bluuebunny/crossref_metadata_2025 huggingface dataset:
Visual Attention toward Patients with Hemifacial Microsomia Reconstruction: A Prospective Eye-Tracking Study
Authors: Villavisanis Dillan F. , Workman Clifford I. , Zapatero Zachary D. , Vu Giap H. , Humphries Stacey A. , Cho Daniel Y. , Swanson Jordan W. , Bartlett Scott P. , Chatterjee Anjan , Taylor Jesse A.
Published: December 2023

Background:

Facial areas attracting the most visual attention in hemifacial microsomia (HFM) are poorly understood. Furthermore, it is not clear whether and how visual attention changes from before surgery to after surgery. This study characterized layperson visual attention to before and after reconstruction HFM using eye-tracking technology.

Methods:

Visual fixations (Tobii Pro Nano) were recorded in 4 areas of interest from 60 participants completing 2 consecutive trials of 68 total images in each hemiface of 17 patients with HFM before and after orthognathic jaw reconstruction. Linear mixed effect models evaluated whether visual fixations were affected by surgical reconstruction.

Results: A total of

47,354 visual fixations were captured over 120 trials within defined areas of interest. Linear mixed effect models revealed significantly decreased postoperative visual fixations in the mandible and chin region [before reconstruction, 716 (54.8%); after reconstruction, 591 (45.2%); β = −0.198, SE = 0.056, z = −3.550, P < 0.001). Analysis also revealed significantly increased postoperative visual fixations in the forehead and orbit region (before reconstruction, 11,350 [48.6%]; after reconstruction, 12,000 [51.4%]; β = 0.086, SE = 0.015, z = 5.664, P < 0.00001).

Conclusions:

Following corrective jaw surgery for HFM, laypersons demonstrated significantly less visual attention to the mandible and chin and increased visual attention to the forehead and orbit. These findings suggest that postoperative improvement toward aesthetic normalcy may reduce visual attention to previously anomalous anatomy.
Nasal Dorsum Anatomy of Major Different Ethnicities—Surgical Implications: A Multicenter Radiologic Study
Authors: Rodrigues Dias David , Santos Mariline , Sharafi Maryam , Jalessi Maryam , McIntosh Cameron , Stutterheim James , Kim Jisun , Jeon Seung Yeon , Kang Sun Seong , Pedroza Carlos , Pedroza Daniel , Rusetsky Yury , Dobrokhotova Margarita , Lezhnev Dmitry , Gonçalves Ferreira Miguel
Published: December 2023

Background:

The heterogeneity of nasal features across different racial and ethnic groups is evident. This large-scale multicenter study was performed to evaluate the dorsal keystone area and its relation to superficial nasal anatomy through computed tomography (CT) scans.

Methods:

Six populations were included: South Caucasian, Middle Eastern, Black South African, Eastern Asian, Mestizo, and Eastern European. Each center obtained CT scans performed between January of 2020 and December of 2022 from patients presenting a nasal hump and from an age- and sex-matched control group. Osteocartilaginous measurements in relation to ethmoidal point and to rhinion, as well as their relation to superficial nasal anatomy, were collected from nasal CT scans in midsagittal view. These were compared between populations and, in each center, between patient groups (nasal hump versus no nasal hump).

Results:

The study population included 600 patients (254 with nasal hump) with a mean age of 33.98 years (range, 18 to 59 years); 55.6% were women. Average distances from the ethmoidal point were 10.1 ± 3.5 mm to the rhinion and 1.68 ± 0.23 mm to the beginning point of the nasal hump. In 96% of cases, the ethmoidal point was cranial or no more than 5 mm caudal to the beginning of the nasal hump. S-shaped nasal bones were associated with nasal hump, but angulation (kyphion angle) did not correlate with nasal hump height.

Conclusions:

In most patients, the nasal hump has no ethmoid bone underneath it, and the apex is located over the septal cartilage. The ethmoidal point is a reliable landmark and should be considered when evaluating established and new preservation and structural rhinoplasty approaches.
Local Postoperative Graft Inflammation in Pancreas Transplant Patients With Early Graft Thrombosis
Authors: Rydenfelt Kristina , Kjøsen Gisle , Horneland Rune , Krey Ludviksen Judith , Jenssen Trond Geir , Line Pål-Dag , Tønnessen Tor Inge , Mollnes Tom Eirik , Haugaa Håkon , Pischke Søren Erik
Published: December 2023

Background.

Graft thrombosis is the main cause of early graft loss following pancreas transplantation, and is more frequent in pancreas transplant alone (PTA) compared with simultaneous pancreas-kidney (SPK) recipients. Ischemia-reperfusion injury during transplantation triggers a local thromboinflammatory response. We aimed to evaluate local graft inflammation and its potential association with early graft thrombosis.

Methods.

In this observational study, we monitored 67 pancreas-transplanted patients using microdialysis catheters placed on the pancreatic surface during the first postoperative week. We analyzed 6 cytokines, interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-8, interferon gamma-induced protein 10 (IP-10), macrophage inflammatory protein 1β (MIP-1β), IL-10, and the complement activation product complement activation product 5a (C5a) in microdialysis fluid. We compared the dynamic courses between patients with pancreas graft thrombosis and patients without early complications (event-free) and between PTA and SPK recipients. Levels of the local inflammatory markers, and plasma markers C-reactive protein, pancreas amylase, and lipase were evaluated on the day of thrombosis diagnosis compared with the first week in event-free patients.

