinical trial
Authors: Matsuda Kazuki M , Ebata Satoshi , Iwadoh Kazuhiro , Kotani Hirohito , Hisamoto Teruyoshi , Kuzumi Ai , Fukasawa Takemichi , Yoshizaki-Ogawa Asako , Sato Shinichi , Yoshizaki Ayumi
Published: July 2024

Systemic sclerosis (SSc) is a progressive fibrotic disorder with a high mortality rate, characterized by extensive autoantibody production. Despite recent advancements, effective treatments remain limited. Rituximab (RTX), a B-cell depleting agent, has shown promise in clinical trials. The DESIRES trial highlighted the reduction in modified Rodnan Skin Score (mRSS) and the association between serum immunoglobulin levels and RTX responsiveness. We employed proteome-wide autoantibody screening (PWAS) using wet protein arrays (WPAs) that display 13,455 human autoantigens to analyze serum samples from SSc patients in the DESIRES trial and age- and sex-matched healthy controls (HCs). As a result, the sum of autoantibody levels (SAL) was significantly higher in SSc patients compared to HCs. High responders (HRs) to RTX showed a greater initial SAL and significant reductions post-treatment, unlike low responders (LRs). Machine learning identified specific autoantibodies linked to disease status, and 58 autoantibodies were identified as clinically relevant. Some of those autoantibodies targeted membrane proteins including G protein-coupled receptors, associated with better differentiation between HRs and LRs. Our findings underscore the significance of autoantibodies in SSc pathogenesis and their potential role in predicting RTX responsiveness. This comprehensive autoantibody profiling could enhance diagnostic and therapeutic strategies, and moreover, better understanding of the pathophysiology of SSc.
Diversification ofPseudomonas aeruginosabiofilm populations under repeated phage exposures decreases the efficacy of the treatment
Authors: Martinet Mark Grevsen , Lohde Mara , Higazy Doaa , Brandt Christian , Pletz Mathias W. , Middelboe Mathias , Makarewicz Oliwia , Ciofu Oana
Published: July 2024

Phage therapy has been proposed as a therapeutic alternative to antibiotics for treatment of chronic, biofilm-relatedP. aeruginosainfections. To get a deeper insight into the complex biofilm-phage interactions, we investigated in the present study the effect of three successive exposures to lytic phages of biofilms formed by the reference strains PAO1 and PA14 as well as of two sequential clinicalP. aeruginosaisolates from the sputum of a patient with cystic fibrosis (CF). The Calgary device was employed as biofilm model and the efficacy of phage treatment was evaluated by measurements of the biomass stained with crystal violet (CV) and of the cell density of the biofilm bacterial population (CFU/ml) after each of the three phage exposures. The genetic alterations ofP. aeruginosaisolates from biofilms exposed to phages were investigated by whole genome sequencing.

We show here that the anti-biofilm efficacy of the phage treatment decreased rapidly with repeated applications of lytic phages onP. aeruginosastrains with different genetic background. Although we observed the maintenance of a small subpopulation of sensitive cells after repeated phage treatments, a fast recruitment of mechanisms involved in the persistence of biofilms to the phage attack occurred, mainly by mutations causing alterations of the phage receptors. However, mutations causing phage tolerant phenotypes such as alginate-hyperproducing mutants were also observed.

In conclusion, a decreased anti-biofilm effect occurred after repeated exposure to lytic phages ofP. aeruginosabiofilms due to recruitment of different resistance and tolerance mechanisms.
Ciliary biology intersects autism and congenital heart disease
Authors: Teerikorpi Nia , Lasser Micaela C. , Wang Sheng , Kostyanovskaya Elina , Bader Ethel , Sun Nawei , Dea Jeanselle , Nowakowski Tomasz J. , Willsey A. Jeremy , Willsey Helen Rankin
Published: July 2024

