bluuebunny/crossref_metadata_2025 huggingface dataset:
Large scale serum proteomics identifies proteins associated with performance decline and clinical milestones in Duchenne muscular dystrophy
Authors: Ikelaar N.A. , Barnard A.M. , Eng S.W.M. , Vajargah S. Hosseini , Ha K.C.H. , Kan H.E. , Vandenborne K. , Niks E.H. , Walter G.A. , Spitali P.
Published: August 2024

Serum biomarkers are promising minimally invasive outcome measures in clinical studies in Duchenne muscular dystrophy (DMD). However, biomarkers strongly associated with clinical progression and predicting performance decline are lacking. In this study we aimed to identify serum biomarkers associated with clinical performance and able to predict clinical milestones in DMD. Towards this aim we present a retrospective multi-center cohort study including serum samples and clinical data collected in research participants with DMD as part of a natural history study at the University of Florida (UF) and real-world observations at Leiden University Medical Center (LUMC) between 2009-2022. The 7K SomaScan® assay was used to analyse protein levels in in individual serum samples. Serum biomarkers predicted age at loss of ambulation (LoA), age at loss of overhead reach (OHR) and age at loss of hand to mouth function (HTM). Secondary outcomes were the association of biomarkers with age, corticosteroid (CS) usage, and clinical performance based on the North Star Ambulatory Assessment (NSAA), 10 meter run velocity (10mrv), 6 minute walk (6MWT) and Performance of the Upper Limb (PUL2.0). A total of 716 serum samples were collected in 79 participants at UF and 74 at LUMC (mean[SD] age; 10.9[3.2] vs 8.4[3.4]). 244 serum proteins showed an association with CS usage in both cohorts independent of CS type and regimen, including MMP3 and IGLL1. 318 probes (corresponding to 294 proteins) showed significant associations with NSAA, 10mrv, 6MWT and/or PUL2.0 across both cohorts. The expression of 38 probes corresponding to 36 proteins such as RGMA, EHMT2, ART3, ANTXR2 and DLK1 was associated with risk of both lower and upper limb clinical milestones in both the LUMC and UF cohort. In conclusion, multiple biomarkers were associated with CS use, motor function and upper lower and upper limb disease milestones in DMD. These biomarkers were validated across two independent cohorts, increasing their likelihood of translation for use within the broader DMD population.
Formation of brain-wide neural geometry during visual item recognition in monkeys
Authors: Chen He , Kunimatsu Jun , Oya Tomomichi , Imaizumi Yuri , Hori Yukiko , Matsumoto Masayuki , Tsubo Yasuhiro , Hikosaka Okihide , Minamimoto Takafumi , Naya Yuji , Yamada Hiroshi
Published: August 2024

Neural dynamics reflect canonical computations that relay and transform information in the brain. Previous studies have identified the neural population dynamics in many individual brain regions as a trajectory geometry in a low-dimensional neural space. However, whether these populations share particular geometric patterns across brain-wide neural populations remains unclear. Here, by mapping neural dynamics widely across temporal/frontal/limbic regions in the cortical and subcortical structures of monkeys, we show that 10 neural populations, including 2,500 neurons, propagate visual item information in a stochastic manner. We found that the visual inputs predominantly evoked rotational dynamics in the higher-order visual area, the TE and its downstream striatum tail, while curvy/straight dynamics appeared more frequently downstream in the orbitofrontal/hippocampal network. These geometric changes were not deterministic but rather stochastic according to their respective emergence rates. These results indicated that visual information propagates as a heterogeneous mixture of stochastic neural population signals in the brain.
Towards an automated protocol for wildlife density estimation using camera-traps
Authors: Zampetti Andrea , Mirante Davide , Palencia Pablo , Santini Luca
Published: August 2024

Camera-traps are valuable tools for estimating wildlife population density, and recently developed models enable density estimation without the need for individual recognition. Still, processing and analysis of camera-trap data are extremely time-consuming. While algorithms for automated species classification are becoming more common, they have only served as supporting tools, limiting their true potential in being implemented in ecological analyses without human supervision. Here, we assessed the capability of two camera-trap based models to provide robust density estimates when image classification is carried out by machine learning algorithms.

We simulated density estimation with Camera-Traps Distance Sampling (CT-DS) and Random Encounter Model (REM) under different scenarios of automated image classification. We then applied the two models to obtain density estimates of three focal species (roe deerCapreolus capreolus, red foxVulpes vulpes, and Eurasian badgerMeles meles) in a reserve in central Italy. Species detection and classification was carried out both by the user and machine learning algorithms (respectively, MegaDetector and Wildlife Insights), and all outputs were used to estimate density and ultimately compared. Simulation results suggested that the CT-DS model could provide robust density estimates even at poor algorithm performances (down to 50% of correctly classified images), while the REM model is more unpredictable and depends on multiple factors. Density estimates obtained from the MegaDetector output were highly consistent for both models with the manually labelled images. While Wildlife Insights’ performance differed greatly between species (recall: badger = 0.15; roe deer = 0.56; fox = 0.75), CT-DS estimates did not vary significantly; on the contrary, REM systematically overestimated density, with little overlap in standard errors.

