bluuebunny/crossref_metadata_2025 huggingface dataset:
Zebrafish Avatar-test predicts patient’s tumor response to chemotherapy in breast cancer: a co-clinical study towards personalized medicine
Authors: Mendes Raquel V. , Ribeiro Joana M. , Gouveia Helena , de Almeida Cátia Rebelo , Castillo-Martin Mireia , Brito Maria José , Canas-Marques Rita , Batista Eva , Alves Celeste , Sousa Berta , Gouveia Pedro , Ferreira Miguel Godinho , Cardoso Maria João , Cardoso Fatima , Fior Rita
Published: October 2024

Chemotherapy remains the mainstay in most high-risk breast cancer (BC) settings, with several equivalent options of treatment. However, the efficacy of each treatment varies between patients and there is currently no test to determine which option will be the most effective for each individual patient. Here, we developed a fast in-vivo test for BC therapy screening: the zebrafish patient derived xenograft model (zAvatars), where in-vivo results can be obtained in just 10 days. To determine the predictive value of the BC zAvatars we performed a clinical study, where zAvatars were treated with the same therapy as the donor-patient and their response to therapy was compared. Our data shows a 100% correlation between patient’s clinical response to treatment and its matching zAvatar. Altogether, our results suggest that the zAvatar model constitutes a promising in-vivo assay to optimize cancer treatments in truly personalized manner.
Evoked response signatures explain deep brain stimulation outcomes
Authors: Bahners Bahne H. , Goede Lukas L. , Meyer Garance M. , Poser Luise , Hart Lauren A. , Pijar Julianna , Rajamani Nanditha , Hollunder Barbara , Madan Savir , Oxenford Simón , Waterstraat Gunnar , Curio Gabriel , Schnitzler Alfons , Florin Esther , Kühn Andrea A. , Fox Michael D. , Horn Andreas
Published: October 2024

Deep brain stimulation (DBS) is an established treatment for Parkinson’s disease. Still, DBS parameter programming currently follows a tedious trial-and-error process. DBS-evoked cortical potentials (EP) might guide parameter selection but this concept has not yet been tested. Further, mountingwetEEG systems is too time-consuming to scale in outpatient clinic settings. Here, we test the utility of a novel method that leverages thespatial patternof EP using adryEEG setup. We acquired EP in 58 hemispheres in patients with Parkinson’s disease and compute a model which represents the optimal EP response pattern associated with maximal clinical improvements. Once defined, we use this pattern to estimate stimulation outcomes in unseen patients. Finally, we utilize it to identify optimal stimulation contacts in five unseen hemispheres where it selected the correct contact in all cases. The simple setup makes this novel method an attractive option to guide DBS programming in clinical practice.
Personalized Thalamic Electrical Stimulation for Focal Epilepsy
Authors: Damiani Arianna , Nouduri Sirisha , Ho Jonathan C. , Salazar Steven , Jegou Aude , Reedy Eliza , Ikegaya Naoki , Sarma Sridevi , Aung Thandar , Pirondini Elvira , Gonzalez-Martinez Jorge A.
Published: October 2024

Targeted electrical stimulation to specific thalamic regions offers a therapeutic approach for patients with refractory focal and generalized epilepsy who are not candidates for resective surgery. However, clinical outcome varies significantly, in particular for focal epilepsy, influenced by several factors, notably the precise anatomical and functional alignment between cortical regions generating epileptic discharges and the targeted thalamic stimulation sites.

Here we hypothesized that targeting thalamic nuclei with precise anatomical and functional connections to epileptic cortical areas (an approach that we refer to as hodological matching) could enhance neuromodulatory effects on focal epileptic discharges. To investigate this, we examined three thalamic subnuclei (pulvinar nucleus, anterior nucleus, and ventral intermediate nucleus/ventral oral posterior nuclei) in 32 focal epilepsy patients.

Specifically, we first identified hodologically organized thalamocortical fibers connecting these nuclei to individual seizure onset zones (SOZs), combining neuroimaging and electrophysiological techniques. Further, analysis of 216 spontaneous seizures revealed the critical role of matched thalamic nuclei in seizure development and termination. Importantly, electrical stimulation of hodologically-matched thalamic nuclei immediately suppressed intracortical interictal epileptiform discharges, contrasting with ineffective outcomes from stimulation of unmatched targets. Finally, we retrospectively evaluated 7 patients with a chronic hodologically-matched neurostimulation system, which led to a clinically relevant reduction in seizure frequency (median reduction 86.5%), that outstands the current clinical practice of unmatched targets (39%).

Our results underscore the potential of hodological thalamic targeting to modulate epileptiform activity in specific cortical regions, highlighting the promise of precision medicine in thalamic neuromodulation for focal refractory epilepsy.
Growth-coupled microbial biosynthesis of the animal pigment xanthommatin
Authors: Bushin Leah B. , Alter Tobias B. , Alván-Vargas María V.G. , Dürr Lara , Olson Elina C. , Avila Mariah J. , Puiggené Òscar , Kim Taehwan , Deravi Leila F. , Feist Adam M. , Nikel Pablo I. , Moore Bradley S.
Published: October 2024