Autism spectrum disorder (ASD) commonly co-occurs with congenital heart disease (CHD), but the molecular mechanisms underlying this comorbidity remain unknown. Given that children with CHD come to clinical attention by the newborn period, understanding which CHD variants carry ASD risk could provide an opportunity to identify and treat individuals at high risk for developing ASD far before the typical age of diagnosis. Therefore, it is critical to delineate the subset of CHD genes most likely to increase the risk of ASD. However, to date there is relatively limited overlap between high confidence ASD and CHD genes, suggesting that alternative strategies for prioritizing CHD genes are necessary. Recent studies have shown that ASD gene perturbations commonly dysregulate neural progenitor cell (NPC) biology. Thus, we hypothesized that CHD genes that disrupt neurogenesis are more likely to carry risk for ASD. Hence, we performed anin vitropooled CRISPR interference (CRISPRi) screen to identify CHD genes that disrupt NPC biology similarly to ASD genes. Overall, we identified 45 CHD genes that strongly impact proliferation and/or survival of NPCs. Moreover, we observed that a cluster of physically interacting ASD and CHD genes are enriched for ciliary biology. Studying seven of these genes with evidence of shared risk (CEP290, CHD4, KMT2E, NSD1, OFD1, RFX3, TAOK1), we observe that perturbation significantly impacts primary cilia formationin vitro. Whilein vivoinvestigation ofTAOK1reveals a previously unappreciated role for the gene in motile cilia formation and heart development, supporting its prediction as a CHD risk gene. Together, our findings highlight a set of CHD risk genes that may carry risk for ASD and underscore the role of cilia in shared ASD and CHD biology.
Myeloid-Specific Thrombospondin-1 Deficiency Exacerbates Aortic Rupture via Broad Suppression of Extracellular Matrix Proteins
Authors: Zhou Ting , Yang Huan , Assa Carmel , DeRoo Elise , Bontekoe Jack , Burkel Brian , Ponik Suzanne , Lu Hong S. , Daugherty Alan , Liu Bo
Published: July 2024

Rationale

Rupture of abdominal aortic aneurysms (AAA) is associated with high mortality. However, the precise molecular and cellular drivers of AAA rupture remain elusive. Our prior study showed that global and myeloid-specific deletion of matricellular protein thrombospondin-1 (TSP1) protects mice from aneurysm formation primarily by inhibiting vascular inflammation.

Objective

To investigate the cellular and molecular mechanisms that drive AAA rupture by testing how TSP1 deficiency in different cell populations affects the rupture event.

Methods and Results

We deleted TSP1 in endothelial cells and macrophages --- the major TSP1-expressing cells in aneurysmal tissues ---- by crossbreedingThbs1flox/floxmice withVE-cadherin CreandLyz2-cremice, respectively. Aortic aneurysm and rupture were induced by angiotensin II in mice with hypercholesterolemia. Myeloid-specificThbs1knockout, but not endothelial-specific knockout, increased the rate of lethal aortic rupture by more than 2 folds. Combined analyses of single-cell RNA sequencing and histology showed a unique cellular and molecular signature of the rupture-prone aorta that was characterized by a broad suppression in inflammation and extracellular matrix production. Visium spatial transcriptomic analysis on human AAA tissues showed a correlation between low TSP1 expression and aortic dissection.

Conclusions

TSP1 expression by myeloid cells negatively regulates aneurysm rupture, likely through promoting the matrix repair phenotypes of vascular smooth muscle cells thereby increasing the strength of the vascular wall.
Pigment-dispersing factor neuropeptides act as multifunctional hormones and modulators in tardigrades
Authors: Dutta Soumi , Hering Lars , Grollmann Milena M. , Metzendorf Niklas , Gross Vladimir , Arakawa Kazuharu , Neupert Susanne , Stengl Monika , Herberg Friedrich W. , Mayer Georg
Published: July 2024

Pigment-dispersing factors (PDFs) are neuropeptides that play key roles in controlling the circadian rhythms in various insects, whereas their function remains elusive in other protostomes including tardigrades (water bears). Here we show that the three PDFs of the tardigrade Hypsibius exemplaris are co-localized in two pairs of inner lobe cells in the brain, whereas only one PDF occurs in four additional cerebral and two extracerebral cells. The axons of the inner lobe cells pass through the contralateral brain hemisphere, descend to the ventral nerve cord and terminate in two pairs of potential release sites in the posteriormost trunk ganglion. Using in vitro assays, we demonstrate that all three PDFs and their deorphanized receptor (PDFR) are functional. Widespread localization of PDFR suggests that tardigrade PDFs may act as multifunctional hormones and neuromodulators that control major functions including light detection, neural processing, locomotion, feeding, digestion, osmoregulation, growth, embryonic development, and oogenesis/reproduction.
Enhanced detection for antibiotic resistance genes in wastewater samples using a CRISPR-enriched metagenomic method
Authors: Mao Yuqing , Shisler Joanna L. , Nguyen Thanh H.
Published: July 2024

