bluuebunny/crossref_metadata_2025 huggingface dataset:
Measuring Professional Governance
Authors: Lundmark Martina , Antonsson Linda , Nobrell Anette , Hommel Ami , Ramji Rathi
Published: October 2024

OBJECTIVE

To translate the Verran Professional Governance Scale© (VPGS©) into Swedish, adapt it to the Swedish context, and validate it.

BACKGROUND

Magnet®-recognized hospitals have proven successful in reversing negative trends regarding nursing shortage. A change in organizational and management structures is required, and professional governance is fundamental. However, in a Swedish context, there are no validated instruments to measure professional governance.

METHODS

The instrument was translated from English to Swedish and synthesized into a unified version. It was back translated, discussed in an expert panel, and pilot tested with cognitive interviews of nurses.

RESULTS

A new Swedish version of the VPGS© was developed. The expert group reached a consensus, and the scale-level Content Validity Index value shows high relevance. Some words and sentences were revised, and an introduction was added.

CONCLUSIONS

The study generated a Swedish version of the VPGS©, which can be used to measure nurses' perceptions of professional governance behaviors.
Aligning the World Health Organization's (WHO) package of interventions for rehabilitation for cancer with the mission of the International Psycho-Oncology Society's: promoting psychosocial care for all people affected by cancer
Authors: Signorelli Christina , Hart Nicolas H. , Mullen Louise , Nekhlyudov Larissa , Travado Luzia , Lam Wendy W. T. , Henry Melissa , László Dégi Csaba , Haywood Darren , Jefford Michael
Published: October 2024

The number of people living with and beyond cancer continues to increase worldwide, bringing significant attention to their rehabilitation needs. Globally, psychosocial services are largely inadequate, with many cancer survivors experiencing unmet psychosocial needs. The World Health Organization (WHO) recognizes rehabilitation as an essential component of universal health coverage to prevent disease-related conditions, while also improving physical and mental functioning and overall well-being. The Package of Interventions for Rehabilitation (PIR) was developed by the WHO to address the global need for rehabilitation across 20 conditions with high prevalence and high levels of associated disability, including cancer. Many aspects of the WHO PIR align with the mission and focus of the International Psycho-Oncology Society (IPOS). This commentary describes the WHO PIR for Cancer and proposes opportunities to advance cancer rehabilitation research, policy, and practice as they align with recent and ongoing initiatives of IPOS.
Multiorgan Crystal Deposition in Acute Ethylene Glycol Toxicity
Authors: Uy Matthew , Molina Kimberley
Published: October 2024

Ethylene glycol (EG) is a widely available chemical and a well-known toxin in forensic pathology, which can lead to severe metabolic acidosis and death. Its metabolism in the body leads to formation of calcium oxalate (CO) crystals, which can precipitate in the kidney leading to renal failure. Although the identification of CO crystals in the kidney is widely known, the deposition of CO crystals in other organs has only occasionally been reported and seldom studied. This report examines 18 deaths due to EG toxicity for the presence of CO crystals in various organs. CO crystals were identified most often in the kidneys, followed by the brain and lungs. It is hypothesized that crystal deposition in these other organs may contribute to the toxicity of EG.
Immersive virtual reality for chronic neuropathic pain after spinal cord injury: a pilot, randomized, controlled trial
Authors: Tabacof Laura , Salazar Sophia I. , Breyman Erica , Nasr Leila , Dewill Sophie , Aitken Annie , Canori Alexandra , Kypros Michael , Cortes Mar , Fry Adam , Wood Jamie , Putrino David
Published: October 2024

Introduction:

Neuropathic pain (NP) poses significant challenges for individuals with spinal cord injury (SCI), often inadequately managed by current interventions. Immersive virtual reality (IVR) has emerged as a promising approach for pain modulation, yet robust evidence is lacking.

Objectives:

This pilot study investigated the analgesic effects of different IVR environments (scenic, somatic) compared with a control environment, and explored psychomotor properties influencing pain attenuation.

Methods:

Twenty-two participants with NP caused by SCI were randomized into 3 IVR environments: somatic (n = 8), scenic (n = 7), and control (n = 8), undergoing 3 weekly sessions over 4 weeks with baseline, postintervention, and one-month follow-ups.

Results:

There was a significant interaction effect between VR environment and time point on Neuropathic Pain Symptom Inventory scores (F(4,37.0) = 2.80, P = 0.04). Scenic VR participants exhibited reduced scores postintervention and at follow-up, with no significant changes in somatic VR or control environments. Similar trends were observed in secondary measures, such as Neuropathic Pain Scale and pain numeric rating scale. Enjoyment and presence were associated with decreased pain-change scores (F(1, 252) = 4.68, P = 0.03 for enjoyment; F(1, 223.342) = 7.92, P = 0.005 for presence), although not significantly influenced by VR environment or time point.