We conclude that CT-DS and REM models can be robust to the loss of images when machine learning algorithms are used to identify animals, with the CT-DS being an ideal candidate for applications in a fully unsupervised framework. We propose guidelines to evaluate when and how to integrate machine learning in the analysis of camera-trap data for density estimation, further strengthening the applicability of camera traps as a cost-effective method for density estimation in (spatially and temporally) extensive multi-species monitoring programs.
Rare earth elements extraction from Idaho-sourced surface soil by phytomining
Authors: Richardson Kathryn , Mirkouei Amin , Duellman Kasia , Aylward Anthony , Zirker David , Schwarz Eliezer , Sun Ying
Published: August 2024

Environmentally-friendly and low emission extraction methods are needed to meet worldwide rare earth element (REE) demand. Within a greenhouse setting, we assessed the REE hyperaccumulation ability of four plant species (e.g.,Phalaris arundinacea, Solanum nigrum, Phytolacca americana, andBrassica juncea) and the impact of amending REE-rich soil with biochar or fertilizer and watering with citric acid solution. Harvested samples were pyrolyzed, and the resulting bio-ores were acid-digested and underwent elemental analysis to determine REE content. Amending soil with fertilizer and biochar increased bio-ore production, while plant species explained most variation in bioaccumulation factor.Phalaris arundinaceaachieved the highest average REE concentration of 27,940 ppm for targeted REEs (i.e., cerium, lanthanum, neodymium, praseodymium, and yttrium) and 37,844 ppm for total REEs. We successfully extracted REE-rich bio-ore from plant biomass and determined that soil amendment and plant species will be critical parameters in design and implementation of Idaho-based REE phytomining operations.

Graphical Abstract
GBA1mutations alter neuronal firing and structure, regulating VGLUT2 and CRYAB in dopamine neurons
Authors: Rodríguez-Traver Eva , Suárez Luz M. , Crespo Carlos , González-Burgos Irene , Vecino Rebeca , Jurado-Coronel Juan C. , Galán María , González-González Marta , Moratalla Rosario , Vicario Carlos
Published: August 2024

Mutations in theGBA1gene are major risk factors for Parkinsońs disease (PD), but their role in PD pathology is not fully understood. The impact ofGBA1mutations was investigated in dopamine (DA) neurons obtained from induced pluripotent stem cells (iPSCs) derived from PD patients carrying the N370S or L444PGBA1mutation. DA neurons co-expressing TH and VGLUT2 were detected in the cultures, and their number and/or expression ofVGLUT2/SLC17A6mRNA was markedly reduced in both N370S and L444P cultures compared to controls. A significant increase in the firing rate of N370S neurons was found, whereas evoked dopamine release was stronger from neurons carrying either mutation. Furthermore, mutant neurons accumulated abundant degenerative structures, and there was a significant accumulation of α-synuclein aggregates in N370S neurons. Notably, a significant upregulation of the chaperoneCRYAB/HSPB5/alpha-crystallin-Bwas found early in DA neuron differentiation and in the substantia nigra of PD patients. Our findings indicate that N370S and L444PGBA1mutations impair midbrain DA neurons expressing VGLUT2, and provoke molecular, functional and structural changes, possibly involved in PD pathology.
Multimodal electrical impedance tomography and electroencephalography imaging: Does higher skull conductivity resolution in EIT imaging improve accuracy of EEG source localization?
Authors: Rimpiläinen Ville , Koulouri Alexandra
Published: August 2024

Objective

Unknown conductivities of the head tissues, particularly the skull, is a major factor of uncertainty in electroencephalography (EEG) source imaging. Here, we develop a personalized skull conductivity framework aiming to improve the head models used in the EEG source imaging and to reduce localization errors.

Methods

We employ Electrical Impedance Tomography (EIT) and convex optimization to produce high resolution skull conductivity maps that are subsequently embedded in the EEG modeling.

Results

First, we demonstrate through simulations that locally varying conductivity values of the skull can be estimated from EIT measurements. Second, we show how the choice of the skull conductivity resolution of the EIT imaging affects the EEG source reconstructions.

Conclusions

EIT estimated conductivities can signicantly improve the source reconstructions, particularly in cortical areas under bones that exhibit high conductivity variations.

Significance

This work acts as a steppingstone in defining a protocol for the preparation of patient-specic head conductivity models that are essential for accurate examination and systematic monitoring of the brain activity via EEG.
Connectivity loss in experimental pond networks leads to biodiversity loss in microbial communities
Authors: Szabó Beáta , Váczy-Földi Máté , Vad Csaba F. , Pálffy Károly , Huỳnh Thu-Hương , Dobosy Péter , Fierpasz Ádám , Márton Zsuzsanna , Felföldi Tamás , Horváth Zsófia
Published: August 2024

Habitat fragmentation is among the most important global threats to biodiversity, however, the direct effects of its components including connectivity loss are still lesser known. Our understanding of these drivers is especially limited in microbial communities. Here, by conducting a four-month outdoor experiment with artificial pond (mesocosm) metacommunities, we studied the effects of connectivity loss on planktonic prokaryote and microeukaryote communities. Connectivity loss was simulated by stopping the dispersal among local habitats while keeping the habitat amount constant and the abiotic environment homogeneous. We found that connectivity loss led to higher levels of extinction and a decrease in both local and regional diversity in microeukaryotes. In contrast, diversity patterns of prokaryotes remained largely unaffected, with some indications of extinction debt. Connectivity loss also led to lower evenness in microeukaryotes, likely through changes in biotic interactions with zooplankton grazers. Our results imply that connectivity loss can directly translate into species losses in communities and highlight the importance of conserving habitat networks with sufficient dispersal among local habitats.
Inflammatory cytokines mediate the induction of and awakening from metastatic dormancy
Authors: Pereira Paulo , Panier Joshua , Nater Marc , Herbst Michael , Calvanese Anna Laura , Köksal Hakan , Castañón Héctor , Cecconi Virginia , Tallón de Lara Paulino , Pascolo Steve , van den Broek Maries
Published: August 2024

Metastases arise from disseminated cancer cells (DCCs) that detach from the primary tumor and seed distant organs. There, quiescent DCCs can survive for an extended time, a state referred to as metastatic dormancy. The mechanisms governing the induction, maintenance, and awakening from metastatic dormancy are unclear. We show that the differentiation of dormancy-inducing CD8+T cells requires CD4+T cell help, and that IFNγ directly induces dormancy in DCCs. The maintenance of metastatic dormancy, however, is independent of T cells. Instead, awakening from dormancy requires an inflammatory signal, and we identified CD4+T cell-derived IL- 17A as an essential wake-up signal for dormant DCCs in the lungs.