The spread of antibiotic resistance genes (ARGs) in the environment is a global public health concern. To date, over 5,000 genes have been identified to express resistance to antibiotics. ARGs are usually low in abundance for wastewater samples, making them difficult to detect. Metagenomic sequencing and quantitative polymerase chain reaction (qPCR), two conventional ARG detection methods, have low sensitivity and low throughput limitations, respectively. We developed a CRISPR-Cas9-modified next-generation sequencing (NGS) method to enrich the targeted ARGs during library preparation. The false negative and false positive of this method were determined based on a mixture of bacterial isolates with known whole-genome sequences. Low values of both false negative (2/1,208) and false positive (1/1,208) proved the method’s reliability. We compared the results obtained by this CRISPR-NGS and the conventional NGS method for six untreated wastewater samples. As compared to the ARGs detected in the same samples using the regular NGS method, the CRISPR-NGS method found up to 1,189 more ARGs and up to 61 more ARG families in low abundances, including the clinically important KPC beta-lactamase genes in the six wastewater samples collected from different sources. Compared to the regular NGS method, the CRISPR-NGS method lowered the detection limit of ARGs from the magnitude of 10−4to 10−5as quantified by qPCR relative abundance. The CRISPR-NGS method is promising for ARG detection in wastewater. A similar workflow can also be applied to detect other targets that are in low abundance but of high diversity.
Unique longitudinal contributions of sulcal interruptions to reading acquisition in children
Authors: Bouhali Florence , Dubois Jessica , Hoeft Fumiko , Weiner Kevin S.
Published: July 2024

A growing body of literature indicates strong associations between indentations of the cerebral cortex (i.e., sulci) and individual differences in cognitive performance. Interruptions, or gaps, of sulci (historically known aspli de passage) are particularly intriguing as previous work suggests that these interruptions have a causal effect on cognitive development. Here, we tested how the presence and morphology of sulcal interruptions in the left posterior occipitotemporal sulcus (pOTS) longitudinally impact the development of a culturally-acquired skill: reading. Forty-three children were successfully followed from age 5 in kindergarten, at the onset of literacy instruction, to ages 7 and 8 with assessments of cognitive, pre-literacy, and literacy skills, as well as MRI anatomical scans at ages 5 and 8. Crucially, we demonstrate that the presence of a left pOTS gap at 5 years is a specific and robust longitudinal predictor of better future reading skills in children, with large observed benefits on reading behavior ranging from letter knowledge to reading comprehension. The effect of left pOTS interruptions on reading acquisition accumulated through time, and was larger than the impact of benchmark cognitive and familial predictors of reading ability and disability. Finally, we show that increased local U-fiber white matter connectivity associated with such sulcal interruptions possibly underlie these behavioral benefits, by providing a computational advantage. To our knowledge, this is the first quantitative evidence supporting a potential integrative gray-white matter mechanism underlying the cognitive benefits of macro-anatomical differences in sulcal morphology related to longitudinal improvements in a culturally-acquired skill.
Multiplicity of Type 6 Secretion System toxins limits the evolution of resistance
Authors: Smith William P. J. , Armstrong-Bond Ewan , Coyte Katharine Z. , Knight Christopher G. , Basler Marek , Brockhurst Michael A.
Published: July 2024

The bacterial Type 6 Secretion System (T6SS) is a toxin-injecting nanoweapon that mediates competition in plant- and animal-associated microbial communities. Bacteria can evolvede novoresistance against T6SS attacks, but resistance is far from universal in natural communities, suggesting key features of T6SS weaponry may act to limit its evolution. Here, we combine eco-evolutionary modelling and experimental evolution to examine how toxin type and multiplicity inAcinetobacter baylyiattackers shape resistance evolution in susceptibleEscherichia colicompetitors. In both our models and experiments, we find that combinations of multiple distinct toxins limit resistance evolution by creating genetic bottlenecks, driving resistant lineages extinct before they can reach high frequency. We also show that, paradoxically, single-toxin attackers often drive the evolution of cross-resistance, protecting bacteria against unfamiliar toxin combinations, even though such evolutionary pathways were inaccessible against multi-toxin attackers. Our findings indicate that, comparable to antimicrobial and anticancer combination therapies, multi-toxin T6SS arsenals function to limit resistance evolution in competing microbes. This helps us to understand why T6SSs remain widespread and effective weapons in microbial communities, and why many bacteria T6SS-armed encode functionally diverse anti-competitor toxins.