Conclusion:

Both environments showed reduced pain outcomes, underscoring the need for personalized IVR pain therapies and informing further technology development for NP management.
Diffusely Increased FDG Uptake of the Kidney Caused by Severe Renal Artery Stenosis
Authors: Jiao Benzheng , Yang Liping , Ma Xiaobo , Dong Aisheng , Zhao Hongguang
Published: October 2024

Renal artery stenosis can result in renovascular hypertension and ischemic nephropathy. We describe FDG PET/CT and delayed abdominal FDG PET/MRI findings in a kidney associated with severe renal artery stenosis resulting from renal artery invasion in retroperitoneal alveolar echinococcosis. The renal parenchyma showed diffusely increased activity on both FDG PET/CT and delayed FDG PET/MRI. There was no activity in the renal collecting system on FDG PET/CT and focal urine activity in the renal calyces on delayed FDG PET/MRI. This case indicates that renal artery stenosis should be included in the differential diagnosis of diffuse renal parenchymal FDG uptake.
Quantitative Evaluation of the Effects of Blepharoplasty on Visual Field, Corneal Changes, and Cosmetic Appearance
Authors: Akyol Gözde , Muslu Ümran , Demir Emre , Duran Mustafa , Gölpinar Murat
Published: October 2024

Blepharoplasty is an important eyelid surgical procedure, involving aesthetic and functional changes to the eyelids. The aim of this study is to investigate the effects of upper eyelid blepharoplasty on changes in the visual field, corneal changes, and cosmetic appearance. This study was performed with preoperative and postoperative facial photographs of 32 patients who underwent bilateral blepharoplasty. Marginal reflex distance (MRD1), percentage of corneal exposure area (CEA), and brow height (BH) were obtained from photographs. intraocular pressure (IOP) and ocular biometric parameters were also obtained. The morphometric and ocular parameters obtained from preoperative, postoperative first-month, and postoperative third-month patients were compared using repeated measures ANOVA test. Significant differences in MRD1, CEA, and BH were observed between preoperative, postoperative first-month, and postoperative third-month patients. Improvements were observed in left axis and right corneal astigmatism axis measurements in the postoperative third month compared with preoperative measurements, and the positive change was statistically significant (P=0.020, P=0.036). Upper eyelid blepharoplasty could provide satisfactory functional and aesthetic outcomes by contributing to the improvement of pseudoptosis and reduction in eyebrow height postoperatively.
Secondary Reconstruction of Premaxilla With a π-Shaped Fibula Osteocutaneous Flap
Authors: Miyamoto Shimpei , Arikawa Masaki , Okazaki Mutsumi
Published: October 2024

Midface deformities due to oncologic bony defects are often difficult to secondarily correct. The authors herein report 2 cases of secondary reconstruction of an oncological premaxillary defect using a π-shaped fibula osteocutaneous flap. The authors divided the fibula into 3 pieces and made it π-shaped to reconstruct the curvature of the premaxilla. The palatal mucosal defect was closed with a skin paddle. The vascular pedicle was hooked up to the neck vessels either directly or by interposition of vessel grafts. Reconstruction was successful in both cases. The facial appearance was greatly improved, the palatal defects were closed, and the need for obturator prosthetics was eliminated. Immediate bony reconstruction is preferred for premaxilla defects. However, secondary reconstruction with a π-shaped fibula osteocutaneous flap is a feasible option with high potential for improving aesthetic and functional outcomes.
Spatial Transcriptomic Signatures of Early Acute T Cell–mediated Rejection in Kidney Transplants
Authors: Kang Minji , Kwon Haeyoon , Song Jeongin , Jang Yunyoung , Yang Seung Hee , Cha Seung-Min , Moon Ji Hwan , Kim Yong Chul , Kim Hyun Je
Published: October 2024

Background.

Kidney transplantation significantly improves the quality of life for those with end-stage renal failure, yet allograft rejection resulting from immune cell interactions remains a persistent challenge. Although T cell–directed immunosuppressive drugs effectively contain graft rejection in most patients, a notable proportion still experiences acute T cell–mediated rejection (TCMR). Despite an emphasis on suppressing T cell–mediated immune responses, successful control over TCMR is not always achieved, suggesting the potential involvement of factors beyond T cells.

Methods.

Biopsy samples from suspicious (borderline) for acute TCMR (borderline TCMR) and non-TCMR patients were obtained 9 d postsurgery, and spatial transcriptomics profiling was conducted using the GeoMx Digital Spatial Profiler platform. Regions of interest in the glomerulus and interstitium were selected on the basis of immunohistochemistry staining anti-CD3 to identify areas with T-lymphocyte infiltration. Differential gene expression analysis was performed using unpaired t tests.

Results.

Unbiased clustering of transcriptional profiles across all regions of interest showed distinct transcriptional profiles between glomeruli and interstitium in non-TCMR samples, whereas borderline TCMR samples displayed no distinct transcriptional profiles between these regions. Contrary to the prevailing T cell–centric view, we observed pathways and genes associated with innate immunity-related inflammatory conditions expressed in glomerular regions of borderline TCMR biopsies. Immunofluorescence staining for CD68 confirmed the presence of macrophages in the glomeruli of the post-TCMR sample in a validation cohort, indicating macrophage involvement in the glomerular response after TCMR.

Conclusions.

Activation of the innate immune response in borderline TCMR appears to impact not only the interstitium but also the glomerulus. Glomerulus-specific immune signatures suggest the role of the innate immune system in rejection. This nuanced understanding proposes the necessity for tailored therapeutic interventions targeting both innate and adaptive immune pathways to enhance transplant outcomes.
Nova Scotia’s Deemed Consent for Deceased Organ Donation: Family Member Perspectives and Experiences in the ICU Setting
Authors: Sarti Aimee J. , Sutherland Stephanie , Weiss Matthew J. , Landry Alain , Hemming Heather , Dirk Jade , Lotherington Ken , Beed Stephen
Published: October 2024

Background.