Thus, the induction and awakening from metastatic dormancy require an external stimulus, while the maintenance of dormancy does not rely on the continuous surveillance by lymphocytes.
Mast cell-derived chymases are essential for the resolution of inflammatory pain in mice
Authors: de Souza Sabrina , Laumet Sophie , Inyang Kufreobong E. , Hua Hannah , Sim Jaewon , Folger Joseph K. , Moeser Adam J. , Laumet Geoffroy
Published: August 2024

Immune cells play a critical role in the transition from acute to chronic pain. However, the role of mast cells in pain remains under-investigated. Here, we demonstrated that the resolution of inflammatory pain is markedly delayed in mast-cell-deficient mice. In response to Complete Freund Adjuvant (CFA), mast-cell-deficient mice showed greater levels of nitric oxide and altered cytokine/chemokine profile in inflamed skin in both sexes. In Wild-Type (WT) mice, the number of mast cell and mast cell-derived chymases; chymase 1 (CMA1) and mast cell protease 4 (MCPT4) increased in the inflamed skin. Inhibiting chymase enzymatic activity delayed the resolution of inflammatory pain. Consistently, local pharmacological administration of recombinant CMA1 and MCPT4 promoted the resolution of pain hypersensitivity and attenuated the upregulation of cytokines and chemokines under inflammation. We identified CCL9 as a target of MCPT4. Inhibition of CCL9 promoted recruitment of CD206+myeloid cells and alleviated inflammatory pain. Our work reveals a new role of mast cell-derived chymases in preventing the transition from acute to chronic pain and suggests new therapeutic avenues for the treatment of inflammatory pain.

Mast cell-derived chymases play an unexpected role in the resolution of inflammatory pain and regulate the immune response.

Graphical abstract

Mast cells derived chymase MCPT4 degrades CCL9 to promote acute inflammatory pain resolution and prevent chronic pain.

CFA-induced inflammation increases mast cells that degranulate and release chymases, like MCPT4 and CMA1, which in turn cleaves cytokines and chemokines such as CCL9. CCL9 cleavage induces the recruitment of CD206+myeloid cells to promote the resolution of pain and prevent the transition from acute to chronic pain.
PGSFusionstreamlines polygenic score construction and epidemiological applications in biobank-scale cohorts
Authors: Yang Sheng , Ye Xiangyu , Ji Xiaolong , Li Zhenghui , Tian Min , Huang Peng , Cao Chen
Published: August 2024

Background

The polygenic score (PGS) is an estimate of an individual’s genetic susceptibility to a specific complex trait and has been instrumental to the development of precision medicine. Clinically, the simplest form of PGS, which is calculated as a weighted sum of variant counts, has been widely applied to conduct disease risk classification. Unfortunately, despite the critical importance of PGS, there are few online resources available to biologists and epidemiologists to calculate PGS in a user-friendly manner.

Results

To address this need, we have developed a web server, PGSFusion, that streamlines the construction of PGS using a large variety of methods targeting different epidemiological requirements. PGSFusion included 16 PGS methods in four categories, which are single-trait, annotation-based, multiple-trait, and cross-ancestry. In addition, PGSFusion also utilizes UK Biobank data to provide two kinds of in-depth analyses: i) prediction performance evaluation to display the consistency between PGS and specific traits and the effect size of PGS in different genetic risk groups; ii) joint effect analysis to investigate the interaction between PGS and covariates, as well as the genetic effect size in different subgroups of covariates. PGSFusion automatically identifies the required information in uploaded summary statistics files, provides a selection of suitable methods, and outputs calculated PGSs and their corresponding epidemiological results, all without requiring prior programming knowledge. To demonstrate the function of PGSFusion, we showcase three case studies in different application scenario, highlighting its versatility and values to researchers.

Conclusions

Overall, PGSFusion presents an easy-to-use, effective, and extensible platform for PGS construction, promoting the accessibility and utility of PGS for researchers in the field of precision medicine.
Specific light-regime adaptations, terpenoid profiles and engineering potential in ecologically diversePhaeodactylum tricornutumstrains
Authors: Morelli Luca , Patwari Payal , Pruckner Florian , Bastide Maxime , Fabris Michele
Published: August 2024