The mining of genomes across life has unearthed a bounty of biosynthetic potential to diverse molecules key to a biobased future. While the heterologous expression of metabolic pathways has achieved broad success, most approaches suffer a similar fate in low initial production levels that require extensive, resource-heavy iterative strain engineering refinement. Herein we introduce a growth-coupled biosynthetic (GrowBio) strategy that irrevocably connects microbial growth with specialized compound production. We demonstrate the plug-and-play versatility of GrowBio in the production of the structurally complex animal biopigment xanthommatin, a color-changing ommochrome with material and cosmetic potential. Xanthommatin biosynthesis directly fuels growth of a newly designedPseudomonas putida5,10-methylenetetrahydrofolate auxotroph (PUMA). Aided by genome-scale metabolic modeling, PUMA was designed and built to be controlled by endogenous formate co-produced as a coupled biosynthetic byproduct in the multistep conversion of tryptophan to xanthommatin. Adaptive laboratory evolution was utilized to streamline xanthommatin’s gram-scale bioproduction via growth rate selection, establishing GrowBio as a promising biotechnological approach for establishing and optimizing the microbial production of value-added molecules.
Antisense oligonucleotide targeting pathogenic sense repeat RNA inC9ORF72suppresses production of antisense-dependent dipeptide repeat proteins implicated in ALS/FTD
Authors: Gu Yuanzheng , Kankel Mark W. , Watts Jonathan , Jafar-nejad Paymaan , Almeida Sandra
Published: October 2024

A six nucleotide repeat expansion in intron-1 of theC9ORF72gene is the most common genetic mutation affecting individuals with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Bi-directional transcription of the repeat expansion generates sense and antisense repeat RNAs that can then be translated in all reading frames to produce six distinct dipeptide repeat (DPR) proteins with unique termini. The precise site of translation initiation of these proteins within theC9ORF72repeat expansion remains elusive. We used CRISPR-Cas9 genome editing and steric-blocking antisense oligonucleotides (ASOs) to investigate the contribution of different AUG codons in the antisense repeat RNA to the production of DPR proteins, poly(GP) and poly(PR) inC9ORF72expansion carrier motor neurons and lymphoblast cells. We then utilized ASOs targetingC9ORF72sense repeat RNA to examine whether sense or antisense RNA is the major source of the poly(GP) protein - a question for which conflicting evidence exists. We found that these ASOs reduced the intended sense RNA target, but also the antisense RNA, thus preventing the production of poly(PR). Our data highlights the importance of the sequences preceding the antisense CCCCGG repeat expansion for the synthesis of antisense DPR proteins and supports the use of senseC9ORF72ASOs to prevent the accumulation of both sense- and antisense-dependent DPR proteins inC9ORF72ALS/FTD.
Complex slow waves radically reorganise human brain dynamics under 5-MeO-DMT
Authors: Blackburne George , McAlpine Rosalind G. , Fabus Marco , Liardi Alberto , Kamboj Sunjeev K. , Mediano Pedro A. M. , Skipper Jeremy I.
Published: October 2024

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a psychedelic drug known for its uniquely profound effects on subjective experience, reliably eradicating the perception of time, space, and the self. However, little is known about how this drug alters large-scale brain activity. We collected naturalistic electroencephalography (EEG) data of 29 healthy individuals before and after inhaling a high dose (12mg) of vaporised synthetic 5-MeO-DMT. We replicate work from rodents showing amplified low-frequency oscillations, but extend these findings with novel tools for characterising the organisation and dynamics of complex low-frequency spatiotemporal fields of neural activity. We find that 5-MeO-DMT radically reorganises low-frequency flows of neural activity, causing them to become incoherent, heterogeneous, viscous, fleeting, nonrecurring, and to cease their typical travelling forwards and backwards across the cortex compared to resting state. Further, we find a consequence of this reorganisation in broadband activity, which exhibits slower, more stable, low-dimensional behaviour, with increased energy barriers to rapid global shifts. These findings provide the first detailed empirical account of how 5-MeO-DMT sculpts human brain dynamics, revealing a novel set of cortical slow wave behaviours, with significant implications for extant neuroscientific models of serotonergic psychedelics.
Wheat stripe rust resistance geneYr9, derived from rye, is aCC-NBS-LRRgene in a highly conservedNLRcluster
Authors: Yu Yang , Liu Jiajun , Lan Shengjie , Chen Qihang , Li Jinlong , Song Haoyuan , Pan Chen , Qi Juan , Ni Fei , Epstein Lynn , Fu Daolin , Wu Jiajie
Published: October 2024

Wheat stripe rust, caused byPuccinia striiformisf. sp.tritici(Pst), is a significant threat to global wheat production. Genetic resistance plays a crucial role in controlling this disease. Among wheat breeding innovations, the wheat-rye 1BL.1RS translocations are notable for introducing alien genetic diversity, partly due to the presence of the stripe rust resistance geneYr9on 1RS. To cloneYr9, we first identified fourPst-susceptible mutants from Lumai 15, which carries the 1BL.1RS translocation andYr9. Using these mutants, we performed Sequencing Trait-Associated Mutations (STAM). A single candidate gene,YrChr1B, was identified within theYr9locus and later confirmed asYr9through genetic complementation and gene editing. TheYr9gene encodes a coiled-coil nucleotide-binding site leucine-rich repeat (CC-NBS-LRR or NLR) protein and is part of a 14-memberNLRgene cluster. This cluster is conserved among Triticeae species and is an ortholog of the barleyMlalocus. CloningYr9expands the genetic resources available for molecular wheat breeding aimed at durable and broad-spectrum disease resistance.
pLM-DBPs: Enhanced DNA-Binding Protein Prediction in Plants Using Embeddings From Protein Language Models
Authors: Pokharel Suresh , Barasa Kepha , Pratyush Pawel , Kc Dukka
Published: October 2024