The purpose of this study was to explore the experience of family members of potential organ donors in the intensive care unit following the change to deemed consent legislation in Nova Scotia.

Methods.

This was a qualitative study with semistructured, in-depth interviews with 17 family members who were asked to make an organ donation decision on behalf of patients admitted to the intensive care unit in Nova Scotia. We analyzed themes using a descriptive approach. Participants were recruited from the organ donation organization in Nova Scotia, Canada.

Results.

Participant awareness and knowledge of the Human Organ and Tissue Donation Act legislation varied from individuals having no awareness and knowledge of the bill to those who had awareness and optimism that the legislation would be beneficial for increasing organ donation rates in the province. Other themes emerging from the interviews included (1) COVID context, (2) quality of healthcare professional care, (3) family support, and (4) barriers to donation (waiting, consent questionnaire, and patient transfers).

Conclusions.

The Human Organ and Tissue Donation Act legislation included enhanced support, which was viewed positively by family members. There is a need for continued evaluation as most participants felt it was too early to see the tangible impacts of the newly implemented legislation.
A Novel GelMA-OrnMA Electrically Conductive Bioink for Developing Engineered Neural Tissues
Authors: Sakr Mahmoud A. , Dixit Kartikeya , Hyun Kinam , Siddiqua Sumi , Shin Su Ryon , Kumar Hitendra , Kim Keekyoung
Published: October 2024

Electrical conductivity is a crucial requirement of matrices for developing engineered neural tissues. A conductive matrix not only supports cell growth but also provides potential to stimulate the cells. However, electrically conductive matrices often require inclusion of synthetic polymers, nanomaterials and large number of ionic species. While enhancing electrical conductivity, often properties like transparency, mechanical stiffness and biocompatibility are compromised which can render the resulting matrices partially suitable for neural tissue engineering. Further, the byproducts of matrix degradation can have unforeseen influences. Therefore, electrically active matrices are required which provide a suitable combination of electrical conductivity, mechanical properties and biocompatibility. In this work, a novel biomaterial is described which results in optically transparent, electrically conductive and highly biocompatible matrices along with ability to match the native neural tissue stiffness. Using gelatin methacryloyl (GelMA) as base hydrogel, we covalently incorporated zwitterionic functional groups to obtain a composite matrix. The zwitterion moieties were derived from Ornithine by synthesizing ornithine methacryloyl (OrnMA) and blending with GelMA inks. Through systematic characterization we demonstrated the suitability of GelMA-OrnMA hydrogels in providing mechanical stiffness matching the native neural tissues, supporting proliferation of human astrocytes in 3D culture and electrical conductivity in the range required for electrically active cell types like astrocytes. Owing to their electrical conductivity, these matrices also influenced the growth of astrocytes which manifested as significant changes in their organization and morphology. These findings suggest that GelMA-OrnMA has immense potential as a bioink for developing engineered neural tissues.
Benchmarking Sequence-Based and AlphaFold-Based Methods for pMHC-II Binding Core Prediction: Distinct Strengths and Consensus Approaches
Authors: Ko Soobon , Li Honglan , Kim Hongeun , Shin Woong-Hee , Ko Junsu , Choi Yoonjoo
Published: October 2024

Background

Interactions between peptide and MHC class II (pMHC-II) are crucial for T-cell recognition and immune responses, as MHC-II molecules present peptide fragments to T cells, enabling the distinction between self and non-self antigens. Accurately predicting the pMHC-II binding core is particularly important because it provides insights into pMHC-II interactions and T-cell receptor engagement. Given the high polymorphism and peptide-binding promiscuity of MHC-II molecules, computational prediction methods are essential for understanding pMHC-II interactions. While sequence-based methods are widely used, recent advances in AlphaFold-based structure prediction have opened new possibilities for improving pMHC-II binding core predictions.

Results

We benchmarked four recent pMHC-II prediction methods with a focus on binding core prediction: two sequence-based methods, NetMHCIIpan and DeepMHCII, and two AlphaFold-based structure prediction methods, AlphaFold2 fine-tuned for peptide interactions (AF2-FT) and AlphaFold3 (AF3). The AlphaFold-based methods showed strong performance in predicting positive binders, with AF3 achieving the highest positive recall (0.86) and AF2-FT performing similarly (0.81). However, both methods frequently misclassified unbound peptides as binders. NetMHCIIpan excelled at identifying non-binders, achieving the highest negative recall (0.93), but had lower positive recall (0.44). In contrast, DeepMHCII demonstrated moderate performance without any notable strength. Consensus approaches combining AlphaFold-based methods for binder identification with filtering using NetMHCIIpan improved overall prediction precision (0.94 and 0.87 for known and unknown binding status, respectively).