Microalgae, and among them, the diatomPhaeodactylum tricornutumstand out with their remarkable versatility and metabolic engineering potential. Diatoms exhibit substantial variability in metabolism, photosynthetic physiology and environmental adaptation, even across the same species. These factors can affect the design and outcome of metabolic engineering strategies. In this study, we profiled the diversity of biotechnologically relevant traits of threeP. tricornutumstrains (Pt1, Pt6, and Pt9) under different light regimes to identify the most suitable chassis to be employed as bio-factory to produce high-value terpenoids. We conducted detailed assessments of these strains, using pulse amplitude modulated (PAM) fluorometry to measure photosynthetic efficiency and we analyzed the composition of pigments and triterpenoids, as main terpenoid metabolic sinks. Parameters such as the maximum quantum yield of PSII (Fv/Fm), the efficiency of excitation energy capture (Fv’/Fm’), and OJIP kinetics were used to estimate photosynthetic performance in different light regimes. Additionally, we evaluated their transformation efficiency and their capacity to produce heterologous monoterpenoids, using geraniol as a model product. Our findings revealed that Pt1, widely used in laboratories, exhibits robust growth and photosynthetic performance under standard laboratory conditions. Pt6, adapted to intertidal environments, shows unique resilience in fluctuating conditions, while Pt9, with its high-temperature tolerance, excels under continuous high irradiance. Additionally, this variability across strains and light conditions influenced the metabolic output of each strain. We concluded that understanding the physiological responses of differentP. tricornutumstrains to light is crucial for optimizing their use in metabolic engineering. The insights gained from this research will facilitate the strategic selection and exploitation of these strains in algae biotechnology, enhancing the production of commercially valuable compounds such as high-value terpenoids and derivatives. This comprehensive characterization of strains under varying light conditions offers a pathway to more efficient and targeted metabolic engineering applications.

Highlights

Pt1, Pt6, and Pt9 exhibit distinct physiology under different light regimes.

Pt9 is photosynthetically more performant in continuous light, Pt6 in photoperiod.

Light regimes affect pigments and triterpenoid content in all three strains.

Each strain exhibits a specific carotenoid and triterpenoid composition.

Bacterial conjugation of episomes varies across strains, it is more efficient in Pt1.

Pt1 is suited for the heterologous synthesis of monoterpenes (geraniol).
Brief encounters with real objects modulate medial parietal but not occipitotemporal cortex
Authors: Wardle Susan G. , Rispoli Beth , Roopchansingh Vinai , Baker Chris I.
Published: August 2024

Humans are skilled at recognizing everyday objects from pictures, even if we have never encountered the depicted object in real life. But if we have encountered an object, how does that real-world experience affect the representation of its photographic image in the human brain? We developed a paradigm that involved brief real-world exploration of everyday objects prior to the measurement of brain activity with fMRI while viewing pictures of the objects. We discovered that while object-responsive regions in lateral occipital and ventral temporal cortex were visually driven and contained highly invariant representations of specific objects, those representations were not modulated by real-world exploration. However, real-world experience with an object produced foci of increased activation in medial parietal and posterior cingulate cortex, identifying an important associative region for the experience gained from manual object exploration. The richness of object representations beyond their photographic image has important implications for understanding object recognition in both the human brain and in computational models.
Untargeted proteomics enables ultra-rapid variant prioritization in mitochondrial and other rare diseases
Authors: Hock Daniella H. , Caruana Nikeisha J. , Semcesen Liana N. , Lake Nicole J. , Formosa Luke E. , Amarasekera Sumudu S. C. , Stait Tegan , Tregoning Simone , Frajman Leah E. , Robinson David R. L. , Ball Megan , Reljic Boris , Ryder Bryony , Wallis Mathew J. , Vasudevan Anand , Beck Cara , Peters Heidi , Lee Joy , Tan Natalie B. , Freckmann Mary-Louise ,   MitoMDT Diagnostic Network for Genomics and Omics, Karlaftis Vasiliki , Attard Chantal , Monagle Paul , Samarasinghe Amanda , Brown Rosie , Bi Weimin , Lek Monkol , McFarland Robert , Taylor Robert W. , Ryan Michael T. , Stark Zornitza , Christodoulou John , Compton Alison G. , Thorburn David R. , Stroud David A.
Published: August 2024

Only half of individuals with suspected rare diseases receive a definitive genetic diagnosis following genomic testing. A genetic diagnosis allows access to appropriate patient care and reduces the number of potentially unnecessary interventions and related healthcare costs. Here, we demonstrate that an untargeted quantitative mass-spectrometry approach quantifying >6,000 proteins in primary fibroblasts representing >80% of known mitochondrial disease genes can provide functional evidence for 83% of individuals in a cohort of known primary mitochondrial diseases. We profiled >90 individuals, including 28 with confirmed disease and diagnosed 6 individuals with variants in both nuclear and mitochondrial genes. Lastly, we developed an ultra-rapid proteomics pipeline using minimally invasive peripheral blood mononuclear cells to support upgrade of variant pathogenicity in as little as 54 hours in critically ill infants with suspected mitochondrial disorders. This study supports the integration of a single untargeted proteomics test into routine diagnostic practice for the diagnosis of rare genetic disorders in clinically actionable timelines, offering a paradigm shift for the functional validation of genetic variants.
Relationships between depression, anxiety, and motivation in the real-world: Effects of physical activity and screentime
Authors: Beltrán J. , Jacob Y. , Mehta M. , Hossain T. , Adams A. , Fontaine S. , Torous J. , McDonough C. , Johnson M. , Delgado A. , Murrough J. W. , Morris L. S.
Published: August 2024

Background

Mood and anxiety disorders are highly prevalent and comorbid worldwide, with variability in symptom severity that fluctuates over time. Digital phenotyping, a growing field that aims to characterize clinical, cognitive and behavioral features via personal digital devices, enables continuous quantification of symptom severity in the real world, and in real-time.

Methods

In this study, N=114 individuals with a mood or anxiety disorder (MA) or healthy controls (HC) were enrolled and completed 30-days of ecological momentary assessments (EMA) of symptom severity. Novel real-world measures of anxiety, distress and depression were developed based on the established Mood and Anxiety Symptom Questionnaire (MASQ). The full MASQ was also completed in the laboratory (in-lab). Additional EMA measures related to extrinsic and intrinsic motivation, and passive activity data were also collected over the same 30-days. Mixed-effects models adjusting for time and individual tested the association between real-world symptom severity EMA and the corresponding full MASQ sub-scores. A graph theory neural network model (DEPNA) was applied to all data to estimate symptom interactions.

Results

There was overall good adherence over 30-days (MA=69.5%, HC=71.2% completion), with no group difference (t(58)=0.874, p=0.386). Real-world measures of anxiety/distress/depression were associated with their corresponding MASQ measure within the MA group (t’s > 2.33, p’s < 0.024). Physical activity (steps) was negatively associated with real-world distress and depression (IRRs > 0.93, p’s ≤ 0.05). Both intrinsic and extrinsic motivation were negatively associated with real-world distress/depression (IRR’s > 0.82, p’s < 0.001). DEPNA revealed that both extrinsic and intrinsic motivation significantly influenced other symptom severity measures to a greater extent in the MA group compared to the HC group (extrinsic/intrinsic motivation: t(46)= 2.62, p < 0.02, q FDR < 0.05, Cohen’sd= 0.76; t(46)= 2.69, p < 0.01, q FDR < 0.05, Cohen’sd= 0.78 respectively), and that intrinsic motivation significantly influenced steps (t(46)= 3.24, p < 0.003, q FDR < 0.05, Cohen’sd= 0.94).

Conclusions

Novel real-world measures of anxiety, distress and depression significantly related to their corresponding established in-lab measures of these symptom domains in individuals with mood and anxiety disorders. Novel, exploratory measures of extrinsic and intrinsic motivation also significantly related to real-world mood and anxiety symptoms and had the greatest influencing degree on patients’ overall symptom profile. This suggests that measures of cognitive constructs related to drive and activity may be useful in characterizing phenotypes in the real-world.
Talking while Walking After Concussion: Acute effects of concussion on speech pauses and gait speed
Authors: Yang Shu , Johnson Paula K. , Hansen Colby R. , Wilde Elisabeth A. , Cortez Melissa M. , Dibble Leland E. , Fino Peter C. , Raffegeau Tiphanie E.
Published: August 2024

Background

Deficits in dual-tasks (DT) are frequently observed post-concussion (i.e., mild Traumatic Brain Injury). However, traditional DT may not be relevant to daily life. Walking while talking elicits DT costs in healthy adults and is part of daily life.

Objective

We investigated the effect of concussion on walking with extemporaneous speech and explored relationships between DT and acute symptoms.

Methods

Participants with recent concussion (<14 days post-injury) and controls completed three tasks: single-task gait without speaking (STG), single-task speaking without walking (STS) and walking while speaking (DT). Silent pauses in speech audio reflected cognitive performance, and gait was quantified using inertial sensors. We used linear mixed models to compare groups and conditions and explored associations with self-reported symptoms.

Results

Both concussion (n=19) and control (n=18) groups exhibited longer speech pauses (p< 0.001), slower walking speeds (p< 0.001), and slower cadence (p< 0.001) during the DT compared to ST conditions. There were no group differences or interactions for speech pauses (p> 0.424). The concussion group walked slower (p= 0.010) and slowed down more during DT than the control group (group*taskp= 0.032). Vestibular symptoms strongly associated with ST speech pause duration (ρ= 0.72), ST gait speed (ρ= −0.75), and DT gait speed (ρ= −0.78).

Conclusions

Extemporaneous speech is well-practiced, but challenging to complete while walking post-concussion. Strong associations between DT outcomes and vestibular-related symptoms suggest DT deficits vary with post-concussion symptomology. DT deficits may be deleterious to daily tasks post-concussion.
Clonal Hematopoiesis of Indeterminate Potential in Crohn’s Disease and Ulcerative Colitis
Authors: Esai Selvan Myvizhi , Nathan Daniel I. , Guisado Daniela , Collatuzzo Giulia , Iruvanti Sushruta , Boffetta Paolo , Mascarenhas John , Hoffman Ronald , Cohen Louis J. , Marcellino Bridget K. , Gümüş Zeynep H.
Published: August 2024

Clonal hematopoiesis of indeterminate potential (CHIP) is the presence of somatic mutations in myeloid and lymphoid malignancy genes in the blood cells of individuals without a hematologic malignancy. Inflammation is hypothesized to be a key mediator in the progression of CHIP to hematologic malignancy and patients with CHIP have a high prevalence of inflammatory diseases. This study aimed to identify the prevalence and characteristics of CHIP in patients with inflammatory bowel disease (IBD). We analyzed whole exome sequencing data from 587 Crohn’s disease (CD), 441 ulcerative colitis (UC), and 293 non-IBD controls to assess CHIP prevalence and used logistic regression to study associations with clinical outcomes. Older UC patients (age>45) harbored increased myeloid-CHIP mutations compared to younger patients (age≤45) (p=0.01). Lymphoid-CHIP was more prevalent in older IBD patients (p=0.007). Young CD patients were found to have myeloid-CHIP with high-risk features. IBD patients with CHIP exhibited unique mutational profiles compared to controls. Steroid use was associated with increased CHIP (p=0.05), while anti-TNF therapy was associated with decreased myeloid-CHIP (p=0.03). Pathway enrichment analyses indicated overlap between CHIP genes, IBD phenotypes, and inflammatory pathways. Our findings underscore a connection between IBD and CHIP pathophysiology. Patients with IBD and CHIP had unique risk profiles especially among older UC patients and younger CD patients. These findings suggest distinct evolutionary pathways for CHIP in IBD and necessitate awareness among IBD providers and hematologists to identify patients potentially at risk for CHIP-related complications including malignancy, cardiovascular disease and acceleration of their inflammatory disease.
Evaluating Traditional, Deep Learning, and Subfield Methods for Automatically Segmenting the Hippocampus from MRI
Authors: Sghirripa Sabrina , Bhalerao Gaurav , Griffanti Ludovica , Gillis Grace , Mackay Clare , Voets Natalie , Wong Stephanie , Jenkinson Mark ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: August 2024

Given the relationship between hippocampal atrophy and cognitive impairment in various pathological conditions, hippocampus segmentation from MRI is an important task in neuroimaging. Manual segmentation, though considered the gold standard, is time-consuming and error-prone, leading to the development of numerous automatic segmentation methods. However, no study has yet independently compared the performance of traditional, deep learning-based, and hippocampal subfield segmentation methods within a single investigation. We evaluated nine automatic hippocampal segmentation methods (FreeSurfer, FastSurfer, FIRST, e2dhipseg, HippMapper, Hippodeep, FreeSurfer-Subfields, HippUnfold and HSF) across three datasets with manually segmented hippocampus labels. Performance metrics included overlap with manual labels, correlations between manual and automatic volumes, diagnostic group differentiation, and systematically located false positives and negatives. Most methods, especially deep learning-based ones, performed well on public datasets but showed more error and variability on unseen data. Many methods tended to over-segment, particularly at the anterior hippocampus border, but were able to distinguish between healthy controls, MCI, and dementia patients based on hippocampal volume. Our findings highlight the challenges in hippocampal segmentation from MRI and the need for more publicly accessible datasets with manual labels across diverse ages and pathological conditions.

Key Messages

We evaluated nine automatic hippocampal segmentation methods, including traditional and deep learning-based approaches, across three datasets with manually segmented hippocampus labels.

While deep learning-based methods perform well on public datasets, they show more error and variability on unseen data that is more reflective of a clinical population.

More publicly accessible datasets with manual labels are required for automatic hippocampal segmentations to be accurate and reliable, particularly for clinical populations.

Practitioner Points

Although deep learning based automatic hippocampal segmentation methods offer faster processing times—a requirement for translation to clinical practice—the lack of variance within training sets (such as sample demographics and scanner sequences) currently prevents transfer of learning to novel data, such as those acquired clinically.

More training data with varying demographics, scanner sequences and pathologies are required to adequately train deep learning methods to quickly, accurately and reliably segment the hippocampus for use in clinical practice.
Pilot Study of Large Language Models as an Age-Appropriate Explanatory Tool for Chronic Pediatric Conditions
Authors: Young Cameron C. , Enichen Elizabeth , Rao Arya , Hilker Sidney , Butler Alex , Laird-Gion Jessica , Succi Marc D.
Published: August 2024

There exists a gap in existing patient education resources for children with chronic conditions. This pilot study assesses large language models’ (LLMs) capacity to deliver developmentally appropriate explanations of chronic conditions to pediatric patients. Two commonly used LLMs generated responses that accurately, appropriately, and effectively communicate complex medical information, making them a potentially valuable tool for enhancing patient understanding and engagement in clinical settings.
Online sexual, reproductive, and transgender healthcare for LGBTQI+ youth: A scoping review
Authors: McLeod Julie , Estcourt Claudia S. , Flowers Paul , Gibbs Jo , MacDonald Jennifer
Published: August 2024

Background

Lesbian, gay, bisexual, trans, queer, questioning, intersex, and other sexual and gender minority (LGBTQI+) youth have poor sexual and reproductive health outcomes and low uptake of sexual and reproductive healthcare (SRHC). Online SRHC and transgender healthcare could overcome known barriers to in-person SRHC, such as confidentiality concerns. Therefore, we aimed to describe existing literature on online SRHC and transgender healthcare for LGBTQI+ youth, synthesise study findings, and make recommendations for future research.

Methods

We conducted a scoping review following the Joanna-Briggs Institute methodology. Eligibility were online SRHC and transgender healthcare for LGBTQI+ youth (aged 10-35 years) in high-income countries. Search strings were framed around the eligibility criteria and 265 search terms were selected to identify published literature from nine databases. Searches were exported to Rayyan and studies screened by two reviewers. Data from included studies were extracted to Excel and analyzed descriptively.

Results

Of 91 included papers, 41 were quantitative, 26 were qualitative, and 24 were mixed methods. Seventy-one papers focused on sexual health (HIV/sexually transmitted infection (STI) prevention 52/71; HIV management 9/71; sexual healthper se9/71; and HIV stigma reduction 2/71); 3/91 on reproductive health (pregnancy prevention 2/3); 2/91 sexual and reproductive health; and 16/91 on transgender health (gender identity/transitionper se8/16; gender affirming care 8/16). Papers explored the provision of or engagement with education/information (72/91); non-clinical support (56/91, e.g., reminders for HIV/STI testing); and clinical care (18/91) for sexual health (10/18, e.g., home HIV/STI self-sampling kits 6/10) or transgender health (8/18, i.e., eConsultation with a healthcare provider 8/8). Studies targeted young men who have sex with men (62/91) for sexual health; trans and gender diverse youth (26/91) for transgender healthcare (16/26) and sexual health (14/26); LGBTQI+ youth (6/91); and young sexual minority women (4/91) for reproductive health (3/4) and sexual and reproductive health (1/4).

Conclusions

There is a large and varied literature base for online SRHC and transgender healthcare for LGBTQI+ youth. However, most research focused on sexual healthcare, particularly HIV/STI prevention, for men who have sex with men. Very little explored reproduction or sexual health other than HIV prevention. Young sexual minority women and trans and gender diverse youth are notably under-researched for online SRHC. Research is needed to understand how to enhance the potential of online healthcare for LGBTQI+ youth.
Astrocyte extracellular matrix modulates neuronal dendritic development
Authors: Hashimoto Joel G. , Margolies Nicholas , Zhang Xiaolu , Karpf Joshua , Song Yuefan , Davis Brett A. , Zhang Fuming , Linhardt Robert J. , Carbone Lucia , Guizzetti Marina
Published: August 2024

Major developmental events occurring in the hippocampus during the third trimester of human gestation and neonatally in altricial rodents include rapid and synchronized dendritic arborization and astrocyte proliferation and maturation. We tested the hypothesis that signals sent by developing astrocytes to developing neurons modulate dendritic development in vivo. We altered neuronal development by neonatal (third trimester-equivalent) ethanol exposure in mice; this treatment increased dendritic arborization in hippocampal pyramidal neurons. We next assessed concurrent changes in the mouse astrocyte translatome by translating ribosomal affinity purification (TRAP)-seq. We followed up on ethanol-inhibition of astrocyte Chpf2 and Chsy1 gene translation because these genes encode for biosynthetic enzymes of chondroitin sulfate glycosaminoglycan (CS-GAG) chains (extracellular matrix components that inhibit neuronal development and plasticity) and have not been explored before for their roles in dendritic arborization. We report that Chpf2 and Chsy1 are enriched in astrocytes and their translation is inhibited by ethanol, which also reduces the levels of CS-GAGs measured by Liquid Chromatography/Mass Spectrometry. Finally, astrocyte-conditioned medium derived from Chfp2-silenced astrocytes increased neurite branching of hippocampal neurons in vitro. These results demonstrate that CS-GAG biosynthetic enzymes in astrocytes regulates dendritic arborization in developing neurons.
On the possibility of yet a third kinetochore system in the protist phylum Euglenozoa
Authors: Benz Corinna , Raas Maximilian W.D. , Tripathi Pragya , Faktorová Drahomíra , Tromer Eelco C. , Akiyoshi Bungo , Lukeš Julius
Published: August 2024

Transmission of genetic material from one generation to the next is a fundamental feature of all living cells. In eukaryotes, a macromolecular complex called the kinetochore plays crucial roles during chromosome segregation by linking chromosomes to spindle microtubules. Little is known about this process in evolutionarily diverse protists. Within the supergroup Discoba, Euglenozoa forms a speciose group of unicellular flagellates - kinetoplastids, euglenids, and diplonemids. Kinetoplastids have an unconventional kinetochore system, while euglenids have subunits that are conserved amongst most eukaryotes. For diplonemids, a group of extremely diverse and abundant marine flagellates, it remains unclear what kind of kinetochores are present. Here, we employed deep homology detection protocols using profile-versus-profile Hidden Markov Model searches and AlphaFold-based structural comparisons to detect homologies that might have been previously missed. Interestingly, we still could not detect orthologs for most of the kinetoplastid nor canonical kinetochore subunits with few exceptions including a putative centromere-specific histone H3 variant (cenH3/CENP-A), the spindle checkpoint protein Mad2, the chromosomal passenger complex members Aurora and INCENP, and broadly conserved proteins like CLK kinase and the meiotic synaptonemal complex proteins SYCP2/3 that also function at kinetoplastid kinetochores. We examined the localization of five candidate kinetochore-associated proteins in the model diplonemid,Paradiplonema papillatum.PpCENP-A shows discrete dots in the nucleus, implying that it is likely a kinetochore component.PpMad2,PpCLKKKT10/19,PpSYCP2L1KKT17/18and INCENP reside in the nucleus, but no clear kinetochore localization was observed. Altogether, these results point to the possibility that diplonemids evolved a hitherto unknown type of kinetochore system.
Locating the Missing Chlorophyllsfin Far-red Photosystem I
Authors: Consoli Giovanni , Tufail Fiazall , Leong Ho Fong , Viola Stefania , Davis Geoffry A. , Medranda Daniel , Rew Nicholas , Hofer Michael , Simpson Paul , Sandrin Marco , Chachuat Benoit , Nelson Jenny , Renger Thomas , Murray James W. , Fantuzzi Andrea , Rutherford A. William
Published: August 2024

The discovery of chlorophyllf-containing oxygenic photosynthesis, with its long-wavelength photochemistry, represented a new low-energy paradigm. However, subsequent structural studies on chlorophyllf-containing Photosystem I (PSI) found five chlorophyllsfbut none among the photochemically active pigments and concluded that chlorophyllfplays no photochemical role. Here we report a cryo-EM structure (2.01 Å) of far-red PSI fromChroococcidiopsis thermalisPCC 7203, showing all eight chlorophyllsf, including the redox active A-1B. Simulations of absorption difference spectra induced by charge separation indicate that the A-1Bchlorophyllfabsorbs at 755 nm. The chlorophyllfsites, some wavelength assignments, and conserved far-red-specific amino acids, provide functional insights, including redox tuning of chlorophyllfas the primary donor and far-red excitation energy-sharing over the PSI trimer.
A vaccine antigen central in influenza A(H5) virus antigenic space confers subtype-wide immunity
Authors: Kok Adinda , Wilks Samuel H. , Tureli Sina , James Sarah L. , Bestebroer Theo M. , Burke David F. , Funk Mathis , van der Vliet Stefan , Spronken Monique I. , Rijnink Willemijn F. , Pattinson David , de Meulder Dennis , Rosu Miruna E. , Lexmond Pascal , van den Brand Judith M.A. , Herfst Sander , Smith Derek J. , Fouchier Ron A.M. , Richard Mathilde
Published: August 2024

Highly pathogenic avian influenza A(H5) viruses globally impact wild and domestic birds, and mammals, including humans, underscoring their pandemic potential. The antigenic evolution of the A(H5) hemagglutinin (HA) poses challenges for pandemic preparedness and vaccine design. Here, the global antigenic evolution of the A(H5) HA was captured in a high-resolution antigenic map. The map was used to engineer immunogenic and antigenically central vaccine HA antigens, eliciting antibody responses that broadly cover the A(H5) antigenic space. In ferrets, a central antigen protected as well as homologous vaccines against heterologous infection with two antigenically distinct viruses. This work showcases the rational design of subtype-wide influenza A(H5) pre-pandemic vaccines and demonstrates the value of antigenic maps for the evaluation of vaccine-induced immune responses through antibody profiles.
Autophagosomes coordinate an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling
Authors: Segura-Roman Ashley , Citron Y. Rose , Shin Myungsun , Sindoni Nicole , Maya-Romero Alex , Rapp Simon , Goul Claire , Mancias Joseph D. , Zoncu Roberto
Published: August 2024

Protein Kinase A (PKA) is regulated spatially and temporally via scaffolding of its catalytic (Cα/β) and regulatory (RI/RII) subunits by the A-kinase-anchoring proteins (AKAP). PKA engages in poorly understood interactions with autophagy, a key degradation pathway for neuronal cell homeostasis, partly via its AKAP11 scaffold. Mutations in AKAP11 drive schizophrenia and bipolar disorders (SZ-BP) through unknown mechanisms. Through proteomic-based analysis of immunopurified lysosomes, we identify the Cα−RIα-AKAP11 holocomplex as a prominent autophagy-associated protein kinase complex. AKAP11 scaffolds Cα−RIα to the autophagic machinery via its LC3-interacting region (LIR), enabling both PKA regulation by upstream signals, and its autophagy-dependent degradation. We identify Ser83 on the RIα linker-hinge region as an AKAP11-dependent phospho-residue that modulates RIα-Cα binding and cAMP-induced PKA activation. Decoupling AKAP11-PKA from autophagy alters Ser83 phosphorylation, supporting an autophagy-dependent checkpoint for PKA signaling. Ablating AKAP11 in induced pluripotent stem cell-derived neurons reveals dysregulation of multiple pathways for neuronal homeostasis. Thus, the autophagosome is a novel platform that modulate PKA signaling, providing a possible mechanistic link to SZ/BP pathophysiology.
Novel replication-competent reporter-expressing Rift Valley Fever Viruses for molecular studies
Authors: Nogales Aitor , Alonso Celia , Moreno Sandra , Lorenzo Gema , Borrego Belén , Martinez-Sobrido Luis , Brun Alejandro
Published: August 2024

Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic disease that causes severe disease in both domestic and wild ungulates and humans, making it a significant threat to livestock and public health. The RVFV genome consists of three single-stranded, negative-sense RNA segments differing in size: Small (S), Medium (M) and Large (L). Segment S encodes the virus nucleoprotein N and the virulence-associated factor non-structural (NSs) protein in opposite orientations, separated by an intergenic region (IGR). To overcome the current need of using secondary techniques to detect the presence of RVFV in infected cells, we used T7-driven polymerase plasmid-based reverse genetics to generate replication-competent recombinant (r)RVFV expressing Nanoluciferase (Nluc) or Venus fluorescent proteins. These reporter genes were used as valid surrogates to track the presence of RVFV in mammalian and insect cells. Notably, we explored the genome plasticity of RVFV and compared four different strategies by modifying the viral segment S in order to introduce the reporter gene foreign sequences. The reporter-expressing rRVFV were stable and able to replicate in cultured mammalian and insect cells, although to a lesser extent than the recombinant wild-type (WT) counterpart. Moreover, rRVFV expressing reporter genes were validated to identify neutralizing antibodies or compounds with antiviral activity.In vivo, all mice infected with the reporter-expressing rRVFV displayed an attenuated phenotype, although at different levels. These rRVFV expressing reporter genes provide a novel approach to better understand the biology and pathogenesis of RVFV, and represent an excellent biotechnological tool for developing new therapeutics against RVFV infections.

IMPORTANCE

Rift Valley fever virus (RVFV) is a mosquito-borne virus and zoonotic agent threat that can be deadly to domestic or wild ungulates, and humans. In this work, we used reverse genetics approaches to explore the genome plasticity of RVFV by generating a set of recombinant rRVFV that express fluorescent or luminescent proteins to track viral infection. All the generated reporter-expressing rRVFV were able to propagate in mammalian or insect cells, and in a mouse model of infection. Our studies may contribute to advances in research on RVFV and other bunyaviruses and pave the way for the development of novel vaccines and the identification of new antivirals for the prophylactic and therapeutic treatment, respectively, of RVFV infections.