DNA-binding proteins (DBPs) play critical roles in gene regulation, development, and environmental response across various species, including plants, animals, and microorganisms. While various machine learning and deep learning models have been developed to distinguish DNA-binding proteins (DBPs) from non-DNA-binding proteins (NDBPs), most available tools have focused on human and mouse datasets. As a result, there are limited studies specifically addressing plant-based DNA-binding proteins, which restricts our understanding of their unique roles and functions in plant biology. Developing an efficient framework for improving DBP prediction in plants would enhance our knowledge and enable precise gene expression control, accelerate crop improvement, enhance stress resilience, and optimize metabolic engineering for agricultural advancement. In this work, we developed a tool that uses a protein language model (pLM) pre-trained on millions of sequences. We evaluated several leading models, including ProtT5, Ankh, and ESM-2, and leveraged their high-dimensional, information-rich representations to improve the accuracy of DNA-binding protein prediction in plants significantly. Our final model, pLM-DBPs, a feed-forward neural network classifier utilizing ProtT5-based representations, outperformed existing approaches with a Matthews Correlation Coefficient (MCC) of 83.8% on the independent test set. This represents a 10% improvement over the previous state-of-the-art model for plant-based DBP prediction, highlighting its superior performance compared to the existing approaches.
MicroBayesAge: A Maximum Likelihood Approach to Predict Epigenetic Age Using Microarray Data
Authors: Nolan Nicole , Mitchell Megan , Mboning Lajoyce , Bouchard Louis-S. , Pellegrini Matteo
Published: October 2024

Certain epigenetic modifications, such as the methylation of CpG sites, can serve as biomarkers for chronological age. Previously, we introduced our BayesAge frameworks for accurate age prediction through the use of locally weighted scatterplot smoothing (LOWESS) to capture the non-linear relationship between methylation or gene expression and age, and Maximum Likelihood Estimation (MLE) for bulk bisulfite and RNA sequencing data. Here we now introduce MicroBayesAge, a framework that enhances prediction accuracy by subdividing input data into age-specific co-horts and employing a new two-stage process for training and testing. Age prediction for younger patients was significantly improved. MicroBayesAge also exhibited minimal bias in its age predictions. Additionally, we explored the performance of our model for sex-specific age prediction which revealed slight improvements in accuracy for male patients, while no changes were observed for female patients. MicroBayesAge provides more accurate age predictions by accounting for variations in epigenetic markers of aging among different subgroups, which have been over-looked by commonly used models.
Cooperation shapes bacterial niche breadth evolution and patterns of diversification
Authors: Hao Chunhui , Konno Naoki , Ito Makoto , Belcher Laurence J , Iwasaki Wataru , West Stuart
Published: October 2024

Bacteria exhibit varying niche breadths, with generalists thriving in diverse environments and specialists confined to specific habitats. This variability reflects the adaptability of bacteria to their environment and may influence their speciation and extinction rates. We used phylogenetic causal inference and diversification analysis techniques to investigate the influence of cooperation on bacterial niche breadth evolution and patterns of diversification across 25,785 species. We found: (1) a positive correlation between the proportion of genes for cooperation and niche breadth; (2) a decreased proportion of genes for cooperation promotes niche contraction; and (3) species with a higher proportion of genes for cooperation show increased speciation and extinction rates when their niche breadths are narrower. Our study highlights the role of genes for cooperation in shaping both niche breadth and diversification of bacteria, underscoring their critical function in maintaining the ecological versatility and diversity of bacteria.
Portable In-Field DNA Sequencing for Rapid Detection of Pathogens and Antimicrobial Resistance: A Proof-of-Concept Study
Authors: Pillay Stephanie , Calderón-Franco David , Abeel Thomas
Published: October 2024

Purpose

Infectious diseases represent a major global health threat due to the rapid spread of pathogens, leading to widespread outbreaks. Concurrently, antimicrobial resistance (AMR) is increasing, making standard treatments less effective and complicating infection management. Effective surveillance systems are essential to address these challenges.

Methods

We conducted a proof-of-concept study to evaluate a portable in-field microbial lab against a traditional molecular lab for DNA isolation, sequencing, microbial detection, antibiotic resistance gene identification, and plasmid classification. Samples from lake water, wastewater treatment plant sludge, and retail meat were selected to reflect relevant surveillance vectors. This approach provides valuable data for environmental monitoring, public health, and food safety, aiding in outbreak preparedness. We compared results using five metrics: DNA yield and purity, read N50, taxonomic classification, antibiotic resistance gene identification (ARGs), and plasmid classification.

Results

Our study found that metagenomic bacterial DNA isolation from environmental and food sources is feasible with portable lab technology, producing ≥800ng of DNA, suitable for Nanopore sequencing. DNA from retail meat, lake, and sludge samples resulted in similar read numbers and read N50 values. Taxonomic classification was achieved at the genus and species levels. A Jaccard similarity of over 50% was observed in the top 20 most abundant species between chicken samples, and lake samples. ESKAPE pathogens were detected in chicken and lake samples. ARGs and plasmids were also identified in both retail meat and lake samples.