Conclusions

This study highlights the complementary strengths of AlphaFold-based and sequence-based methods for predicting pMHC-II binding core regions. AlphaFold-based methods excel in predicting positive binders, while NetMHCIIpan is highly effective at identifying non-binders. Future research should focus on improving the prediction of unbound peptides for AlphaFold-based models. Since NetMHCIIpan’s binding core predictive ability is already high, future efforts should concentrate on enhancing its binding prediction to further improve overall accuracy.
Unraveling the Potential of Hypericin: A Novel Approach to Targeting PCSK9 Mutations in Cholesterol Management
Authors: Ferrari Ivan Vito
Published: October 2024

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a pivotal role in regulating cholesterol metabolism by promoting the degradation of low-density lipoprotein receptors (LDLR), leading to elevated levels of LDL cholesterol in the bloodstream. Recent studies have identified key residues—Arg-194, Asp-374, and Phe-379—that are crucial for the interaction between PCSK9 and LDLR, and mutations in these residues can significantly alter this interaction. In this study, we employed molecular docking and in silico mutational analysis to assess the binding affinities of natural compounds, including Hypericin, amentoflavone, Bilobetin, Gingetin, and Progesterone, to wild-type and mutant PCSK9. We explored nine specific PCSK9 mutations (R194, D374Y, F379), targeting changes in residues known to influence LDLR binding affinity. Our results indicate that Hypericin demonstrates favorable binding to wild-type PCSK9, interacting with the critical residues involved in LDLR binding, while other mutations yield diverse effects on compound affinities. Notably, certain mutations, such as R194A and D374Y, significantly impact binding affinities, revealing both potential benefits and challenges in targeting PCSK9 with natural compounds. This study provides insights into potential therapeutic strategies for modulating PCSK9 activity and suggests new avenues for developing safer, more effective treatments for hypercholesterolemia.
Relation of CMV and brain atrophy to trajectories of immunosenescence in diverse populations
Authors: Touil Hanane , Luquez Tain , Comandante-Lou Natacha , Lee Annie J , Fujita Masashi , Habeck Christian , Kroshilina Alex , Hegewisch-Solloa Everardo , McInvale Julie , Zuroff Leah , Isnard Stephane , Walker Elisabeth , Zhang Lili , Routy Jean-Pierre , Zhang Ya , Mace Emily M. , Klotz Luisa , Wiendl Heinz , Xia Zongqi , Bar-Or Amit , Menon Vilas , Stern Yaakov , De Jager Philip L.
Published: October 2024

Immunosenescence (ISC), the aging of the immune system, has largely been studied in populations of European descent. Here, circulating immune cell cytometric data from African-American, Hispanic, and non-Hispanic White participants were generated. Known and novel age effects were identified using either a meta-analysis approach or a parallel genetic approach. Most results are consistent across the three populations, but some cell populations display evidence of heterogeneity, such as a PD-L1+CD56+NK cell subset. The study estimated “Immunological Age” (IA) during physiologic aging. While we found no relation of IA to Multiple Sclerosis, IA is associated with entorhinal cortex atrophy, a presymptomatic feature of Alzheimer’s disease, linking neurodegeneration and peripheral immunity. ISC trajectories were also inferred, highlighting age, CMV status, and genetic ancestry as key influences. Our assessment offers reference ISC trajectories for personalization of assessments of immune function over the life course in diverse populations.
Improving gut virome comparisons using predicted phage host information
Authors: Shamash Michael , Sinha Anshul , Maurice Corinne F.
Published: October 2024

The human gut virome is predominantly made up of bacteriophages (phages), viruses that infect bacteria. Metagenomic studies have revealed that phages in the gut are highly individual specific and dynamic. These features make it challenging to perform meaningful cross-study comparisons. While several taxonomy frameworks exist to group phages and improve these comparisons, these strategies provide little insight into the potential effects phages have on their bacterial hosts. Here, we propose the use of predicted phage host families (PHFs) as a functionally relevant, higher rank unit of phage taxonomy to improve these cross-study analyses. We first show that bioinformatic predictions of phage hosts are accurate at the host family level by measuring their concordance to Hi-C sequencing-based predictions in human and mouse fecal samples. Next, using phage host family predictions, we determined that PHFs reduce intra- and interindividual ecological distances compared to viral contigs in a previously published cohort of 10 healthy individuals, while simultaneously improving longitudinal virome stability. Lastly, by reanalyzing a previously published metagenomics dataset with > 1,000 samples, we determined that PHFs are prevalent across individuals and can aid in the detection of inflammatory bowel disease-specific virome signatures. Overall, our analyses support the use of predicted phage hosts in reducing between-sample distances and providing a biologically relevant framework for making between-sample virome comparisons.
ProFit-1D for quantifying J-difference edited data at 3T
Authors: Chan Kimberly L. , Borbath Tamas , Sherlock Sydney , Maher Elizabeth A. , Patel Toral R. , Henning Anke
Published: October 2024

Reproducible and accurate fitting of the magnetic resonance spectrum is critical for estimating metabolite concentrations. We have previously developed a fitting software called ProFit-1D which was shown to fit 9.4T semi-LASER data from the human brain with high accuracy and precision. In this study, we adapted ProFit-1D to fit J-difference edited spectra acquired at a clinical field strength of 3T and to assessed its performance in simulated and in vivo data. ProFit-1D was adapted to fit J-difference edited data with alterations to the fitting range to exclude the 1.3 ppm lipid resonance, starting T2relaxation constants, initial fit parameters, and adaptive spectral baseline determination. The accuracy of ProFit-1D was systematically evaluated on simulated GABA-edited and 2-hydroxyglutarate-edited (2HG-edited) data with different types of in vivo parameter variations and compared to that of LCModel and Gannet, two software commonly used to fit J-difference edited data. The precision of ProFit-1D was also evaluated in GABA-edited spectra acquired in vivo in the occipital cortex (OCC) and medial prefrontal cortex (mPFC) of healthy participants at 3T using subsets of averages and compared to that of LCModel and Gannet. The 2HG fit error was also evaluated for ProFit-1D in 2HG-edited spectra acquired in glioma patients and compared to that of LCModel. Overall, it was found that ProFit-1D generally produced fits with low parameter fit errors across a variety of parameter variations. GABA, glutamate plus glutamine (Glx), and 2HG levels were also more accurately estimated with ProFit-1D than with LCModel and Gannet across different spectral disturbances and simulated concentrations. ProFit-1D was found to be as precise as LCModel and more precise than Gannet in estimating GABA and Glx. 2HG fit errors were 45% lower with ProFit-1D than with LCModel. Thus, ProFit-1D was found to produce high-quality fits to J- difference edited data with high accuracy and precision.
AI driven approaches in Nanobody Epitope Prediction: Are We There Yet?
Authors: Eshak Floriane , Goupil-Lamy Anne
Published: October 2024