Results.

IL-10 and C5a were not detectable. Patients with no early complications (n = 34) demonstrated high IL-1ra, IL-6, IL-8, IP-10, and MIP-1β concentrations immediately after surgery, which decreased to steady low levels during the first 2 postoperative days (PODs). Patients with early graft thrombosis (n = 17) demonstrated elevated IL-6 (P = 0.003) concentrations from POD 1 and elevated IL-8 (P = 0.027) concentrations from POD 2 and throughout the first postoperative week compared with patients without complications. IL-6 (P < 0.001) and IL-8 (P = 0.003) were higher on the day of thrombosis diagnosis compared with patients without early complications. No differences between PTA (n = 35) and SPK (n = 32) recipients were detected.

Conclusions.

Local pancreas graft inflammation was increased in patients experiencing graft thrombosis, with elevated postoperative IL-6 and IL-8 concentrations, but did not differ between PTA and SPK recipients. Investigating the relationship between the local cytokine response and the formation of graft thrombosis warrants further research.
Special considerations for assessing and caring for autism in girls and women
Authors: Rynkiewicz Agnieszka , Zheng Shuting , Lacroix Adeline
Published: December 2023

Purpose of review

As the specificities of autistic women are increasingly recognized, this review aims to highlight emerging areas of research. These areas primarily focus on measurement bias of diagnostic tools, the physical and mental health of autistic women, and the unique aspects of the lives of autistic women, both personally and professionally across all life stages.

Recent findings

Conventional diagnostic tools struggle to capture the specificities of autism in females, but more sensitive instruments like the GQ-ASC (Girls’ Questionnaire for Autism Spectrum Conditions), later also referred to as Q-ASC (Questionnaire for Autism Spectrum Conditions) in the scientific literature, show better performances. Autistic women face particular challenges, including an increased risk of physical and mental health problems throughout their lives as women (puberty, motherhood, menopause). Autistic women also encounter specific difficulties in their employment that require greater consideration.

The findings of this review identify research areas that need to be developed to better understand and support autistic girls and women and to enhance clinical practice for them.
The mobilome of Lactobacillus crispatus M247 includes two novel genetic elements: Tn7088 coding for a putative bacteriocin and the siphovirus prophage ΦM247
Authors: Colombini Lorenzo , Santoro Francesco , Tirziu Mariana , Lazzeri Elisa , Morelli Lorenzo , Pozzi Gianni , Iannelli Francesco
Published: December 2023

Lactobacillus crispatus

is a member of the vaginal and gastrointestinal human microbiota. Here we determined the complete genome sequence of the probiotic strain M247 combining Nanopore and Illumina technologies. The M247 genome is organized in one circular chromosome of 2 336 109 bp, with a GC content of 37.04 % and 2303 ORFs, of which 1962 could be annotated. Analysis of the M247 mobilome, which accounts for 14 % of the whole genome, revealed the presence of: (i) Tn7088, a novel 14 105 bp long integrative and mobilizable element (IME) containing 16 ORFs; (ii) ΦM247, a novel 42 510 bp long siphovirus prophage containing 52 ORFs; (iii) three clustered regularly interspaced short palindromic repeats (CRISPRs); and (iv) 226 insertion sequences (ISs) belonging to 14 different families. Tn7088 has a modular organization including a mobilization module encoding FtsK homologous proteins and a relaxase, an integration/excision module coding for an integrase and an excisionase, and an adaptation module coding for a class I bacteriocin and homologous to the listeriolysin S (lls) locus of

Listeria monocytogenes

. Genome-wide homology search analysis showed the presence of Tn7088-like elements in 12 out of 23

L

.

crispatus

complete public genomes. Mobilization and integration/excision modules are essentially conserved, while the adaptation module is variable since it is the target site for the integration of different ISs. Prophage ΦM247 contains genes for phage structural proteins, DNA replication and packaging, lysogenic and lytic cycles. ΦM247-like prophages are present in seven

L

.

crispatus

complete genomes, with sequence variability mainly due to the integration of ISs. PCR and sequencing showed that the Tn7088 IME excises from the M247 chromosome producing a circular form at a concentration of 4.32×10−5 copies per chromosome, and reconstitution of the Tn7088 chromosomal target site occurred at 6.65×10−4 copies per chromosome. The ΦM247 prophage produces an excised form and a reconstituted target site at a level of 3.90×10−5 and 2.48×10−5 copies per chromosome, respectively. This study identified two novel genetic elements in

L. crispatus

. Tn7088 represents the first example of an IME carrying a biosynthetic gene cluster for a class I bacteriocin in

L. crispatus

.
Variability in single-cell oxygen consumption kinetics
Authors: Botte Ermes , Cui Yuan , Magliaro Chiara , Tenje Maria , Koren Klaus , Rinaldo Andrea , Stocker Roman , Behrendt Lars , Ahluwalia Arti
Published: December 2023

We combined microfabricated devices with multiparameter identification algorithms to probe the variability in size-dependent oxygen consumption parameters of single human hepatic cells. We demonstrate that single cells exhibit an oxygen-dependent metabolic rate, typical of Michaelis-Menten kinetics, and that their maximal oxygen consumption is significantly lower than that of monolayers or 3D hepatic cell aggregates. Notably, we found that clusters of two or more cells competing for a limited oxygen supply reduced their maximal single-cell consumption rate, highlighting their ability to adapt to local resource availability and the presence of nearby cells. Next, we used our high-throughput approach to characterize the covariance of size and oxygen consumption within a cell population.