Conclusion

This study demonstrates that in-field DNA isolation and sequencing are feasible with minimal equipment, yielding results comparable to traditional lab methods.
Nutri Complex 150+: a new and effective approach to facial rejuvenation
Authors: Privitera Anna , Ferruggia Greta , Contino Martina , Maugeri Salvatore , Zimbone Massimo , Cardile Venera , Caruso Giuseppe , Brundo Maria Violetta
Published: October 2024

Skin is the largest multifunctional human organ and possesses a complex multilayered structure with the ability to regenerate and renew. The key role in skin regeneration is played by fibroblasts, also playing an important role in wound healing process. We used different methods to evaluate on human fibroblasts thein vitroeffects of a new compound called Nutri Complex 150+ (NC150+), containing a mixture of 20 different biologically active factors (GF20) and exosomes isolated and purified from bovine colostrum. NC150+ was able to significantly enhance cell proliferation/metabolic status of fibroblasts at both 24 and 48 hours compared to untreated (control) cells. NC150+ was also able to enhance the ability of human fibroblasts to close the wound scratch. Our findings demonstrate the ability of NC150+, based on a new technology called AMPLEX plus, to enhance cell proliferation/metabolic status of fibroblasts. The obtained results also suggest how NC150+ could be potentially effective in treating skin injury.
The GLP-1 analogue, exendin-4, improves bone material properties and strength through a central relay in ovariectomized mice
Authors: Mermet Morgane , Denom Jessica , Mieczkowska Aleksandra , Biggs Emma , Gribble Fiona M. , Reimann Frank , Magnan Christophe , Cruciani-Guglielmacci Celine , Mabilleau Guillaume
Published: October 2024

Glucagon-like peptide-1 (GLP-1) has previously been shown to be indispensable for optimal bone strength by acting at the bone material level. However, it was not fully clear whether the effects of GLP-1 were mediated by direct or indirect actions on bone cells. In the present study, we were unable to demonstrate the expression of the GLP-1 receptor (GLP-1r) in bone tissue at the gene expression level using qPCR and in situ hybridization, or at the protein level. Furthermore, the peripheral administration of exendin-4, a specific GLP-1r agonist, in ovariectomized (OVX) BALB/c mice enhanced post-yield displacement (18%) and energy-to-fracture (24%), as well as bone volume/total volume (BV/TV) (11%), trabecular number (Tb.N) (6%), and collagen maturity (18%). These bone effects were still observed when exendin-4 was centrally administered into the lateral cerebral ventricle. On the other hand, the peripheral administration of exendin-4 coupled to bovine serum albumin, a GLP-1r agonist that cannot penetrate the brain, failed to replicate the positive effects on bone despite increased calcitonin secretion. Altogether, these data confirm that GLP-1r agonists represent an interesting approach for managing bone fragility due to ovariectomy, but also suggest that GLP-1r agonists require a central relay yet to be identified to exert positive effects on bone physiology. Further studies are needed to decipher the mechanisms of action of GLP-1 and GLP-1r agonists on bone physiology.
Soil microbiome perturbation impedes growth ofBouteloua curtipendulaand increases relative abundance of soil microbial pathogens
Authors: Hobbs Alisiara , Ochoa-Rojas Daisy , Humphrey Christine E. , Kyndt John A. , Moore Tyler C.
Published: October 2024

Abstract

Bouteloua curtipendula(sideoats grama) is a valuable prairie grass for livestock forage, supporting food webs of herbivorous insects, reducing soil erosion, and limiting weed infiltration in urban grasslands. Efficient establishment ofB. curtipendulain prairie restorations and urban plantings could drastically improve long-term functionality of the space. Soil microbial communities have been linked to plant germination, growth, and drought tolerance in many plant species, however little is known about the factors contributing toB. curtipendulagermination and early growth. In this study, we used sterilized soil to examine the impact of soil microbes onB. curtipendulagrowth under greenhouse conditions. We foundBouteloua curtipendulaemergence and growth to be impaired in sterilized soil compared to non-sterilized soil. Using high throughput sequencing of the soil, we found thatB. curtipendulagrown in sterilized soil induced a greater proportion of plant pathogens and fewer nitrifying bacteria when grown in non- sterilized soil. For example, there was a significantly higher proportion ofAcidovorax,Cellvibrio, andXanthomonaswhich are known to contain plant pathogens, while plant- growth promoting bacteria, likeRhodopseudomonas,were significantly higher in the non-sterile conditions. We found that soil sterilization and growth ofB. curtipendulachanged the relative abundance of metabolic subsystem genes in the soil, however, by seven weeks after seeding,B. curtipendulatransformed the bacterial community of sterile soil such that it was indiscernible from non-sterile soil. In contrast, fungal communities in sterilized soil were still different from non-sterilized soil seven weeks post-seeding. It appears that the bacteria are involved in the initial establishment of beneficial conditions that set the stage for a robust fungal and plant seedling development.
Hydrothermal pretreatment renders peat susceptible to enzymatic saccharification
Authors: Thomsen Jonas , Lett Signe , Martens Helle , Sørensen Helle , Kelleher Darragh , Tryfona Theodora , Dupree Paul , Johansen Katja S.
Published: October 2024

Sphagnumpeat bogs store a large fraction of biologically-bound carbon, due to a steady accumulation of plant material over millennia. The resistance ofSphagnumbiomass to decay is poorly understood but of high importance for preservation efforts and climate models. It is shown that peat cellulose and other glucose-rich polysaccharides are readily degradable by a commercial enzyme cocktail designed for the industrial saccharification of lignocellulose of vascular plants. However, prior hydrothermal pretreatment of peat was required for the enzymes to gain access to the polysaccharides. The pretreatment itself released monosaccharides and glucose-containing soluble oligosaccharides. The monosaccharide profile released from hydrothermal pretreatment was consistent with the expected hemicellulose content ofSphagnumand was clearly different from that seen for pretreated tissue from vascular plants, such as pretreated wheat straw. Cellulose retained in the insoluble part of peat was cleaved at a similar or higher rate compared to cellulose from vascular plant tissues. Confocal laser scanning microscopy showed that the hydrothermal pretreatment disrupted the cells and relocated lignin-like compounds. Peat contains a high concentration of iron, which likely explains the pronounced acidification observed for the pretreated peat slurry at ambient conditions during saccharification assays. The acidification is due to abiotic oxidative reactions that also inactivate the enzymes. Adding catalase to the reactions alleviated enzyme inactivation and essentially stopped acidification during saccharification. This study confirms the importance of considering those abiotic oxidative reactions that take place in drained peat material.
Cytokine-Driven NF-κB Activation in Retinal Cells and Its Impact on the Pathogenesis of Age-Related Macular Degeneration: A Systematic Review
Authors: Shafi Viqas , Khan Nabeel Ahmad , Kazmi Javeria , Siddiqui Ifrah
Published: October 2024

Objective

To investigate the role of cytokine-induced NF-κB activation in retinal pigment epithelium (RPE) and photoreceptor cells, elucidating its contribution to the pathogenesis of Age-related Macular Degeneration (AMD) and identifying potential therapeutic targets.

Background

AMD is a leading cause of vision loss in older adults, driven by inflammation, oxidative stress, and immune dysregulation, particularly in RPE and photoreceptor cells. The NF-κB signaling pathway, activated by cytokines such as TNF-α, IL-6, and IL-1β, regulates these pathological processes. Understanding cytokine-induced NF-κB activation may provide insight into AMD progression and facilitate the development of novel therapeutic strategies.

Methods

A systematic review of literature from databases including PubMed, MEDLINE, and Google Scholar was conducted to evaluate the involvement of TNF-α, IL-6, IL-1β, IL-8, IFN-γ, IL-17, IL-12, IL-18, IL-33, and IL-25 in activating NF-κB in RPE and photoreceptor cells, contributing to AMD pathogenesis. The search was performed with no date restrictions and followed PRISMA guidelines. Eligible studies were selected based on predefined criteria assessing NF-κB activation mechanisms and its effects on inflammation, oxidative stress, and retinal degeneration.

Results

The investigation revealed that cytokines TNF-α, IL-6, IL-1β, IL-8, IFN-γ, IL-17, IL-12, IL-18, IL-33, and IL-25 activate the NF-κB signaling pathway in retinal pigment epithelium (RPE) and photoreceptor cells. This activation triggers the transcription of genes involved in inflammation, oxidative stress, and immune responses. Chronic NF-κB activation leads to persistent inflammation, increased oxidative stress, and immune cell recruitment, contributing to retinal cell dysfunction and degeneration. Additionally, NF-κB-driven upregulation of angiogenic factors such as VEGF promotes neovascularization in wet AMD. These findings highlight the central role of NF-κB in AMD pathogenesis and suggest that targeting this pathway could mitigate inflammatory and oxidative damage, offering potential therapeutic benefits for AMD patients.

Conclusion

Cytokine-induced NF-κB activation plays a central role in AMD pathogenesis by promoting chronic inflammation, oxidative stress, and angiogenesis in retinal cells. Targeting NF-κB could present a therapeutic strategy to reduce inflammatory and oxidative damage, preserving retinal function and preventing vision loss in AMD. Further research is required to develop effective NF-κB-targeted interventions.
Lutetium-177 hydroxyapatite radiosynovectomy in refractory chronic inflammatory arthritis of the knee joint
Authors: Sarwal Tanvi , Kumar Rajesh , Taywade Sameer , Gopalakrishnan Maya , Elhence Abhay , Didel Siyaram , Gaur Ravi
Published: October 2024

Objective

To determine the efficacy of177Lutetium hydroxyapatite radiosynovectomy (RSV) in patients with refractory chronic inflammatory arthritis of the knee joint.

Materials and Methods

Overall, 24 knees in 22 patients with refractory chronic inflammatory arthritis were enrolled in this prospective study. All patients were assessed clinically for pain, tenderness, range of motion, analgesic intake, Oxford knee score and blood pool activity on three phase bone scan. Various scores were assigned to clinical these parameters. RSV of the knee joint was done using intra-articular injection of177Lutetium hydroxyapatite. Patients were assessed clinically at 1 and 3 months, and scintigraphically at 3 months using blood pool index on three phase bone scan. Patients were categorised as responders and non-responders on the basis of change in percentage of cumulative scores.

Results

Out of 24 knees, 18 knees were responders and 6 knees were non-responders at 3 months. There was a significant improvement in clinical scores at 1 month post RSV, which persisted at 3 months post RSV (p < 0.05). However, the change in blood pool activity on three phase bone scan was not significant. Reported adverse effects were mild and not significant.

Conclusion

This study confirmed the safety and efficacy of177Lutetium hydroxyapatite radiosynovectomy for patients with chronic inflammatory knee joint arthritis refractory to conventional medical treatment.
Biomarkers of insulin resistance and their performance as predictors of treatment response in adults with risk factors for type 2 diabetes
Authors: Brogan RJ , Rooyackers O , Phillips BE , Twelkmeyer B , Ross LM , Atherton PJ , Kraus WE , Timmons JA , Gallagher IJ
Published: October 2024

Insulin Resistance (IR) is a component of the pathogenesis of type 2 diabetes mellitus (T2DM), and risk factor for cardiovascular and neurodegenerative diseases. Amino acid and lipid metabolomic IR diagnostics associate with future T2DM risk in epidemiological cohorts. Whether these assays can accurately detect altered IR following treatment has not been established. In the present study we evaluated the ability of metabolomic diagnostics to predict altered IR following exercise treatment. We evaluated the performance of two distinct insulin assays and built combined clinical and metabolomic IR diagnostics. These were utilised to stratify IR status in the pre-intervention fasting samples in three independent cohorts (META-PREDICT (MP, n=179), STRRIDE-AT/RT (S-2, n=116) and STRRIDE-PD (S-PD, n=149)). Linear and Bayesian projective prediction strategies were used to evaluate biomarkers for fasting insulin and HOMA2- IR and change in fasting insulin with treatment. Both insulin assays accurately quantified international standard insulin (R2>0.99), yet agreement for fasting insulin was less congruent (R2=0.65). Only the high-sensitivity ELISA assay could identify the mean effect of treatment on fasting insulin. Clinical-metabolomic models were statistically related to fasting insulin (R20.33 – 0.39) but had modest capacity to classify HOMA2-IR at a clinically relevant threshold. Furthermore, no model predicted treatment responses in any cohort. Thus, we demonstrate that the choice of insulin assay is critical when quantifying the influence of life-style on fasting insulin, while none of the clinical-metabolomic biomarkers, validated in cross-sectional data, are suitable for monitoring longitudinally changes in IR status.
Hippocampal ripples during offline periods predict human motor sequence learning
Authors: Chen Pin-Chun , Stritzelberger Jenny , Walther Katrin , Hamer Hajo , Staresina Bernhard P.
Published: October 2024

High-frequency bursts in the hippocampus, known as ripples (80-120 Hz in humans), have been shown to support episodic memory processes. However, converging recent evidence in rodent models as well as human neuroimaging suggests that the hippocampus may be involved in a wider range of memory domains, including motor sequence learning (MSL). Nevertheless, no direct link between hippocampal ripples and MSL has yet been established. Here, we recorded intracranial electroencephalography from the hippocampus in 20 epilepsy patients during a MSL task in which participants showed steady improvement across nine 30-second training blocks interspersed with 30-second rest (‘offline’) periods. We first demonstrate that ripple rates strongly increase during rest periods relative to training blocks. Importantly, ripple rates during rest periods tracked learning behaviour, both across blocks and across participants. These results suggest that hippocampal ripples during offline periods play a functional role in motor sequence learning and that the hippocampus may be involved in offline learning beyond episodic memory.
The Impact of Host Genetics and/or its Microbiota on the Severity ofCorynebacterium-Associated Hyperkeratosis in Outbred Athymic Nude Mice
Authors: Michelson Abigail , Cheleuitte-Nieves Christopher , Miranda Ileana C. , Dobtsis Irina , Lipman Neil S
Published: October 2024

Corynebacterium bovis(Cb), the etiology ofCorynebacterium-associated hyperkeratosis (CAH) in nude mice, may impact research outcomes. Little is known about the differences in the course and severity of CAH in different outbred athymic nude mice stocks. Three genetic stocks (designated A, B, and C), 1 of which was obtained from 2 geographically separate colonies with distinct microbiota (A1 and A2), were inoculated topically with 1 × 108CFUs of a pathogenic Cb field isolate (#7894; n = 6/stock) or sterile media (n=2/stock; controls). Clinical signs were assessed daily and scored 0 – 5 based on lesion severity. Mice were euthanized at 14 (A1, A2, B, and C) or 28 (B) days-post-inoculation (dpi), macroscopic changes documented, and 6 skin samples per mouse were obtained and histologically scored 0 – 4 based on the presence and severity of hyperkeratosis, acanthosis, inflammation, and bacterial colonies. No stock A1 or control mice developed clinical disease; 1 of 6 stock B mice developed mild CAH (mean peak clinical score [MPCS] – 0.33) at 14 dpi (14 day group) and 2 of 6 stock B (28 day group) developed mild CAH at 15 dpi (MPCS -0.33); and, all stock C and A2 mice developed significant clinical signs at 5 dpi (MPCS – 2.5 and 3, respectively) which resolved by 11 dpi. Despite differences in clinical presentation, all Cb-infected mice had hyperkeratosis and/or acanthosis with associated bacterial colonies. Stocks A1 and B, which had minimal or no clinical signs, were colonized withCorynebacterium amycolatum(Ca). In contrast, stocks C and A2 were not colonized with Ca, raising the possibility that Ca and/or other components of the skin microbiota may mitigate clinical signs but not necessarily all histopathologic changes associated with infection. These findings suggest host genetics and/or the skin microbiota can markedly influence the presentation of CAH in nude mice.
E(Q)AGNN-PPIS: Attention Enhanced Equivariant Graph Neural Network for Protein-Protein Interaction Site Prediction
Authors: Animesh  , Suvvada Rishi , Bhowmick Plaban Kumar , Mitra Pralay
Published: October 2024

Identifying protein binding sites, the specific regions on a protein’s surface where interactions with other molecules occur, is crucial for understanding disease mechanisms and facilitating drug discovery. Although numerous computational techniques have been developed to identify protein binding sites, serving as a valuable screening tool that reduces the time and cost associated with conventional experimental approaches, achieving significant improvements in prediction accuracy remains a formidable challenge. Recent advancements in protein structure prediction, notably through tools like AlphaFold, have made vast numbers of 3-D protein structures available, presenting an opportunity to enhance binding site prediction methods. The availability of detailed 3-D structures has led to the development of Equivariant Graph Neural Networks (GNNs), which can analyze complex spatial relationships in protein structures while maintaining invariance to rotations and translations. However, current equivariant GNN methods still face limitations in fully exploiting the geometric features of protein structures. To address this, we introduce E(Q)AGNN-PPIS1, an Equivariant Attention-Enhanced Graph Neural Network designed for predicting protein binding sites by leveraging 3-D protein structure. Our method augments the Equivariant GNN framework by integrating an attention mechanism. This attention component allows the model to focus on the most relevant structural features for binding site prediction, significantly enhancing its ability to capture complex spatial patterns and interactions within the protein structure. Our experimental findings underscore the enhanced performance of E(Q)AGNN-PPIS compared to current state-of-the-art approaches, exhibiting gains of 8.33% in the Area Under the Precision-Recall Curve (AUPRC) and 10% in the Matthews Correlation Coefficient (MCC) across benchmark datasets. Additionally, our method demonstrates robust generalization across proteins with varying sequence lengths, outperforming baseline methods.
Neuronal plasticity at puberty in hypothalamic neurons controlling fertility in female mice
Authors: Zhang Yuanxin , Pakulat Leonie M. , Galliano Elisa , Colledge William H. , Jones Susan
Published: October 2024

Puberty is a critical transition period to achieve fertility and reproductive capacity in all mammalian species. At puberty, the hypothalamic-pituitary-gonadal (HPG) is activated by neuroendocrine changes in the brain. Central to this areKiss1neurons that produce kisspeptin, a neuropeptide which is a potent stimulator of gonadotropin releasing hormone (GnRH) secretion.Kiss1neurons in the arcuate region of the hypothalamus (Kiss1ARC) increase pulsatile secretion of GnRH at puberty. Other developmental maturational changes in the brain are often accompanied by neuronal plasticity changes but this has not been studied inKiss1neurons. Electrophysiological characterisation ofKiss1ARCneurons from female mice shows that these neurons undergo profound intrinsic plasticity at puberty with a critical window between 3 and 4 weeks. ImmatureKiss1ARCneurons cannot sustain depolarisation-evoked firing for even 500 ms and instead fire a brief burst of high frequency spikes before falling silent. This would make them unsuitable for the sustained activity that is needed to activate GnRH neurons and trigger LH secretion in the HPG axis. After puberty, sustained firing can be maintained, which endows post-pubertyKiss1ARCneurons with a mature physiological phenotype that is amenable to neuropeptide modulation for generation of burst firing and pulsatile release of kisspeptin. There is a corresponding decrease in the threshold for action potential initiation, a more hyperpolarised post-spike trough and a larger medium after-hyperpolarisation (mAHP). Gene expression analysis showed a significant decrease inScn2a(Nav1.2 channel),Kcnq2(Kv7.2 channel) andLrrc55(BK channel auxiliary γ3-subunit) expression and an increase inHcn1(hyperpolarization activated cyclic nucleotide-gated potassium channel) expression which may contribute to the observed electrophysiological changes. Ovariectomy and β-estradiol replacement defined a window of estrogen-dependent plasticity of action potential firing at puberty, such that post-pubertyKiss1ARCneurons achieve a mature physiological phenotype for activation of the HPG axis.
Turgor limitation of tree height: no evidence from leaf epidermal cell anatomy
Authors: Alemán-Sancheschúlz Gilberto , Olson Mark E. , Rosell Julieta , Salgado-Ugarte Isaías , Pérez-Maussán Isabel
Published: October 2024

The turgor limitation hypothesis (TLH) predicts that reduced turgor caused by gravity and hydraulic resistance at the treetop makes cell expansion beyond a certain size impossible. This environmentally-imposed upper limit on cell size should be manifest as an abrupt right-hand threshold in cell size distributions. Selection is limited from reaching the favored cell size, which remains on the right-hand, inaccessible, side of the developmental threshold. The TLH thus predicts that as trees grow taller, treetop leaf cell size distributions should become increasingly narrowas selection pushes as close as possible toward the inaccessible, favored values with a right-hand threshold. To test this, we sampled 58 individuals of two tree species across different heights, along with 24 canopy-dominant rainforest species. We measured guard, subsidiary, and pavement cell lengths from apicalmost leaves. Contrary to TLH predictions, leaf cell dimension distributions were symmetrical, without right-hand thresholds, even in the tallest trees. Regression analyses mostly revealed positive or non-significant relationships between cell size, skewness, variance, and tree height, rather than the predicted negative trends. Our findings suggest that, instead of turgor-imposed limitation, it is more plausible that trees produce the heights, leaf sizes, and cell dimensions favored by selection in a given environment.
Neural correlates differ between crystallized and fluid intelligence in adolescents
Authors: Qiu Bowen , Qian Rui , Gu Baorong , Chen Zhifan , Li Zichao , Li Mingyang , Wu Dan
Published: October 2024

Fluid and crystallized intelligence are acknowledged as distinct facets of cognitive ability during brain development, but the specific neural substrates and molecular mechanisms underlying them remain unclear. This study used a sample comprising 7471 young adolescents (mean age 9.87 ± 0.62 years) from the ABCD cohort to elucidate the differential neural correlates of fluid and crystallized intelligence. Our findings indicated that micro-level brain MRI phenotypes such as water diffusivity were closely associated with fluid intelligence, whereas macro-level brain MRI phenotypes such as gray matter cortical thickness were indicative of crystallized intelligence. We further investigated the molecular mechanisms underlying fluid and crystallized intelligence by correlating the characteristic MRI markers with spatial transcriptome profiles and PET imaging. Results showed that fluid intelligence had significant associations with serotonin and glutamate system, while crystallized intelligence was related to serotonin, dopamine and acetylcholine system. Furthermore, we examined the impacts of lifestyle factors on these two forms of intelligence and how the molecular pathways mediated these impacts. Our investigation suggested that physical activities, screen use and sleep duration influenced fluid intelligence mainly through mGlu5 receptors and crystallized intelligence through 5HT1a and D2 receptors. In conclusion, these findings illustrated a distinct neural basis between fluid and crystallized intelligence from the perspectives of neuroimaging, neurotransmitters, and lifestyles in young adolescents.
After-effects of Parieto-occipital Gamma Transcranial Alternating Current Stimulation on Behavioral Performance and Neural Activity in Visuo-spatial Attention Task
Authors: Zheng Tianyi , Huang Yunshan , Sugino Masato , Shimba Kenta , Jimbo Yasuhiko , Kotani Kiyoshi
Published: October 2024

Visuo-spatial attention enables selective focus on spatial locations while ignoring irrelevant stimuli which involves both endogenous and exogenous attention. Recent advancements in transcranial alternating current stimulation (tACS) have shown promise in modulating these attentional processes by targeting electrical oscillations in specific brain areas. Despite evidence of the online effects of tACS on the task performance of visuo-spatial attention, whether tACS can produce lasting after-effects on behavioral performance and neural activity during the visuo-spatial attention task remains unknown. This study aims to explore these after-effects on visuo-spatial attention by implementing a single-blind, sham-controlled, between-group experiment design. Twenty young and healthy participants were equally divided into two groups receiving either sham or active gamma tACS at 40 Hz targeted at the right parieto-occipital region. Each participant engaged in a version of the Posner cueing task, conducted with EEG recording before and after the tACS intervention. The results revealed that the active tACS group exhibited significant reductions in reaction time compared to the sham group. These changes were not uniform across different attention types, suggesting specific enhancements in cognitive processing. Additionally, EEG analysis showed that gamma tACS influenced various aspects of neural activity, including event-related potentials to the target, as well as the oscillatory power and long-range temporal correlations of EEG signal during the cue-target interval. The amplitude and latency of N1 and P3 components were modulated by gamma tACS. Notably, there was a decrease in alpha power and an increase in gamma power during the cue-target interval, alongside a decrease in long-range temporal correlations. These findings revealed the after-effect of gamma tACS on modulating the behavioral performance and neural activity in the visuo-spatial attention task, paving the way for future applications in cognitive enhancement and therapeutic interventions.
Unsupervised feature extraction using deep learning empowers discovery of genetic determinants of the electrocardiogram
Authors: Sieliwonczyk Ewa , Sau Arunashis , Patlatzoglou Konstantinos , McGurk Kathryn A. , Pastika Libor , Thami Prisca K , Mangino Massimo , Zheng Sean L , Powell George , Curran Lara , Buchan Rachel J , Theotokis Pantazis , Peters Nicholas S , Loeys Bart , Kramer Daniel B. , Waks Jonathan W , Ng Fu Siong , Ware James S
Published: October 2024

Advanced data-driven methods can outperform conventional features in electrocardiogram (ECG) analysis, but often lack interpretability. The variational autoencoder (VAE), a form of unsupervised machine learning, can address this shortcoming by extracting comprehensive and interpretable new ECG features. Our novel VAE model, trained on a dataset comprising over one million secondary care median beat ECGs, and validated using the UK Biobank, reveals 20 independent features that capture ECG information content with high reconstruction accuracy. Through phenome- and genome-wide association studies, we illustrate the increased power of the VAE approach for gene discovery, compared with conventional ECG traits, and identify previously unrecognised common and rare variant determinants of ECG morphology. Additionally, to highlight the interpretability of the model, we provide detailed visualisation of the associated ECG alterations. Our study shows that the VAE provides a valuable tool for advancing our understanding of cardiac function and its genetic underpinnings.
Applications of Artificial Intelligence in Vasculitides: A Systematic Review
Authors: Omar Mahmud , Agbareia Reem , Naffaa Mohammad E. , Watad Abdulla , Glicksberg Benjamin S , Nadkarni Girish N , Klang Eyal
Published: October 2024

Background and Aim

Vasculitides are rare inflammatory disorders that sometimes can be difficult to diagnose due to their diverse presentations. This review examines the use of Artificial Intelligence (AI) to improve diagnosis and outcome prediction in vasculitis.

Methods

A systematic search of PubMed, Embase, Web of Science, IEEE Xplore, and Scopus identified relevant studies from 2000 to 2024. AI applications were categorized by data type (clinical, imaging, textual) and by task (diagnosis or prediction). Studies were assessed for risk of bias using PROBAST and QUADAS-2 tools.

Results

Forty-six studies were included. AI models achieved high diagnostic performance in Kawasaki Disease, with sensitivities up to 92.5% and specificities up to 97.3%. Predictive models for complications, such as IVIG resistance in Kawasaki Disease, showed AUCs between 0.716 and 0.834. Other vasculitis types, especially those using imaging data, were less studied and often limited by small datasets.

Conclusion

The current literature shows that AI algorithms can enhance vasculitis diagnosis and prediction, with deep and machine learning models showing promise in Kawasaki Disease. However, broader datasets, more external validation, and the integration of newer models like LLMs are needed to advance their clinical applicability across different vasculitis types.