Nanobodies have emerged as a versatile class of biologics with promising therapeutic applications, driving the need for robust tools to predict their epitopes, a critical step for in silico affinity maturation and epitope-targeted design. While molecular docking has long been employed for epitope identification, it requires substantial expertise. With the advent of AI driven tools, epitope identification has become more accessible to a broader community increasing the risk of models’ misinterpretation. In this study, we critically evaluate the nanobody epitope prediction performance of two leading models: AlphaFold3 and AlphaFold2-Multimer (v.2.3.2), highlighting their strengths and limitations. Our analysis revealed that the overall success rate remains below 50% for both tools, with AlphaFold3 achieving a modest overall improvement. Interestingly, a significant improvement in AlphaFold3’s performance was observed within a specific nanobody class. To address this discrepancy, we explored factors influencing epitope identification, demonstrating that accuracy heavily depends on CDR3 characteristics, such as its 3D spatial conformation and length, which drive binding interactions with the antigen. Additionally, we assessed the robustness of AlphaFold3’s confidence metrics, highlighting their potential for broader applications. Finally, we evaluated different strategies aimed at improving prediction success rate. This study can be extended to assess the accuracy of emerging deep learning models adopting a similar approach to AlphaFold3.
Translocations can drive expression changes of multiple genes in regulons covering entire chromosome arms
Authors: Oncins Anna , Zaurin Roser , Toukabri Houyem , Quililan Kimberly , Hernández Mora José R , Karpinska Magdalena A , Wernersson Erik , Smith Alastair , Bianchi Agostina , Albinati Leone , Rivero Andrea , Serra François , Gómez Raúl , López Cristina , Beà Sílvia , Halidi Nadia , Valencia Alfonso , Bienko Magda , Oudelaar A Marieke , Beekman Renée
Published: October 2024

Translocations have largely been implicated in tumor development. However, beyond the consequences of aberrant gene expression near the breakpoint, their effects remain unexplored. In this work, we characterize the interplay between translocations, chromatin organization and gene expression using mantle cell lymphoma (MCL) as a model. We show thatin vitroinduced MCL-associated translocations can drive transcriptional changes at entire chromosome arms affecting multiple genes in a regulon-like fashion. Additionally, overexpressed genes in MCL patients are enriched in the exact same genomic regions, further underlining its potential relevance for lymphomagenesis. Moreover, we demonstrate a clear link between the translocation-induced transcriptional alterations and genome organization, with genes most susceptible to change expression residing in pre-existing long-range interacting loops spanning 50 megabases. The translocation places the strong immunoglobulin enhancer into this loop, allowing the spread of its regulatory potential over the entire affected chromosome arm. Finally, we show that translocation-induced effects mainly represent expression enhancement of genes already active prior to translocation formation, highlighting the importance of the epigenetic state of the cell in which this initial hit occurs. In summary, we show that translocations can induce ample, simultaneous gene expression changes affecting entire chromosome arms, representing an important new mechanism for tumorigenesis.
Towards a greener AlphaFold2 protocol for antibody-antigen modeling: Insights from CAPRI Round 55
Authors: Savaş Büşra , Yılmazbilek İrem , Özsan Atakan , Karaca Ezgi
Published: October 2024

In the 55thround of CAPRI, we used enhanced AlphaFold2 (AF2) sampling and data-driven docking. Our AF2 protocol relies on Wallner’s massive sampling approach, which combines different AF2 versions and sampling parameters to produce thousands of models per target. For T231 (an antibody peptide complex) and T232 (PP2A:TIPRL complex), we employed a 50-fold reduced MinnieFold sampling and a custom ranking approach, leading to a top-ranking medium prediction in both cases. For T233 and T234 (two antibody bound MHC I complexes), we followed data-driven docking, which did not lead to an acceptable model. Our post-CAPRI55 analysis showed that if we would have used our MinnieFold approach on T233 and T234, we could have submitted a medium-quality model for T233 as well. In the scoring challenge, we utilized the scoring function of FoldX, which was effective in selecting acceptable models for T231 and medium quality models for T232. Our success, especially in predicting and ranking a medium quality model for T231 and potentially for T233 underscores the feasibility of green and accurate enhanced AF2 sampling in antibody complex prediction.
NPF4.1 imports embryo-derived GA4to the endosperm to promote seed germination
Authors: Sirlin-Josserand Mathilde , Sakvarelidze-Achard Lali , Pflieger David , Davière Jean-Michel , Achard Patrick
Published: October 2024