The results show that cooperative behaviour emerges in cell clusters, and that single-cell size and metabolism can be described by a lognormal joint probability density. Our study thus serves as a foundation to connect the metabolic activity of single human hepatocytes to their tissue-or organ-level metabolism as well as describe its size-related variability through scaling laws.
Digital breast tomosynthesis(DBT) vs 2D mammography and impact of combined use: A meta-analysis
Authors: Andharia Dev , Shah Hetvi , Prajapati Anushka Dipakkumar , Bhansali Aayushi Darshan , Shah Abhijay B. , Desai Dev
Published: December 2023

Background

Having breast cancer and receiving treatment for it is viewed as a very traumatic experience for women. From the recent advances in breast cancer diagnosis protocol; The triple assessment for a lump in the breast is the best practice and its application towards early disease detection is crucial. For which, 2D mammography is used. The limitation of this technique is a potential tissue overlap in dense breasts. Digital breast tomosynthesis (DBT) is a new imaging technology that can address the limitations of 2D mammography. This study aims to highlight the use of DBT.

Methods

The study population included all women aged from 18 to 80. For this analysis, the subdivision of the population is not created. A total of 28 RCTs with a total of 1,735,126 patients were selected for the DBT+FFDM vs FFDM study and 5 RCTs with a total of 554,419 patients were selected for the DBT vs FFDM study.

Results

For the DBT+FFDM vs FFDM; The overall diagnostic odds ratio was 1.28 with a 95%CI [1.22-1.33], the Decrease in RR is 2.43% and the increase in CDR is 1.583. for DBT vs FFDM; the overall diagnostic odds ratio was 1.38 with a 95%CI [1.28-1.50], a decrease in RR is 1.70%, and an increase in CDR is 1.4.

Conclusion

DBT+FFDM and DBT do outweigh FFDM alone.
Programmed withdrawal of cilia maintenance followed by centriole capping leads to permanent cilia loss during cerebellar granule cell neurogenesis
Authors: Constable Sandii , Ott Carolyn M. , Lemire Andrew L. , White Kevin , Lim Amin , Lippincott-Schwartz Jennifer , Mukhopadhyay Saikat
Published: December 2023

Primary cilia in brain neurons provide a privileged compartment for binding and responding to extracellular ligands such as sonic hedgehog. Paradoxically, cilia in differentiating cerebellar granule cells are deconstructed during neurogenesis. To identify mechanisms underlying this newly defined cilia deconstruction pathway, we used single cell transcriptomic and immunocytological analyses to compare the transcript and protein signatures of differentiating and progenitor granule cells. We found that differentiating granule cells lacked transcripts for key regulators of pre-mitotic cilia resorption, suggesting cilia disassembly in differentiating cells was distinct from pre-mitotic cilia resorption. Further analysis revealed that during differentiation, transcription of genes required for cilia maintenance decreased. Specifically, protein components of intraflagellar transport complexes, pericentrosomal material and centriolar satellites all decreased as granule cells matured. The changes in transcription and translation correlated with the downregulation of sonic hedgehog signaling at the onset of differentiation. We also found binding of centriolar cap proteins to the mother centrioles as granule cell neurons matured. These data indicate that global, developmentally programmed, diminution of cilium maintenance caused cilia deconstruction in differentiating granule cells. Furthermore, the capping of docked mother centrioles prevents cilia regrowth likely blocking dysregulated sonic hedgehog signaling and tumorigenesis.
The NeuroML ecosystem for standardized multi-scale modeling in neuroscience
Authors: Sinha Ankur , Gleeson Padraig , Marin Bóris , Dura-Bernal Salvador , Panagiotou Sotirios , Crook Sharon , Cantarelli Matteo , Cannon Robert C. , Davison Andrew P. , Gurnani Harsha , Silver R. Angus
Published: December 2023

Data-driven models of neurons and circuits are important for understanding how the properties of membrane conductances, synapses, dendrites and the anatomical connectivity between neurons generate the complex dynamical behaviors of brain circuits in health and disease. However, the inherent complexity of these biological processes make the construction and reuse of biologically detailed models challenging. A wide range of tools have been developed to aid their construction and simulation, but differences in design and internal representation act as technical barriers to those who wish to use data-driven models in their research workflows. NeuroML, a model description language for computational neuroscience, was developed to address this fragmentation in modeling tools. Since its inception, NeuroML has evolved into a mature community standard that encompasses a wide range of model types and approaches in computational neuroscience. It has enabled the development of a large ecosystem of interoperable open source software tools for the creation, visualization, validation and simulation of data-driven models. Here, we describe how the NeuroML ecosystem can be incorporated into research workflows to simplify the construction, testing and analysis of standardized models of neural systems, and supports the FAIR (Findability, Accessibility, Interoperability, and Reusability) principles, thus promoting open, transparent and reproducible science.
RluA is the major mRNA pseudouridine synthase inEscherichia coli
Authors: Schaening-Burgos Cassandra , Li Gene-Wei , Gilbert Wendy
Published: December 2023

Pseudouridine (Ψ) is an ubiquitous RNA modification, present in the tRNAs and rRNAs of species across all domains of life. Conserved pseudouridine synthases modify the mRNAs of diverse eukaryotes, but the modification has yet to be identified in bacterial mRNAs. Here, we report the discovery of pseudouridines in mRNA fromE. coli. By testing the mRNA modification capacity of all 11 known pseudouridine synthases, we identify RluA as the predominant mRNA-modifying enzyme. RluA, a known tRNA and 23S rRNA pseudouridine synthase, modifies at least 31 of the 44 high-confidence sites we identified inE. colimRNAs. Using RNA structure probing data to inform secondary structures, we show that the target sites of RluA occur in a common sequence and structural motif comprised of a ΨURAA sequence located in the loop of a short hairpin. This recognition element is shared with previously identified target sites of RluA in tRNAs and rRNA. Overall, our work identifies pseudouridine in key mRNAs and suggests the capacity of Ψ to regulate the transcripts that contain it.

Author Summary

While RNAs are initially transcribed using only the nucleotides A, G, C and U, these can be enzymatically modified into many different post-transcriptional modifications. tRNAs and rRNAs across all domains of life are modified with pseudouridine, an isoform of uridine that is inserted by highly conserved enzymes. In many eukaryotes, it has been demonstrated that some of these enzymes can also insert pseudouridines in mRNA, where they are poised to impact gene expression through their effects on the transcript. Here we show that protein-coding transcripts inE. coliare also modified with pseudouridine, indicating that mRNA pseudouridylation is also a highly conserved activity. RluA is the main mRNA pseudouridine synthase, introducing the modification into the transcripts of dozens of protein coding genes with high specificity. Its target sites are defined by a combined sequence and secondary structure motif. Two additional enzymes, RluC and RluD, introduce a few additional sites. All three of these enzymes belong to the same sub-family of pseudouridine synthases, and homologs of these also modify mRNAs in humans. Thus, mRNA modification by these enzymes might be a conserved activity with the capacity to impact gene regulation.
When to attend? Temporal attention interacts with expectation
Authors: Duyar Aysun , Ren Shiyang , Carrasco Marisa
Published: December 2023

Temporal attention is voluntarily deployed at specific moments, whereas temporal expectation is deployed according to timing probabilities. When the target appears at an expected moment in a sequence, temporal attention improves performance at the attended moments, but the timing and the precision of the attentional window remain unknown. Here we independently and concurrently manipulated temporal attention–via behavioral relevance–and temporal expectation–via session-wise precision and trial-wise hazard rate–to investigate whether and how these mechanisms interact to improve perception. Our results reveal that temporal attention interacts with temporal expectation–the higher the precision, the stronger the attention benefit, but surprisingly this benefit decreased with delayed onset despite the increasing probability of stimulus appearance. When attention was suboptimally deployed to earlier than expected moments, it could not be reoriented to a later time point. These findings provide evidence that temporal attention and temporal expectation are different mechanisms, and highlight their interplay in optimizing visual performance.

Relevance

Our ability to process visual information is limited both across space and time. Here we disentangle how two mechanisms–attention and expectation–help us overcome temporal limitations. We concurrently manipulated attention and expectation independently to investigate whether and how they interact. We found that temporal attention interacts with two distinct forms of expectation. Temporal expectation strengthens the benefits of temporal attention on performance for the attended time points, depending on how precise the expectations are. Surprisingly, the advantages of attention decrease when stimuli occur later than expected, suggesting a limitation of attention to reorient from earlier to later time points. This study provides further evidence that humans cannot sustain temporal attention even over short periods, reveals that although temporal attention and expectation interact to improve visual performance, expectation suboptimally guides attention, and highlights that attention and expectation are different temporal mechanisms.
Multi-assay approach shows species-associated personality patterns in two socially distinct gerbil species
Authors: Tchabovsky Andrey V. , Surkova Elena N. , Savinetskaya Ludmila E.
Published: December 2023

We aimed to investigate whether two closely related but socially distinct species of gerbils differ in personality patterns. Using a suit of multivariate repeated assays (docility test, dark-light emergence test, startle test, novel object test, elevated platform test, and stranger test), we assessed contextual and temporal consistency of docility, boldness, exploration, anxiety, and sociability in the solitary midday gerbil,Meriones meridianus, and social Mongolian gerbil,M. unguiculatus. We revealed contextually consistent and highly repeatable sex-independent but species-specific personality traits. Species differed in temporal repeatability of different behaviours, and contextual consistency was more pronounced in solitaryM. meridianusthan in socialM. unguiculatus. This finding contradicts the social niche specialization hypothesis, which suggests that personality traits should be more consistent in more social species. Instead, we hypothesize that social complexity should favour more flexible and less consistent behavioural traits. The habituation effect indicative of learning abilities was weak in both species yet stronger in socialM. unguiculatus, supporting the relationship between the sociality level and cognitive skills. In both species, only a few different behavioural traits covaried, and the sets of correlated behaviours were species-specific such that the two species did not share any pair of correlated traits. Between-species differences in personality traits, habituation, and behavioural syndromes may be linked to differences in sociality. The lack of prominent behavioural syndromes is consistent with the idea that context-specific individual behavioural traits might be favoured to allow more flexible and adequate responses to changing environments than syndromes of correlated functionally different behaviours.
A Bayesian Approach to Non-Metric Hyperbolic Multi-Dimensional Scaling
Authors: Jolis Milo , Praturu Anoop , Sharpee Tatyana
Published: December 2023

This paper explores the intersection of hyperbolic geometry, non-metric techniques, and Bayesian frameworks to extend the capabilities of Bayesian Hyperbolic Multi-Dimensional Scaling (HMDS). While hyperbolic geometry is gaining attention for its ability to represent hierarchical relationships, traditional metrics impose constraints on distances. Non-metric techniques offer flexibility in capturing complex structures, making them suitable for scenarios where metric distances are less meaningful. The paper introduces a novel extension of Bayesian HMDS, incorporating non-metric techniques, enabling the embedding of Euclidean data within a hyperbolic space. The approach simultaneously fits for curvature and coordinates, leveraging the scaling properties of hyperbolic space. The non-metric Bayesian Hyperbolic MDS is expected to unveil new insights into hierarchical structures within complex datasets, providing a versa-tile tool for analyzing high-dimensional data flexibly and accurately. The efficacy of the proposed method is demonstrated through synthetic data experiments, showcasing its ability to capture non-linear transformations and accurately predict underlying curvature, with an emphasis on its ro-bustness to hyperparameter choices.
Improving peripheral reading with non-invasive transcranial electrical stimulation of early visual areas
Authors: Silva Andrew E. , Mungalsingh Melanie A. , Raudzus Louise , Thompson Benjamin
Published: December 2023

We investigated the ability of two non-invasive transcranial electrical stimulation (tES) protocols targeting early visual areas to improve peripheral visual word recognition in separate within-subject, double-blind, sham-controlled experiments with normal observers. English sentences were presented 10 degrees below fixation using a rapid serial visual presentation (RSVP). Transcranial random noise stimulation (tRNS) applied bilaterally on either size of the occipital pole (Oz) elicited a significant performance benefit, but transcranial direct current stimulation (tDCS) applied to Oz did not. These results highlight important factors that may influence the effectiveness of non-invasive brain stimulation methods for enhancing peripheral processing of text, such as stimulation type. While more work is necessary to better understand the relationship between tES and peripheral reading, the present results contribute to the growing body of work implicating tES as a potential tool for enhancing peripheral visual processing.
Cardiomyocyte Globotriaosylceramide Accumulation in Adult Male Patients with Fabry Disease and IVS4 + 919G>A GLA Mutation is Progressive with Age and Correlates with Left Ventricular Hypertrophy and Reduced Left Ventricular Ejection Fraction
Authors: Chang Fu-Pang , Hsu Ting-Rong , Hung Sheng-Che , Sung Shih-Hsien , Yu Wen-Chung , Niu Dau-Ming , Najafian Behzad
Published: December 2023

Background

While cardiovascular complications are the most common cause of mortality in Fabry disease, the relationship between globotriaosylceramide (GL-3) accumulation, the hallmark of Fabry cardiomyopathy, and cardiac hypertrophy has not been fully elucidated.

Methods

We developed unbiased stereology protocols to quantify the ultrastrcture of Fabry cardiomyopathy. Endomyocardial biopsies from 10 adult male enzyme replacement therapy naïve Fabry patients with IVS4 + 919G>A GLA mutation were studied. The findings were correlated with cardiac MRI and clinical data.

Results

Ultrastructural parameters showed significant relationships with key imaging and clinical and functional variables. Average cardiomyocyte volume and GL-3 volume per cardiomyocyte were progressively increased with age. Eighty-four percent of left ventricular mass index (LVMI) variability was explained by cardiomyocyte nuclear volume, age and plasma globotriaosylsphingosine with cardiomyocyte nuclear volume being the only independent predictor of LVMI. Septal thickness was directly and left ventricular ejection fraction (LVEF) was inversely correlated with cardiomyocyte GL-3 accumulation. Sixty-five percent of left ventricular ejection fraction (LVEF) variability was explained by cardiomyocyte GL3 volume, serum α-galactosidase-A activity and age with cardiomyocyte GL3 volume being the only independent predictor of LVEF. Residual α-galactosidase-A activity was directly correlated with myocardial microvasculature density.

Conclusions

The unbiased stereological methods introduced in this study unraveled novel relationships between cardiomyocyte structure and important imaging and clinical parameters. These novel tools can help better understand Fabry cardiomyopathy pathophysiology.

Clinical Perspective

What is new?

We developed a novel unbiased quantitative approach to study cardiac biopsies by electron microscopy.

Ultrastructural parameters showed significant relationships with key clinical, imaging, cardiac functional variables in cardiac biopsies from patients with Fabry disease.

What are the clinical implications?

These quantitative approaches are powerful tools to better understand pathophysiology of Fabry disease and potentially in other cardiomyopathies.
Polygenic prediction of human longevity on the supposition of pervasive pleiotropy
Authors: Jabalameli M.Reza , Lin Jhih-Rong , Zhang Quanwei , Wang Zhen , Mitra Joydeep , Nguyen Nha , Gao Tina , Khusidman Mark , Atzmon Gil , Milman Sofiya , Vijg Jan , Barzilai Nir , Zhang Zhengdong D.
Published: December 2023

The highly polygenic nature of human longevity renders cross-trait pleiotropy an indispensable feature of its genetic architecture. Leveraging the genetic correlation between the aging-related traits (ARTs), we sought to model the additive variance in lifespan as a function of cumulative liability from pleiotropic segregating variants. We tracked allele frequency changes as a function of viability across different age bins and prioritized 34 variants with an immediate implication on lipid metabolism, body mass index (BMI), and cognitive performance, among other traits, revealed by PheWAS analysis in the UK Biobank. Given the highly complex and non-linear interactions between the genetic determinants of longevity, we reasoned that a composite polygenic score would approximate a substantial portion of the variance in lifespan and developed the integrated longevity genetic scores (iLGSs) for distinguishing exceptional survival. We showed that coefficients derived from our ensemble model could potentially reveal an interesting pattern of genomic pleiotropy specific to lifespan. We assessed the predictive performance of our model for distinguishing the enrichment of exceptional longevity among long-lived individuals in two replication cohorts and showed that the median lifespan in the highest decile of our composite prognostic index is up to 4.8 years longer. Finally, using the proteomic correlates ofiLGS, we identified protein markers associated with exceptional longevity irrespective of chronological age and prioritized drugs with repurposing potentials for gerotherapeutics. Together, our approach demonstrates a promising framework for polygenic modeling of additive liability conferred by ARTs in defining exceptional longevity and assisting the identification of individuals at higher risk of mortality for targeted lifestyle modifications earlier in life. Furthermore, the proteomic signature associated withiLGShighlights the functional pathway upstream of the PI3K-Akt that can be effectively targeted to slow down aging and extend lifespan.
Cold Atmospheric Helium Plasma in the Post-Covid Era: A Promising Tool for the Disinfection of Silicone Endotracheal Prostheses
Authors: da Silva Diego Morais , do Nascimento Fellype , Milhan Noala Vicensoto , de Oliveira Maria Alcionéia Carvalho , Guerreiro Cardoso Paulo Francisco , Legendre Daniel , Aoki Fabio Gava , Kostov Konstantin Georgiev , Koga-Ito Cristiane Yumi
Published: December 2023

The COVID-19 pandemic resulted in a high prevalence of laryngotracheal stenosis. The endoluminal tracheal prostheses used to treat this condition are made of medical-grade silicone (MGS). Despite their excellent properties, the main limitation of these prostheses is the formation of a polymicrobial biofilm on their surfaces that interacts with the underlying mucosa, causing local inflammation and interfering with the local healing process, ultimately leading to further complications in the clinical scenario. Cold atmospheric plasma (CAP) shows antibiofilm properties on several microbial species. The present study evaluated the inhibitory effect of CAP on multispecies biofilms grown on MGS surfaces. In addition to the MGS characterization before and after CAP exposure, the cytotoxicity of CAP on immortalized human bronchial epithelium cell line (BEAS-2B) was evaluated. The aging time test reported that CAP could temporarily change the MGS surface wetting characteristics from hydrophilic (80.5°) to highly hydrophilic (< 5°). ATR-FTIR shows no significant alterations in the surficial chemical composition of MGS before and after CAP exposure for 5 min. A significant log reduction of viable cells in mono-species biofilms (log CFU/mL) ofC. albicans, S. aureus, andP. aeruginosa(0.636, 0.738, and 1.445, respectively) was detected after CAP exposure. Multi-species biofilms exposed to CAP showed significant viability reduction forC. albicansandS. aureus(1.385 and 0.831, respectively). The protocol was not cytotoxic to BEAS-2B. It could be concluded that CAP can be a simple and effective method to delay the multi-species biofilm formation inside the endotracheal prosthesis.
GOAT: efficient and robust identification of geneset enrichment
Authors: Koopmans Frank
Published: December 2023

Geneset enrichment analysis is foundational to the interpretation of high throughput biology. We here present GOAT (https://ftwkoopmans.github.io/goat), a parameter-free permutation-based algorithm for geneset enrichment analysis of preranked genelists. Estimated geneset p-values are well calibrated under the null hypothesis and invariant to geneset size. GOAT consistently identifies more Gene Ontology terms in real-world datasets than current methods and is available as an R package and online tool.
Cognitive Phenotype Shifts in Risk-Taking: Interplay of Non-Suicidal Self-Injury Behaviors and Intensified Depression
Authors: Lu Yi-Long , Ge Yuqi , Li Mingzhu , Liang Shutian , Zhang Xiaoxi , Sui Yupeng , Yang Lei , Li Xueni , Zhang Yuyanan , Yue Weihua , Zhang Hang , Yan Hao
Published: December 2023

Background

Non-suicidal self-injury (NSSI) behavior is significantly prevalent in both adolescents and psychiatric populations, particularly in individuals with major depressive disorder (MDD). NSSI can be considered a result of risky decision-making in response to negative emotions, where individuals choose self-harm over other less harmful alternatives, suggesting a potential decision-making deficit in those engaging in NSSI. This study delves into the complex relationship between NSSI and depression severity in decision-making and its cognitive underpinnings.

Methods

We assessed decision behaviors in 57 MDD patients with NSSI, 42 MDD patients without NSSI and 142 healthy controls using the Balloon Analogue Risk Task, which involves risk-taking, learning, and exploration in uncertain scenarios. Using computational modeling, we dissected the nuanced cognitive dimensions influencing decision behaviors. A novel statistical method was developed to elucidate the interaction effects between NSSI and depression severity.

Results

Contrary to common perceptions, we found that individuals with NSSI behaviors were typically more risk-averse. Meanwhile, there was a complex interaction between NSSI and depression severity in shaping risk-taking behaviors. As depressive symptoms intensified, these individuals with NSSI began to perceive less risk and behave more randomly.

Conclusions

This research provides new insights into the cognitive aspects of NSSI and depression, highlighting the importance of considering the influence of comorbid mental disorders when investigating the cognitive underpinnings of such behaviors, especially in the context of prevalent cross-diagnostic phenomena like NSSI behaviors.
Empowering human-like walking with a bio-inspired gait controller for an under-actuated torque-driven human model
Authors: Amini Samane , Kardan Iman , Seth Ajay , Akbarzadeh Alireza
Published: December 2023

Human gait simulation plays a crucial role in providing insights into various aspects of locomotion, such as diagnosing injuries and impairments, assessing abnormal gait patterns, and developing assistive and rehabilitation technologies. To achieve more realistic results in gait simulation, it is necessary to utilize a comprehensive model that closely replicates the kinematics and kinetics of the human gait pattern. OpenSim software provides anthropomorphic and anatomically accurate human skeletal structures that enable users to create personalized models for individuals to accurately replicate real human behavior. However, torque-driven models face challenges in balancing unactuated degrees of freedom during forward dynamic simulations. Adopting a bio-inspired strategy that ensures an individual’s balance with a minimized energy expenditure, this paper proposes a gait controller for a torque-deriven OpenSim model to achieve a stable walking. The proposed controller takes a model-based approach to calculate a “Balance Equivalent Control Torque” and uses the concept of the hip-ankle strategy to distribute this balance torque to the lower-limb joints. To optimize the controller gains and the “Balance Distribution Coefficients”, an interface is stablished between MATLAB and OpenSim that is capable of conducting controllable forward dynamic simulations. The simulation results demonstrate that the torque-driven model can walk naturally with joint torques suitably matching experimental data. The robustness of the bio-inspired gait controller is also assessed by applying a range of external forces on the upper body to disturb the model. The robustness analysis demonstrates the quick and effective balance recovery mechanism of the proposed bio-inspired controller.
An Automatic Glaucoma Grading Method Based on Attention Mechanism and EfficientNet-B3 Network
Authors: Zhang Xu , Lai Fuji , Chen Weisi , Yu Chengyuan
Published: December 2023

Deep learning has received considerable attention in the computer vision field and has been widely studied, especially in recognizing and diagnosing ophthalmic diseases. Currently, glaucoma recognition algorithms are mostly based on unimodal OCT, the visual field for glaucoma auxiliary diagnosis. Such algorithms have poor robustness and limited help for glaucoma auxiliary diagnosis; therefore, this experiment is proposed to use a 2D fundus image and 3D-OCT scanner two modal data as the experimental dataset and use the EfficientNet-B3 network and ResNet34 network models for feature extraction and fusion to improve automatic glaucoma grading accuracy. Since fundus images usually contain a large number of meaningless black background regions, this may lead to feature redundancy. Therefore, this experiment employs an attention mechanism that focuses the attention of the convolutional neural network on eye subject features to improve the performance of the glaucoma autoclassification model.
Latent Dirichlet Allocation Mixture Models for Nucleotide Sequence Analysis
Authors: Wang Bixuan , Mount Stephen M.
Published: December 2023

Strings of nucleotides that carry biological information are typically described using sequence motifs that can be represented by weight matrices or consensus sequences. However, many biological signals in DNA or RNA are recognized by multiple factors in temporal sequence, consist of a mixture of sometimes dissimilar alternative motifs, or may be described better by base composition. Here we apply the Latent Dirichlet Allocation (LDA) mixture model to nucleotide sequences, using k-mers as features, in three related approaches. First, positions in aligned sequences are used as samples. Alternatively, whole sequences are used as samples, either with positional k-mers or with bulk k-mers occurring throughout the sequence. LDA readily identifies motifs, including such elusive cases as the intron branch site. LDA can also identify subtypes of sequence, such as splice site subtypes enriched in long vs. short introns, and can reliably distinguish such properties as reading frame or species of origin. Our results show that LDA is a useful model for describing heterogeneous signals, for assigning individual sequences to subtypes, and for identifying and characterizing sequences that do not fit recognized subtypes. Because LDA topic models are interpretable, they also aid the discovery of new motifs, even those present in a small fraction of samples, allowing a user to hypothesize potential regulatory factors. In summary, LDA can identify and characterize signals in nucleotide sequences and is useful for identifying candidate regulatory factors involved in complex biological processes.
Changes in internalizing and externalizing problems in Dutch children and adolescents receiving youth care before and during the COVID-19 pandemic
Authors: Broek Emma M. , De Meyer Ronald , van der Rijken Rachel , Zijlmans Josjan , van Oers Hedy A. , Luijten Michiel A.J. , Alrouh Hekmat , Popma Arne , Bartels Meike , Vermeiren Robert R.J.M. , Polderman Tinca J. C. , Tieskens Jacintha M.
Published: December 2023

Background

The COVID-19 pandemic had serious effects on the mental health of children and adolescents. However, it is unclear how the pandemic may have affected treatment effects and outcomes in youth care. We investigated if treatment effects and externalizing and internalizing problems of children and adolescents receiving youth care were affected by the COVID-19 pandemic.

Methods

We used data from children and adolescents in youth care (N= 1,090,Mage= 12.85 (SD= 2.83; range = 8-18 years)). Internalizing and externalizing problems were assessed at the start and end of treatment using the Child Behavior Checklist. We inspected change in internalizing and externalizing problems and clinical status at the end of treatment to investigate treatment effects, and the level of problems at the start and end of treatment. Outcomes were compared between three groups: children treated entirely before the COVID-19 pandemic, children who experienced the transition into COVID-19 measures during treatment, and children treated entirely during the pandemic.

Results

We did not find evidence that the pandemic affected treatment effectiveness. However, fewer children who were treated during the pandemic recovered from externalizing problems compared to children treated before the pandemic. Children who received treatment entirely during the pandemic also showed more internalizing and externalizing problems at both the start and end of their treatment, and children who experienced the transition into the pandemic showed elevated externalizing problems at both timepoints.

Conclusions

Although the change in internalizing and externalizing problems from start to end of treatment was not affected by the pandemic, our findings that children are entering and leaving care with more problems suggest that child mental health has deteriorated since the pandemic.
Plasma p-tau212: antemortem diagnostic performance and prediction of autopsy verification of Alzheimer’s disease neuropathology
Authors: Kac Przemysław R. , González-Ortiz Fernando , Emeršič Andreja , Dulewicz Maciej , Koutarapu Srinivas , Turton Michael , An Yang , Smirnov Denis , Kulczyńska-Przybik Agnieszka , Varma Vijay , Ashton Nicholas J. , Montoliu-Gaya Laia , Camporesi Elena , Winkel Izabela , Paradowski Bogusław , Moghekar Abhay , Troncoso Juan C. , Brinkmalm Gunnar , Resnick Susan M , Mroczko Barbara , Kvartsberg Hlin , Gregorič Kramberger Milica , Hanrieder Jörg , Čučnik Saša , Harrison Peter , Zetterberg Henrik , Lewczuk Piotr , Thambisetty Madhav , Rot Uroš , Galasko Douglas , Blennow Kaj , Karikari Thomas K.
Published: December 2023

Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer’s disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Thereafter, we examined the diagnostic utility of plasma p-tau212. In five cohorts (n=388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a novel peripherally accessible biomarker of AD pathophysiology.
Exploratory electronic health record analysis with ehrapy
Authors: Heumos Lukas , Ehmele Philipp , Treis Tim , Upmeier zu Belzen Julius , Namsaraeva Altana , Horlava Nastassya , Shitov Vladimir A. , Zhang Xinyue , Zappia Luke , Knoll Rainer , Lang Niklas J. , Hetzel Leon , Virshup Isaac , Sikkema Lisa , Roellin Eljas , Curion Fabiola , Eils Roland , Schiller Herbert B. , Hilgendorff Anne , Theis Fabian J.
Published: December 2023

With progressive digitalization of healthcare systems worldwide, large-scale collection of electronic health records (EHRs) has become commonplace. However, an extensible framework for comprehensive exploratory analysis that accounts for data heterogeneity is missing. Here, we introduce ehrapy, a modular open-source Python framework designed for exploratory end-to-end analysis of heterogeneous epidemiology and electronic health record data. Ehrapy incorporates a series of analytical steps, from data extraction and quality control to the generation of low-dimensional representations. Complemented by rich statistical modules, ehrapy facilitates associating patients with disease states, differential comparison between patient clusters, survival analysis, trajectory inference, causal inference, and more. Leveraging ontologies, ehrapy further enables data sharing and training EHR deep learning models paving the way for foundational models in biomedical research. We demonstrated ehrapy’s features in five distinct examples: We first applied ehrapy to stratify patients affected by unspecified pneumonia into finer-grained phenotypes. Furthermore, we revealed biomarkers for significant differences in survival among these groups. Additionally, we quantify medication-class effects of pneumonia medications on length of stay. We further leveraged ehrapy to analyze cardiovascular risks across different data modalities. Finally, we reconstructed disease state trajectories in SARS-CoV-2 patients based on imaging data. Ehrapy thus provides a framework that we envision will standardize analysis pipelines on EHR data and serve as a cornerstone for the community.