Significance

Toxin secretion systems, such as T6SSs, are widely used by bacteria to inhibit competing microorganisms. Here, we show that the secretion of multiple toxins in combination can suppress the evolution of resistance to the T6SS, rationalising its continued widespread use across diverse communities. Our work shows that principles of combination therapy—well known in the context of antimicrobial, antiviral and anticancer therapies—also apply in the context of microbial warfare, helping to explain why many bacteria maintain diverse T6SS toxin arsenals. Resistance suppression is also a technologically useful property of T6SS toxin cocktails, which could be harnessed as part of future biocontrol or biotherapeutic applications, using live T6SS-armed bacteria to limit the growth of problem microorganisms.
Assessing the effects of warming and carbonate chemistry parameters on marine microbes in the Gulf of Mexico through basin-scale DNA metabarcoding
Authors: Anderson Sean R. , Silliman Katherine , Barbero Leticia , Gomez Fabian A. , Stauffer Beth A. , Schnetzer Astrid , Kelble Christopher R. , Thompson Luke R.
Published: July 2024

Ocean acidification and warming threaten marine life, yet the impact of these processes on microbes remains unclear. Here, we performed basin-scale DNA metabarcoding of prokaryotes (16S V4–V5) and protists (18S V9) in the Gulf of Mexico and applied generalized linear models to reveal group-specific environmental correlates of functionally diverse microbes. Models supported prior physiological trends for some groups, like positive temperature effects on SAR11 and SAR86, and a positive effect of pH onProchlorococcusthat implied a negative response to decreasing pH. New insights were revealed for protists, like Syndiniales and Sagenista (e.g., positive pH effects), which offset positive relationships with temperature and reinforced the importance of considering multiple stressors simultaneously. Indicator analysis revealed phytoplankton, likeOstreococcussp. andEmiliania huxleyi, that were associated with more acidic waters and may reflect candidate indicators of ocean change. Our findings highlight the need for sustained microbial sampling in marine systems, with implications for carbon export, nutrient cycling, and ecosystem health.
The big tau splice isoform resists Alzheimer’s-related pathological changes
Authors: Chung Dah-eun Chloe , Deng Xue , Yalamanchili Hari K. , Revelli Jean-Pierre , Han Alexander L. , Tadros Bakhos , Richman Ronald , Dias Michelle , Naini Fatemeh Alavi , Boeynaems Steven , Hyman Bradley T. , Zoghbi Huda Y.
Published: July 2024

In Alzheimer’s disease (AD), the microtubule-binding protein tau becomes abnormally hyperphosphorylated and aggregated in selective brain regions such as the cortex and hippocampus1–3. However, other brain regions like the cerebellum and brain stem remain largely intact despite the universal expression of tau throughout the brain. Here, we found that an understudied splice isoform of tau termed “big tau” is significantly more abundant in the brain regions less vulnerable to tau pathology compared to tau pathology-vulnerable regions. We used various cellular and animal models to demonstrate that big tau possesses multiple properties that can resist AD-related pathological changes. Importantly, human AD patients show a higher expression level of pathology-resisting big tau in the cerebellum, the brain region spared from tau pathology. Our study examines the unique properties of big tau, expanding our current understanding of tau pathophysiology. Altogether, our data suggest that alternative splicing to favor big tau is a viable strategy to modulate tau pathology.
Healthy aging delays and dedifferentiates high-level visual representations
Authors: Haupt Marleen , Garrett Douglas D. , Cichy Radoslaw M.
Published: July 2024

1.

Healthy aging impacts visual information processing with consequences for subsequent high-level cognition and everyday behavior, but the underlying neural changes in visual representations remain unknown. Here, we investigate the nature of representations underlying object recognition in older compared to younger adults by tracking them in time using EEG, across space using fMRI, and by probing their behavioral relevance using similarity judgements. Applying a multivariate analysis framework to combine experimental assessments, four key findings about how brain aging impacts object recognition emerge. First, aging selectively delays the formation of object representations, profoundly changing the chronometry of visual processing. Second, the delay in the formation of object representations emerges in high-level rather than low- and mid-level ventral visual cortex, supporting the theory that brain areas developing last deteriorate first. Third, aging reduces content selectivity in high-level ventral visual cortex, indicating age-related neural dedifferentiation as the mechanism of representational change. Finally, we demonstrate that the identified representations of the aging brain are behaviorally relevant, ascertaining ecological relevance. Together, our results reveal the impact of healthy aging on the visual brain.
patter: particle algorithms for animal tracking in R and Julia
Authors: Lavender Edward , Scheidegger Andreas , Albert Carlo , Biber Stanisław W. , Illian Janine , Thorburn James , Smout Sophie , Moor Helen
Published: July 2024

In the field of movement ecology, state-space models have emerged as a powerful modelling framework that represents individual movements and the processes that connect movements to observations. However, fitting state-space models to animal tracking data is often difficult and computationally expensive.

Here, we introducepatter, a package that provides particle filtering and smoothing algorithms that fit Bayesian state-space models to tracking data, with a focus on data from aquatic animals in autonomous receiver arrays.patteris written inR, with a high-performanceJuliabackend. Package functionality supports data simulation, preparation, filtering, smoothing and mapping.

In two worked examples, we demonstrate how to implementpatterto reconstruct the movements of a tagged animal in an acoustic telemetry system from acoustic detections and ancillary observations. With perfect information, the particle filter reconstructs the true (unobserved) movement path (Example One). More generally, particle-based methods represent an individual’s possible location probabilistically as a weighted series of samples (‘particles’). In our illustration, we resolve an individual’s (unobserved) location every two minutes during one month in minutes and use particles to visualise movements, map space use and quantify residency (Example Two).

patterfacilitates robust, flexible and efficient analyses of animal tracking data. The methods are widely applicable and enable refined analyses of home ranges, residency and habitat preferences.
Chromosome-scale genome assembly of acerola (Malpighia emarginata DC.)
Authors: Shirasawa Kenta , Harada Kazuhiko , Haramoto Noriaki , Aoki Hitoshi , Kammera Shota , Yamamoto Masashi , Nishizawa Yu
Published: July 2024

Acerola (Malpighia emarginata DC.) is a tropical evergreen shrub that produces vitamin C-rich fruits. Increasing fruit nutrition is one of the main targets of acerola breeding programs. Genomic tools have been shown to accelerate plant breeding even in fruiting tree species, which generally have a long life cycle; however, the availability of genomic resources in acerola, so far, has been limited. In this study, as a first step toward developing an efficient breeding technology for acerola, we established a chromosome-scale genome assembly of acerola using high-fidelity long-read sequencing and genetic mapping. The resultant assembly comprises 10 chromosome-scale sequences that span a physical distance of 1,032.5 Mb and contain 35,892 predicted genes. Phylogenetic analysis of genome-wide SNPs in 60 acerola breeding materials revealed three distinct genetic groups. Overall, the genomic resource of acerola developed in this study, including its genome and gene sequences, genetic map, and phylogenetic relationship among breeding materials, will not only be useful for acerola breeding but will also facilitate genomic and genetic studies on acerola and related species.
The role of the synaptic vesicle protein SV2A in regulating mitochondrial morphology and autophagy
Authors: Jörg Marko , Reichert Jonas S. , Pauly Karin , Distler Ute , Tenzer Stephan , Bartholomé Odile , Rogister Bernard , Kern Andreas , Behl Christian , Gellérie Martón , Cremer Christoph , Ritz Sandra , Peslalz Philipp , Plietker Bernd , Friedland Kristina
Published: July 2024

The synaptic vesicle glycoprotein 2A (SV2A) is a transmembrane protein of synaptic vesicles. It is involved in key functions of neurons, focused on the regulation of neurotransmitter release. Here we report three novel findings suggesting a completely new role of SV2A. First, we demonstrate that SV2A is localized at the outer mitochondrial membrane (OMM) using confocal and super-resolution microscopy. Second, Inactivation of SV2A in our cell and animal models leads to fragmented mitochondria. In addition, SV2A also affects the basal autophagic flux as well as mitophagy. Third, using proteomics analysis we demonstrate that SV2A interacts with the fission factor DRP1 and the autophagy factor ATG9A. Using AlphaFold3 we provide a first glimpse of the molecular interaction between DRP1 and SV2A. Our findings demonstrate that SV2A is not only a vesicular protein but also a mitochondrial protein in the OMM with defined functions regulating mitochondrial morphology and autophagy.
Interaural level difference sensitivity in neonatally deafened rats fitted with bilateral cochlear implants
Authors: Buchholz Sarah , Schnupp Jan W. H. , Arndt Susan , Roßkothen-Kuhl Nicole
Published: July 2024

Bilateral cochlear implant (CI) patients exhibit significant limitations in spatial hearing. Their ability to process interaural time differences (ITDs) is often impaired, while their ability to process interaural level differences (ILDs) remains comparatively good. Clinical studies aiming to identify the causes of these limitations are often plagued by confounds and ethical limitations. Recent behavioral work suggests that rats may be a good animal model for studying binaural hearing under neuroprosthetic stimulation, as rats develop excellent ITD sensitivity when provided with suitable CI stimulation. However, their ability to use ILDs has not yet been characterized. Objective of this study is to address this knowledge gap. Neontally deafened rats were bilaterally fitted with CIs, and trained to lateralize binaural stimuli according to ILD. Their behavioral ILD thresholds were measured at pulse rates from 50 to 2400 pps. CI rats exhibited high sensitivity to ILDs with thresholds of a few dB at all tested pulse rates. We conclude that early deafened rats develop good sensitivity, not only to ITDs but also to ILDs, if provided with appropriate CI stimulation. Their generally good performance, in line with expectations from other mammalian species, validates rats as an excellent model for research on binaural auditory prostheses.