Gibberellins (GAs) are plant hormones essential for seed germination. In non-dormant seeds, humidity and light induce a fast increase in GA levels, which in turn enhances the growth potential of the embryo and weakening of the surrounding endosperm. While it is admitted that the tissue-specific distribution of GAs must be finely regulated in germinating seeds, it remains unclear where the bioactive forms are synthetized and how they are transported to their site of action. Here we demonstrate that bioactive GAs are mainly produced in the hypocotyl of the embryo and are transported in the endosperm, a few hours from the onset of imbibition, to induce the expression of cell wall loosening genes such asEXPANSIN2. We further show that NITRATE TRANSPORTER1/PEPTIDE TRANSPORTER FAMILY (NPF) NPF4.1, previously identified as a cellular GA influx transporter, is localized in the plasma membrane of endosperm cells and contributes in the transport of embryo-derived GA4into the endosperm. Accordingly,npf4.1mutant seeds are hypersensitive to the GA biosynthesis inhibitor paclobutrazol in germination assay, and the phenotype is suppressed by application of exogenous bioactive GAs. Finally, we show that two other GA transporters, NPF3.1 and NPF2.13, are expressed in the embryo of germinating seeds and may modulate cellular GA levels in elongating cells of the radicle and cotyledons.
Exploring Log-Likelihood Scores for Ranking Antibody Sequence Designs
Authors: Uçar Talip , Malherbe Cedric , Gonzalez Ferran
Published: October 2024

Generative models trained on antibody sequences and structures have shown great potential in advancing machine learning-assisted antibody engineering and drug discovery. Current state-of-the-art models are primarily evaluated using two categories of in silico metrics: sequence-based metrics, such as amino acid recovery (AAR), and structure-based metrics, including root-mean-square deviation (RMSD), predicted alignment error (pAE), and interface predicted template modeling (ipTM). While metrics such as pAE and ipTM have been shown to be useful filters for experimental success, there is no evidence that they are suitable for ranking, particularly for antibody sequence designs. Furthermore, no reliable sequence-based metric for ranking has been established. In this work, using real-world experimental data from seven diverse datasets, we extensively benchmark a range of generative models, including LLM-style, diffusion-based, and graph-based models. We show that log-likelihood scores from these generative models correlate well with experimentally measured binding affinities, suggesting that log-likelihood can serve as a reliable metric for ranking antibody sequence designs. Additionally, we scale up one of the diffusion-based models by training it on a large and diverse synthetic dataset, significantly enhancing its ability to predict and score binding affinities. Our implementation is available at:https://github.com/AstraZeneca/DiffAbXL
Water immunity overrides stomatal immunity in plant resistance toPseudomonas syringae
Authors: Kemppinen Jasmin , Pollmeier Maximillian , Ehonen Sanna , Brosché Mikael , Sierla Maija
Published: October 2024

Stomata play crucial roles in the multilayered defense system against pathogens. Upon pathogen perception, stomata close promptly, establishing the first line of defense known as stomatal immunity. The bacterial pathogenPseudomonas syringae(Pst) exploits open stomata for entry, however, it can also induce stomatal closure at post-invasive stages to enhance apoplastic hydration. This creates a favorable environment forPstproliferation, evident as water-soaked lesions on leaves. During the post-invasive stages ofPstinfection, plants deploy a second layer of stomatal defense by reopening their stomata, a process termed water immunity. To evaluate the relative importance of stomatal versus water immunity, we utilized a diverse set of Arabidopsis (Arabidopsis thaliana) mutants with impaired stomatal function and monitored bacterial growth, stomatal behavior, and water-soaking capacity afterPstpv.tomatoDC3000 infection. Most mutants with constitutively open stomata and disrupted stomatal closure were more resistant againstPstthan wild-type plants. Also, while some stomatal mutants displayed similar stomatal behavior at the initial steps of defense, their disease outcomes were the opposite, suggesting that stomatal immunity is not the determining factor in disease resistance. Instead, we discovered that the water-soaking capacity, associated with stomatal status at later stages of infection, i.e., water immunity, dictates the disease outcome. Our results show that water immunity can override the lack of stomatal immunity in plant resistance toPst. We also address previous discrepancies in literature showing contradicting results for pathogen growth on stomatal mutants, highlighting the challenges in dissecting stomatal effects on plant resistance.
Complete Reference Genome and Pangenome Expand Biologically Relevant Information for Genome-Wide DNA Methylation Analysis Using Short-Read Sequencing and Array Data
Authors: Dong Zheng (Joe) , Whitehead Joanne , Fu Maggie , MacIsaac Julia L. , Rehkopf David H. , Rosero-Bixby Luis , Kobor Michael S. , Korthauer Keegan
Published: October 2024

Background

The new complete telomere-to-telomere human genome assembly, T2T-CHM13, and the first draft of the human pangenome reference provide unique opportunities to update the reference genome for epigenetics investigations and clinical research. However, it is largely unclear how these reference genome updates may impact DNA methylation (DNAm) analysis.

Results

Compared to the previous GRCh38 assembly, we found an average increase of 7.4% (range 5.4%–9.9% across samples and sequencing methods) in the number of CpGs genome-wide using T2T-CHM13 with data from four commonly used short-read sequencing DNAm profiling methods. The increase in number of CpGs facilitated discovery of 88 new differentially methylated CpGs within cancer driver genes in an epigenome-wide association study (EWAS) of colon cancer. Further, by aligning probe sequences from the commonly used and recently released Illumina DNAm arrays to T2T-CHM13 and GRCh38, we showed the enhanced utility of T2T-CHM13 for evaluation of potential probe cross-reactivity (i.e., where probes match multiple regions) and mismatch (i.e., where probes do not perfectly match the target region), resulting in the identification of new and more reproducible sets of unambiguous probes (i.e., probes uniquely mapping to the target region) (HM450K,n= 430,719; EPIC,n= 777,491; EPICv2,n= 859,216). In EWASs of 24 cancer types, an average of 945 additional differentially methylated CpG sites were identified in the new unambiguous probe set rather than in the GRCh38-based unambiguous probe set, with enrichments in cancer driver genes and cancer signaling pathways. Moreover, the pangenome called 4.5% more CpGs on average in short-read sequencing data than T2T-CHM13 and identified cross-population and population-specific unambiguous probes in DNAm arrays, owing to its improved representation of genetic diversity. These additional CpGs were overlapped with the promoters and gene bodies of various biologically and medically relevant genes and pangenome-based unambiguous probes can potentially facilitate the discovery of DNAm alterations in more than 200 cancer driver genes in each cancer type.

Conclusions

Use of T2T-CHM13 and pangenome references can benefit epigenome-wide association studies by including CpGs previously unobserved in short-read sequencing data and by improving the identification of unambiguous probes for DNAm arrays, thus expanding biologically relevant information. This study highlights the practical applications of T2T-CHM13 and pangenome for genome biology and provides a basis for expansion of epigenetics investigations.
TP53minigene analysis of 161 sequence changes provides evidence for role of spatial constraint and regulatory elements on variant-induced splicing impact
Authors: Canson Daffodil M. , Llinares-Burguet Inés , Fortuno Cristina , Sanoguera-Miralles Lara , Bueno-Martínez Elena , de la Hoya Miguel , Spurdle Amanda B. , Velasco-Sampedro Eladio A.
Published: October 2024

GermlineTP53genetic variants that disrupt splicing are implicated in hereditary cancer predisposition, while somatic variants contribute to tumorigenesis. We investigated the role ofTP53splicing regulatory elements (SREs), including G-runs that act as intronic splicing enhancers, using exons 3 and 6 and their downstream introns as models. Minigene microdeletion assays revealed four SRE-rich intervals: c.573_598, c.618_641, c.653_669 and c.672+14_672+36. A diagnostically reported deletion c.655_670del, overlapping an SRE-rich interval, induced an in-frame transcript Δ(E6q21) from new donor site usage. Within intron 6, deletion of at least four G-runs led to 100% aberrant transcript expression. Additionally, assay results suggested a donor-to-branchpoint distance cutoff of <50 nt for complete splicing aberration due to spatial constraint, and >75 nt for low risk of splicing abnormality. Overall, splicing data for 134 single nucleotide variants (SNVs) and 27 deletions inTP53demonstrated that SRE-disrupting SNVs have weak splicing impact (up to 26% exon skipping), while deletions spanning multiple SREs can have profound splicing effects. Results also provide more data to inform splicing impact prediction for intronic deletions that shorten intron size.
Heterogeneity in ligand-bound TRPV1: A comparison of methods in cryo-EM and molecular dynamics simulation
Authors: Astore Miro A. , Blackwell Robert , Silva-Sánchez David , Cossio Pilar , Hanson Sonya M.
Published: October 2024

Cryogenic electron microscopy (cryo-EM) has emerged as a powerful method for resolving the atomistic details of cellular components. In recent years, several computational methods have been developed to study the heterogeneity of molecules in single-particle cryo-EM. In this study, we analyzed a publicly available single-particle dataset of TRPV1 using five of these methods: 3D Flexible Refinement, 3D Variability Analysis, cryoDRGN, ManifoldEM, and Bayesian ensemble reweighting. Beyond what we initially expected, we have found that this dataset contains significant heterogeneity— indicating that single particle datasets likely contain a rich spectrum of biologically relevant states. Further, we have found that different methods are best suited to studying different kinds of heterogeneity, with some methods being more sensitive to either compositional or conformational heterogeneity. We also apply a combination of Bayesian ensemble reweighting and molecular dynamics as supporting evidence for the presence of these rarer states within the sample. Finally, we developed a quantitative metric based on the analysis of the singular value decomposition and power spectra to compare the resulting volumes from each method. This work represents a detailed view of the variable outcomes of different heterogeneity methods used to analyze a single real dataset and presents a pathway to a deeper understanding of the biology of complex macromolecules like the TRPV1 ion channel.
Sounds and Sights in Sequence Learning: Can Accessory Auditory Cues Enhance Motor Task Performance?
Authors: Leow Li-Ann , Nguyen An , Corti Emily , Marinovic Welber
Published: October 2024

Motor sequence learning, or the ability to learn and remember sequences of actions, such as the sequence of actions required to tie one’s shoelaces, is ubiquitous to everyday life. Contemporary research on motor sequence learning has been largely unimodal, ignoring the possibility that our nervous system might benefit from sensory inputs from multiple modalities. In this study, we investigated the properties of motor sequence learning in response to auditory-visual stimuli. We found that sequence learning with auditory-visual stimuli showed a hallmark feature of traditional unimodal sequence learning tasks: sensitivity to stimulus timing, where lengthier interstimulus intervals of 500 ms improved sequence learning compared to briefer interstimulus intervals of 200 ms. Consistent with previous findings, we also found that auditory-visual stimuli improved learning compared to a unimodal visual-only condition. Furthermore, the informativeness of the auditory stimuli was important, as auditory stimuli which predicted the location of visual cues improved sequence learning compared to uninformative auditory stimuli which did not predict the location of the visual cues. Our findings suggest a potential utility of leveraging audio-visual stimuli in sequence learning interventions to enhance skill acquisition in education and rehabilitation contexts.
Wildland Fire-Related Smoke PM2.5and Cardiovascular Disease ED Visits in the Western United States
Authors: Li Linzi , Wang Wenhao , Chang Howard H. , Alonso Alvaro , Liu Yang
Published: October 2024

Background

The impact of short-term exposure to fine particulate matter (PM2.5) due to wildland fire smoke on the risk of cardiovascular disease (CVD) remains unclear. We investigated the association between short-term exposure to wildfire smoke PM2.5and Emergency Department (ED) visits for acute CVD in the Western United States from 2007 to 2018.

Methods

ED visits for primary or secondary diagnoses of atrial fibrillation (AF), acute myocardial infarction (AMI), heart failure (HF), stroke, and total CVD were obtained from hospital associations or state health departments in California, Arizona, Nevada, Oregon, and Utah. ED visits included those that were subsequently hospitalized. Daily smoke, non-smoke, and total PM2.5were estimated using a satellite-driven multi-stage model with a high resolution of 1 km. The data were aggregated to the zip code level and a case-crossover study design was employed. Temperature, relative humidity, and day of the year were included as covariates.

Results

We analyzed 49,759,958 ED visits for primary or secondary CVD diagnoses, which included 6,808,839 (13.7%) AFs, 1,222,053 (2.5%) AMIs, 7,194,474 (14.5%) HFs, and 808,396 (1.6%) strokes. Over the study period from 2007-01-01 to 2018-12-31, the mean smoke PM2.5was 1.27 (Q1: 0, Q3: 1.29) µg/m3. A 10 µg/m3increase in smoke PM2.5was associated with a minuscule decreased risk for AF (OR 0.994, 95% CI 0.991-0.997), HF (OR 0.995, 95% CI 0.992-0.998), and CVD (OR 0.9997, 95% CI 0.996-0.998), but not for AMI and stroke. Adjusting for non-smoke PM2.5did not alter these associations. A 10 µg/m3increase in total PM2.5was linked to a small increased risk for all outcomes except stroke (OR for CVD 1.006, 95% CI 1.006-1.007). Associations were similar across sex and age groups.

Conclusion

We identified an unexpected slight lower risk of CVD ED visits associated with short-term wildfire smoke PM2.5exposure. Whether these findings are due to methodological issues, behavioral changes, or other factors requires further investigation.
Prompt identification of the location of gap conduction in the mitral isthmus following vein of Marshall ethanol infusion and endocardial ablation
Authors: Li Qiaoyuan , Li Yanguang , Liang Zhuo , Zhang Tao , Liu Xu , Fang Dongping , Bai Jin , Li Jian , Zhang Fengxiang , Wang Yunlong
Published: October 2024

Background

Mitral isthmus (MI) gap conduction is common despite ethanol infusion into the vein of Marshall (EI-VOM) and endocardial ablation of the MI. This study aimed to investigate the characteristics of electrograms of the distal coronary sinus (CSd) to guide the identification of the gap location in the MI.

Methods

A total of 187 patients who underwent EI-VOM and MI ablation were included in the study. After routine completion of EI-VOM and endocardial MI ablation, the characteristics of the electrogram in the CSd during left atrial appendage (LAA) pacing were analyzed in unblocked MI conduction.

Results

Among the 187 patients, 43.3% (81/187) had unblocked MI following EI-VOM and linear lesion creation in the endocardium. In patients with unblocked MI, 84.0% (68/81) showed double potential in the CSd during LAA pacing, among whom 80.9% (55/68) presented with an earlier high-frequency near-field potential (NFP) followed by a low-frequency far-field potential (FFP), suggesting an epicardial gap, whereas 19.1% (13/68) presented with FFP followed by NFP, suggesting an endocardial gap. In patients with single-potential in CSd (16.0%, n = 13), simple activation mapping of the endocardium and CSd revealed the gap location. Intra-CS ablation was necessary in 77.8% (63/81) of the patients, with a mean of 1.3 ± 1.7 sites and 1.1 ± 0.4 min for ablation. Eventually, 95.7 % (179/187) of the patients achieved MI blockage. These findings were confirmed in an external validation cohort, which demonstrated the effectiveness and efficiency of CSd potential-guided gap identification.

Conclusion

The characteristics of the electrograms in the CSd could aid in the prompt identification of the gap(s) location of the MI in patients with unblocked MI conduction.

CLINICAL PERSPECTIVE

What is Known:

Bidirectional mitral isthmus conduction block is challenging despite EI-VOM and endocardial ablation.

What the Study Adds:

The characteristics of the electrogram at the CSd during left atrial appendage pacing could facilitate prompt identification of gap conduction in mitral isthmus mediated by the epicardium or endocardium.

ver 2/3 of patients had an epicardial gap conduction that warranted intra-CS ablation.

blockage rate is achievable using the CSd electrogram guided gap identification approach, with efficiency and effectiveness.

Graphic Abstract: