bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence And Mechanisms For Embolic Stroke In Contralateral Hemispheres From Carotid Artery Sources
Authors: Roopnarinesingh Ricardo , Leppert Michelle , Mukherjee Debanjan
Published: April 2023

Disambiguation of embolus etiology in embolic strokes is often a clinical challenge. One common source of embolic stroke is the carotid arteries, with emboli originating due to plaque build up, or perioperatively during revascularization procedures. While it is commonly thought that thromboemboli from carotid sources travel to cerebral arteries ipsilaterally, there are existing reports of contralateral embolic events which complicate embolus source destination relationship for carotid sources. Here, we hypothesize that emboli from carotid sources can travel to contralateral hemispheres, and that embolus interactions with collateral hemodynamics in the Circle of Willis influences this process. We use a patient-specific computational embolus-hemodynamics interaction model developed in prior works to conduct anin silicoexperiment spanning 4 patient vascular models, 6 Circle of Willis anastomosis variants, and 3 different thromboembolus sizes released from left and right carotid artery sites. This led to a total of 144 different experiments, estimating trajectories and distribution of approximately 1.728 million embolus samples. Across all cases considered, emboli from left and right carotid sources showed non-zero contralateral transport (p value<0.05). Contralateral movement revealed a size-dependence, with smaller emboli traveling more contralaterally. Detailed analysis of embolus dynamics revealed that collateral flow routes in Circle of Willis played a role in routing emboli, and transhemispheric movement occurred through the anterior and posterior communicating arteries in the Circle of Willis. We generated quantitative data demonstrating the complex dynamics of finite size thromboembolus particles as they interact with pulsatile arterial hemodynamics, and traverse the vascular network of the Circle of Willis. This leads to a non-intuitive source-destination relationship for emboli originating from carotid artery sites, and emboli from carotid sources can potentially travel to cerebral arteries on contralateral hemispheres.
Three-Dimensional Echocardiographic Evaluation of Longitudinal and Non-Longitudinal Components of Right Ventricular Contraction Results from the World Alliance of Societies of Echocardiography Study
Authors: Cotella Juan I. , Kovacs Attila , Addetia Karima , Fabian Alexandra , Asch Federico M. , Lang Roberto M.
Published: April 2023

Background

Right ventricular (RV) functional assessment is mainly limited to its longitudinal component. However, due to the complex orientation of the myofibers, the RV contraction involves coordinated motion along multiple planes. Recently developed 3-dimensional echocardiography (3DE) software has enabled the separate assessment of the non-longitudinal components of RV systolic function and their relative contribution to RV performance. The aims of this study were 1) to establish normal values for 3D-derived longitudinal, radial, and anteroposterior RV ejection fraction (LEF, REF, AEF respectively) and their relative contributions to global RVEF, 2) to calculate 3D RV strain normal values and, 3) to determine sex, age and race related differences in these parameters in a large group of normal subjects (WASE study)

Methods

1043 healthy adult subjects prospectively enrolled at 17 centers in 15 countries were used in this study. 3DE RV wide-angle datasets were analyzed to generate a 3D mesh model of the RV cavity (TomTec). Then, dedicated software (ReVISION) was used to analyze RV motion along the three main anatomical planes and the ejection fraction (EF) values corresponding to each plane were identified as LEF, REF, and AEF. Relative contributions were determined by dividing each EF component by the global RVEF. RV strain analysis included longitudinal, circumferential, and global area strains (GLS, GCS and GAS, respectively). Results were categorized by sex, age (18-40, 41-65 and >65 years), and race.

Results

Absolute REF, AEF, LEF and global RVEF were higher in women than in men (p < .001). With aging, both sexes exhibited a decline in all the determinants of longitudinal shortening (p <.001). In elderly women, the lower global RVEF was partially compensated by an increase in radial shortening. Both Black men and women showed lower RVEF, and GAS values compared to White and Asian subjects of the same sex (p < .001). Black men showed significantly higher REF/RVEF and lower LEF/RVEF compared to Asian and White men. These differences in RV contraction patterns across races were not present in women.

Conclusion

3DE evaluation of the non-longitudinal components of RV contraction provides additional information regarding RV physiology, including sex, age and race - related differences in RV contraction patterns that may prove useful in disease states involving the RV.
NR4A3 deficiency in CD8+T cells improves adoptive T cell therapy of cancer
Authors: Odagiu Livia , Maurice De Sousa Dave , Boulet Salix , Labrecque Nathalie
Published: April 2023

NR4A3 is a transcription factor that is rapidly induced in CD8+T cells following antigenic recognition. We have previously shown that NR4A3 deficiency induces an early molecular program that promotes memory generation and enhances effector functions, which are two essential attributes for the success of adoptive cell therapy (ACT). Therefore, we tested the hypothesis thatNr4a3-/-CD8+T cells would have outstanding efficacy in ACT of cancer. Our results show that ACT of melanoma-bearing mice withNr4a3-/-effector CD8+T cells provides a better tumor control than their wild-type counterpart. The therapeutic effect observed withNr4a3-/-effector CD8+T cells is even better than the one observed with ACT ofNr4a3+/+effector CD8+T cells in combination with anti-PD-L1 treatment. scRNA-seq analysis reveals a huge heterogeneity of tumor-infiltrating lymphocytes (TILs) states following ACT. The better tumor control observed with ACT ofNr4a3-/-CD8+effectors without anti-PD-L1 treatment correlates with an enrichment of TILs within the clusters that are associated with the anti-PD-L1 response of wild-type TILs. Moreover, the clusters that are enriched inNr4a3-/-TILs are the ones that are enriched for effector functions. Furthermore,Nr4a3-/-andNr4a3+/+effectors generate distinct progenitor populations. Pseudotime analysis suggests that these progenitors have different differentiation trajectories, which may explain why ACT withNr4a3-/-effectors is more efficient. Therefore, modulation of NR4A3 activity may represent a new strategy to generate long-lived and highly functional T cells for ACT.
Transfer learning on structural brain age models to decode cognition in MS: a federated learning approach
Authors: Denissen Stijn , Grothe Matthias , Vaněčková Manuela , Uher Tomáš , Laton Jorne , Kudrna Matěj , Horáková Dana , Kirsch Michael , Motýl Jiří , De Vos Maarten , Chén Oliver Y. , Van Schependom Jeroen , Sima Diana Maria , Nagels Guy
Published: April 2023

Introduction

Classical deep learning research requires lots of centralised data. However, data sets are often stored at different clinical centers, and sharing sensitive patient data such as brain images is difficult. In this manuscript, we investigated the feasibility of federated learning, sending models to the data instead of the other way round, for research on brain magnetic resonant images of people with multiple sclerosis (MS).

Methods

Using transfer learning on a previously published brain age model, we trained a model to decode performance on the symbol digit modalities test (SDMT) of patients with MS from structural T1 weighted MRI. Three international centers in Brussels, Greifswald and Prague participated in the project. In Brussels, one computer served as the server coordinating the FL project, while the other served as client for model training on local data (n=97). The other two clients were Greifswald (n=104) and Prague (n=100). Each FL round, the server sent a global model to the clients, where its fully connected layer was updated on the local data. After collecting the local models, the server applied a weighted average of two randomly picked clients, yielding a new global model.

Results

After 22 federated learning rounds, the average validation loss across clients reached a minimum. The model appeared to have learned to assign SDMT values close to the mean with a mean absolute error of 9.04, 10.59 and 10.71 points between true and predicted SDMT on the test data sets of Brussels, Greifswald and Prague respectively. The overall test MAE across all clients was 10.13 points.

Conclusion

Federated learning is feasible for machine learning research on brain MRI of persons with MS, setting the stage for larger transfer learning studies to investigate the utility of brain age latent representations in cognitive decoding tasks.
The stem cell-type transcriptome of bioenergy sorghum reveals the spatial regulation of secondary cell wall networks
Authors: Fu Jie , McKinley Brian , James Brandon , Chrisler William , Markillie Lye Meng , Gaffrey Matthew J , Mitchell Hugh D , Orr Galya , Swaminathan Kankshita , Mullet John , Marshall-Colon Amy
Published: April 2023

Bioenergy sorghum is a low-input, drought-resilient, deep-rooting annual crop that has high biomass yield potential enabling the sustainable production of biofuels, biopower, and bioproducts. Bioenergy sorghum’s 4-5 m stems account for ∼80% of the harvested biomass. Stems accumulate high levels of sucrose that could be used to synthesize bioethanol and useful biopolymers if information about stem cell-type gene expression and regulation was available to enable engineering. To obtain this information, Laser Capture Microdissection (LCM) was used to isolate and collect transcriptome profiles from five major cell types that are present in stems of the sweet sorghum Wray. Transcriptome analysis identified genes with cell-type specific and cell-preferred expression patterns that reflect the distinct metabolic, transport, and regulatory functions of each cell type. Analysis of cell-type specific gene regulatory networks (GRNs) revealed that unique TF families contribute to distinct regulatory landscapes, where regulation is organized through various modes and identifiable network motifs. Cell-specific transcriptome data was combined with a stem developmental transcriptome dataset to identify the GRN that differentially activates the secondary cell wall (SCW) formation in stem xylem sclerenchyma and epidermal cells. The cell-type transcriptomic dataset provides a valuable source of information about the function of sorghum stem cell types and GRNs that will enable the engineering of bioenergy sorghum stems.
Saracatinib synergizes with enzalutamide to downregulate androgen receptor activity in castration resistant prostate cancer
Authors: White Ralph E. , Bannister Maxwell , Day Abderrahman , Bergom Hannah E. , Tan Victor M. , Hwang Justin , Nguyen Hai Dang , Drake Justin M.
Published: April 2023

Prostate cancer (PCa) remains the most diagnosed non-skin cancer amongst the American male population. Treatment for localized prostate cancer consists of androgen deprivation therapies (ADTs), which typically inhibit androgen production and the androgen receptor (AR). Though initially effective, a subset of patients will develop resistance to ADTs and the tumors will transition to castration-resistant prostate cancer (CRPC). Second generation hormonal therapies such as abiraterone acetate and enzalutamide are typically given to men with CRPC. However, these treatments are not curative and typically prolong survival only by a few months. Several resistance mechanisms contribute to this lack of efficacy such as the emergence of AR mutations, AR amplification, lineage plasticity, AR splice variants (AR-Vs) and increased kinase signaling. Having identified SRC kinase as a key tyrosine kinase enriched in CRPC patient tumors from our previous work, we evaluated whether inhibition of SRC kinase synergizes with enzalutamide or chemotherapy in several prostate cancer cell lines expressing variable AR isoforms. We observed robust synergy between the SRC kinase inhibitor, saracatinib, and enzalutamide, in the AR-FL+/AR-V+ CRPC cell lines, LNCaP95 and 22Rv1. We also observed that saracatinib significantly decreases AR Y534phosphorylation, a key SRC kinase substrate residue, on AR-FL and AR-Vs, along with the AR regulome, supporting key mechanisms of synergy with enzalutamide. Lastly, we also found that the saracatinib-enzalutamide combination reduced DNA replication compared to the saracatinib-docetaxel combination, resulting in marked increased apoptosis. By elucidating this combination strategy, we provide pre-clinical data that suggests combining SRC kinase inhibitors with enzalutamide in select patients that express both AR-FL and AR-Vs.
Health impact of nuclear waste water discharge from the Fukushima Daiichi nuclear plant
Authors: Liao Huipeng , Sun Danyi , Yang Zifan , Huang Wenyu , Di Qian
Published: April 2023

Tokyo Electric Power Company announced to discharge the contaminated radioactive water resulting from the Fukushima nuclear accident into the ocean after purification from 2023. Concerns remain about safety and removal efficiency of radionuclides. This study calculated the total radioactivity and simulated the marine transport of137Cs,90Sr, and tritium. It assessed activity concentration in ocean and marine products, lifetime doses from marine product consumption, and associated cancer risks. We found the radionuclides would be globally distributed and penetrate into deep ocean, with the highest concentrations along Japan’s eastern coast. If137Cs and90Sr were not removed, related cancer risks would range between 8.64 – 33.35 cases per 100,000 people, depending on age and discharge scenario. Risks would be below one case per 100,000 if only tritium is present. Efficient removal of radionuclides is crucial to mitigating health risks. This study provides evidence of potential health risks and recommendations for prevention.
The burden of dengue and risk factors of transmission in nine districts in Sri Lanka
Authors: Jeewandara Chandima , Karunananda Maneshka Vindesh , Fernando Suranga , Danasekara Saubhagya , Jayakody Gamini , Arulkumaran S. , Samaraweera N.Y. , Kumarawansha Sarathchandra , Sivaganesh Subramaniyam , Amarasinghe P. Geethika , Jayasinghe Chintha , Wijesekara Dilini , Marasinghe Manonath Bandara , Mambulage Udari , Wijayatilake Helanka , Senevirathne Kasun , Bandara A.D.P , Gallage C.P. , Colambage N.R. , Udayasiri A.A. Thilak , Lokumarambage Tharaka , Upasena Y. , Weerasooriya W.P.K.P. ,   seroprevalence study group, Ogg Graham S. , Malavige Gathsaurie Neelika
Published: April 2023

Background

It is crucial to understand the differences in dengue seroprevalence rates in different regions in Sri Lanka to understand the burden of infection to plan dengue vaccination programmes.

Methods

age stratified seroprevalence rates were assessed in 5208 children, aged 10 to 19 years, in nine districts representing the nine provinces in Sri Lanka. A stratified multi-stage cluster was used to select 146 schools representing each district. Probability proportionate to the size (PPS) sampling technique based on the age distribution of general population and the urbanicity in each district was used to select the number of clusters to be enrolled for the study from each district.

Findings

The overall dengue seroprevalence rates in children was 24.8%, with the highest rates reported from Trincomalee (54.3%) and the lowest rates from Badulla (14.2%), which is a high altitude estate area. There was a weak but positive correlation between the dengue antibody positivity rates and age in districts which had seroprevalence rates of >25%, while there was no increase in antibody titres with age in the other districts. While the seroprevalence rates was significantly higher in urban areas (35.8%) compared to rural (23.2%) and estate areas (9.4%), there was no association with seropositivity rates with population density (Spearmans r=-0.01, p=0.98), in each district.

Interpretation

The seroprevalence rates in many districts were <25% and the rates were very different to those reported from Colombo. Therefore, it would be important to take into account these differences when rolling out dengue vaccines in Sri Lanka.

Funding

We are grateful to the World Health Organization and the UK Medical Research Council for support.
FAIR Data Cube, a FAIR data infrastructure for integrated multi-omics data analysis
Authors: Liao Xiaofeng , Ederveen Thomas H.A. , Niehues Anna , de Visser Casper , Huang Junda , Badmus Firdaws , Doornbos Cenna , Orlova Yuliia , Kulkarni Purva , van der Velde K. Joeri , Swertz Morris A. , Brandt Martin , van Gool Alain J. , ’t Hoen Peter A.C.
Published: April 2023

Motivation

We are witnessing an enormous growth in the amount of molecular profiling (-omics) data. The integration of multi-omics data is challenging. Moreover, human multi-omics data may be privacy-sensitive and can be misused to de-anonymize and (re-)identify individuals. Hence, most biomedical data is kept in secure and protected silos. Therefore, it remains a challenge to reuse these data without infringing the privacy of the individuals from which the data were derived. Federated analysis of Findable, Accessible, Interoperable, and Reusable (FAIR) data is a privacy-preserving solution to make optimal use of these multi-omics data and transform them into actionable knowledge.

Results

The Netherlands X-omics Initiative is a National Roadmap Large-Scale Research Infrastructure aiming for efficient integration of data generated within X-omics and external datasets. To facilitate this, we developed the FAIR Data Cube (FDCube), which adopts and applies the FAIR principles and helps researchers to create FAIR data and metadata, to facilitate re-use of their data, and to make their data analysis workflows transparent, and in the meantime ensure data security and privacy.
A Histological Assessment Tool for Breast Implant Capsules Validated in 480 Patients with and without Capsular Contracture
Authors: Larsen Andreas , Timmermann Adam M , Kring Mikela , Weltz Tim K , Ørholt Mathias , Vester-Glowinski Peter , Elberg Jens Jørgen , Trillingsgaard Jesper , Mielke Louise V , Hölmich Lisbet R , Damsgaard Tine E , Roslind Anne , Herly Mikkel
Published: April 2023

Background

Capsular contracture is a severe complication to breast implants, but the pathophysiology remains unclear, and consensus is lacking on how to analyze implant capsules histologically. In this study, we developed and validated a histological semiquantitative assessment tool for analyzing breast implant capsules.

Methods

Biopsies of breast implant capsules from 480 patients who had undergone breast augmentation or reconstruction were collected and stained with hematoxylin and eosin. First, biopsies from 100 patients were used to select parameters for the semiquantitative assessment tool. Then, biopsies from the remaining 380 patients were used to determine intra- and interobserver agreement of two blinded observers and agreement with a pathologist. Finally, we tested the association between the parameters and capsular contracture.

Results

The histological assessment tool consisted of ten parameters assessed on a two-, three-, or four-point scale. Intra- and interobserver agreement was almost perfect (0.83 and 0.80), and agreement with the pathologist was substantial (0.67). Inflammatory infiltration (p<0.01), thickness of the collagen layer (p<0.0001), fiber organization (p<0.01) and calcification (p<0.001) were significantly correlated with capsular contracture.

Conclusions

This is the first validated histological assessment tool for breast implant capsules that provides an objective and precise assessment of hematoxylin and eosin-stained sections of breast implant capsule biopsies which can be used in research and clinical practice.

Level of evidence

No Level Assigned
Anatomically-guided deconvolution of PET using directional total variation regularization
Authors: Gillman Ashley G , Quah Min Han , Papoutsellis Evangelos , Thielemans Kris , Bourgeat Pierrick , Delplancke Claire , Mejan-Fripp Jurgen , Pasca Edoardo , Dowling Jason
Published: April 2023

Abstract. Positron emission tomography (PET) provides quantitative functional imaging of biomarkers unavailable in other modalities, however, images are of relatively low resolution compared to modalities such as magnetic resonance imaging (MRI). A typical approach is to reconstruct to a higher resolution and regularize using a structural image, but there are practical limitations to this approach. Alternatively, post-reconstruction approaches involve image-based correction, but typically rely on a segmentation which may be difficult or even ambiguous to find, depending on the anatomical region or deformities. Here, we perform super-resolution by utilising iterative deconvolution, regularized by minimizing shared directional total variation (dTV) with an anatomical MRI image. We present results on synthetic and clinical data. For the former, PET acquisitions were simulated using an analytic PET simulation. The Gaussian blurring model parameters for deconvolution were optimized on a simplistic phantom simulation with a total variation prior. This model was then applied to deconvolve realistic synthetic data using dTV, which was synthesized to include PET-unique lesions. The model was also applied to a single 18F-florbetaben study acquired over 10 minutes. Gray matter-white matter contrast increased using dTV compared with baseline, however, where an accurate segmentation is available, traditional partial volume correction techniques are superior. Hence, dTV-regularised deconvolution can perform PVC and super-resolution in situations where a reliable segmentation cannot be achieved. With appropriate hyper-parameter selection, dTV deconvolution can preserve PET-unique features.
Pathways that affect anterior morphogenesis inC. elegansembryos
Authors: Boopathi Balasubramaniam , Topalidou Irini , Kelley Melissa , Meadows Sarina M. , Funk Owen , Ailion Michael , Fay David S.
Published: April 2023

During embryogenesis the nascentCaenorhabditis elegansepidermis secretes an apical extracellular matrix (aECM) that serves as an external stabilizer, preventing deformation of the epidermis by mechanical forces exerted during morphogenesis. We showed that two conserved proteins linked to this process, SYM-3/FAM102A and SYM-4/WDR44, colocalize to intracellular and membrane-associated puncta and likely function together in a complex. Proteomics data also suggested potential roles for FAM102A and WDR44 family proteins in intracellular trafficking, consistent with their localization patterns. Nonetheless, we found no evidence to support a clear function for SYM-3 or SYM-4 in the apical deposition of two aECM components, FBN-1 and NOAH. Surprisingly, loss of MEC-8/RBPMS2, a conserved splicing factor and regulator offbn-1, had little effect on the abundance or deposition of FBN-1 to the aECM. Using a focused screening approach, we identified 32 additional proteins that likely contribute to the structure and function of the embryonic aECM. Lastly, we examined morphogenesis defects in embryos lackingmir-51microRNA family members, which display a related embryonic phenotype tomec-8; symdouble mutants. Collectively, our findings add to our knowledge of pathways controlling embryonic morphogenesis.

SUMMARY STATEMENT

We identify new proteins in apical ECM biology inC. elegansand provide evidence that SYM-3/FAM102A and SYM-4/WDR44 function together in trafficking but do not regulate apical ECM protein deposition.
ElegansNet: a brief scientific report and initial experiments
Authors: Bardozzo Francesco , Terlizzi Andrea , Lió Pietro , Tagliaferri Roberto
Published: April 2023

This research report introduces ElegansNet, a neural network that mimics real-world neuronal network circuitry, with the goal of better understanding the interplay between connectome topology and deep learning systems. The proposed approach utilizes the powerful representational capabilities of living beings’ neuronal circuitry to design and generate improved deep learning systems with a topology similar to natural networks. The Caenorhabditis elegans connectome is used as a reference due to its completeness, reasonable size, and functional neuron classes annotations. It is demonstrated that the connectome of simple organisms exhibits specific functional relationships between neurons, and once transformed into learnable tensor networks and integrated into modern architectures, it offers bio-plausible structures that efficiently solve complex tasks. The performance of the models is demonstrated against randomly wired networks and compared to artificial networks ranked on global benchmarks. In the first case,ElegansNetoutperforms randomly wired networks. Interestingly,ElegansNetmodels show slightly similar performance with only those based on the Watts-Strogatz small-world property. When compared to state-of-the-art artificial neural networks, such as transformers or attention-based autoencoders,ElegansNetoutperforms well-known deep learning and traditional models in both supervised image classification tasks and unsupervised hand-written digits reconstruction, achieving top-1 accuracy of 99.99% on Cifar10 and 99.84% on MNIST Unsup on the validation sets.
Culture of Saos-2 cells under hypoxic conditions stimulates rapid differentiation to an osteocyte-like stage
Authors: Zelmer Anja R. , Starczak Yolandi , Solomon Lucian B. , Richter Katharina , Yang Dongqing , Atkins Gerald J.
Published: April 2023

1.

Few human osteocytein vitromodels exist and the differentiation of immature osteoblasts to an osteocyte stage typically takes at least 4-weeks of culture, making the study of this process challenging and time consuming. The osteosarcoma cell line Saos-2 has proved to be a useful model of human osteoblast differentiation through to a mature osteocyte-like stage. Culture under osteogenic conditions in a standard 5% CO2and normoxic (21% O2) atmosphere results in reproducible mineralisation and acquisition of mature osteocyte markers over the expected 28-35 day culture period. In order to expedite experimental assays, we tested whether reducing available oxygen to mimic concentrations experienced by osteocytesin vivowould increase the rate of differentiation of Saos-2 cells. Cells cultured in a 5% CO2, 1% O2atmosphere exhibited accelerated deposition of mineral, reaching near saturation by 14 days as demonstrated with the Alizarin Red and Von Kossa staining. The gene expression of the major hypoxia-induced transcription factorHIF1αand the key osteogenic transcription factorRUNX2were both elevated under 1% O2. Early (COLA1, MEPE) and mature (PHEX, DMP1andSOST) osteocyte markers were also upregulated earlier under hypoxic compared to normoxic growth conditions. Thus, culture under low oxygen accelerates key markers of osteocyte differentiation, resulting in a useful human osteocyte-likein vitrocell model within 14 days.
standR: a Bioconductor package for analysing transcriptomic Nanostring GeoMx DSP data
Authors: Liu Ning , Bhuva Dharmesh D. , Mohamed Ahmed , Bokelund Micah , Kulasinghe Arutha , Tan Chin Wee , Davis Melissa J
Published: April 2023

To gain a better understanding of the complexity of gene expression in normal and diseased tissues it is important to account for the spatial context and identity of cellin situ. State-of-the-art spatial profiling technologies, such as the Nanostring GeoMx Digital Spatial Profiler (DSP), now allow quantitative spatially resolved measurement of the transcriptome in tissues. However, the bioinformatics pipelines currently used to analyse GeoMx data often fail to successfully account for the technical variability within the data and the complexity of experimental designs, thus limiting the accuracy and reliability of subsequent analysis. Carefully designed quality control workflows, that include in-depth experiment-specific investigations into technical variation and appropriate adjustment for such variation can address this issue. Here we presentstandR, a R/Bioconductor package that enables an end-to-end analysis of GeoMx DSP data. With four case studies from previously published experiments, we demonstrate how the standR workflow can enhance the statistical power of GeoMx DSP data analysis and how application of standR enables scientists to develop in-depth insights into the biology of interest.
Reconnecting the Hand and Arm to the Brain: Efficacy of Neural Interfaces for Sensorimotor Restoration after Tetraplegia
Authors: Herring Eric Z. , Graczyk Emily L. , Memberg William D. , Adams Robert D. , Baca-Vaca Guadalupe Fernandez , Hutchison Brianna C. , Krall John T. , Alexander Benjamin J. , Conlan Emily C. , Alfaro Kenya E. , Bhat Preethi R. , Ketting-Olivier Aaron B. , Haddix Chase A. , Taylor Dawn M. , Tyler Dustin J. , Kirsch Robert F. , Ajiboye A. Bolu , Miller Jonathan P.
Published: April 2023

Background

Paralysis after spinal cord injury involves damage to pathways that connect neurons in the brain to peripheral nerves in the limbs. Re-establishing this communication using neural interfaces has the potential to bridge the gap and restore upper extremity function to people with high tetraplegia.

Objective

We report a novel approach for restoring upper extremity function using selective peripheral nerve stimulation controlled by intracortical microelectrode recordings from sensorimotor networks, along with restoration of tactile sensation of the hand using intracortical microstimulation.

Methods

A right-handed man with motor-complete C3-C4 tetraplegia was enrolled into the clinical trial. Six 64-channel intracortical microelectrode arrays were implanted into left hemisphere regions involved in upper extremity function, including primary motor and sensory cortices, inferior frontal gyrus, and anterior intraparietal area. Nine 16-channel extraneural peripheral nerve electrodes were implanted to allow targeted stimulation of right median, ulnar (2), radial, axillary, musculocutaneous, suprascapular, lateral pectoral, and long thoracic nerves, to produce selective muscle contractions on demand. Proof-of-concept studies were performed to demonstrate feasibility of a bidirectional brain-machine interface to restore function of the participant’s own arm and hand.

Results

Multi-unit neural activity that correlated with intended motor action was successfully recorded from intracortical arrays. Microstimulation of electrodes in somatosensory cortex produced repeatable sensory percepts of individual fingers for restoration of touch sensation. Selective electrical activation of peripheral nerves produced antigravity muscle contractions. The system was well tolerated with no operative complications.

Conclusion

The combination of implanted cortical electrodes and nerve cuff electrodes has the potential to allow restoration of motor and sensory functions of the arm and hand after neurological injury.
Strategies to support substance use disorder care transitions from acute-care to community-based settings: A Scoping review and typology
Authors: Krawczyk Noa , Rivera Bianca D. , Chang Ji E. , Grivel Margaux , Chen Yu-Heng , Nagappala Suhas , Englander Honora , McNeely Jennifer
Published: April 2023

Background

Acute-care interventions that identify patients with substance use disorders (SUDs), initiate treatment, and link patients to community-based services, have proliferated in recent years. Yet, much is unknown about the specific strategies being used to support continuity of care from emergency department (ED) or inpatient hospital settings to community-based SUD treatment. In this scoping review, we synthesize the existing literature on patient transition interventions, and form an initial typology of reported strategies.

Methods

We searched Pubmed, Embase, CINAHL and PsychINFO for peer-reviewed articles published between 2000-2021 that studied interventions linking SUD patients from ED or inpatient hospital settings to community-based SUD services. Eligible articles measured at least one post-discharge treatment outcome and included a description of the strategy used to promote linkage to community care. Detailed information was extracted on the components of the transition strategies and a thematic coding process was used to categorize strategies into a typology based on shared characteristics. Facilitators and barriers to transitions of care were synthesized using the Consolidated Framework for Implementation Research.

Results

Forty-five articles met inclusion criteria. 62% included ED interventions and 44% inpatient interventions. The majority focused on patients with opioid (71%) followed by alcohol (31%) use disorder. The transition strategies reported across studies were heterogeneous and often not well described. An initial typology of ten transition strategies, including five pre- and five post-discharge transition strategies is proposed. The most common strategy was scheduling an appointment with a community-based treatment provider prior to discharge. A range of facilitators and barriers were described, which can inform efforts to improve hospital-to-community transitions of care.

Conclusions

Strategies to support transitions from acute-care to community-based SUD services, although critical for ensuring continuity of care, vary greatly across interventions and are inconsistently measured and described. More research is needed to classify SUD care transition strategies, understand their components, and explore which lead to the best patient outcomes.
A Compressed Language Model Embedding Dataset of ICD 10 CM Descriptions
Authors: Kane Michael J. , King Casey , Esserman Denise , Latham Nancy K. , Greene Erich J. , Ganz David A.
Published: April 2023

This paper presents novel datasets providing numerical representations of ICD-10-CM codes by generating description embeddings using a large language model followed by a dimension reduction via autoencoder. The embeddings serve as informative input features for machine learning models by capturing relationships among categories and preserving inherent context information. The model generating the data was validated in two ways. First, the dimension reduction was validated using an autoencoder, and secondly, a supervised model was created to estimate the ICD-10-CM hierarchical categories. Results show that the dimension of the data can be reduced to as few as 10 dimensions while maintaining the ability to reproduce the original embeddings, with the fidelity decreasing as the reduced-dimension representation decreases. Multiple compression levels are provided, allowing users to choose as per their requirements. The readily available datasets of ICD-10-CM codes are anticipated to be highly valuable for researchers in biomedical informatics, enabling more advanced analyses in the field. This approach has the potential to significantly improve the utility of ICD-10-CM codes in the biomedical domain.
Variability in excess deaths across countries with different vulnerability during 2020-2023
Authors: Ioannidis John P.A. , Zonta Francesco , Levitt Michael
Published: April 2023

Excess deaths provide total impact estimates of major crises, such as the COVID-19 pandemic. We evaluated excess death’s trajectories during 2020-2023 across countries with accurate death registration and population age structure data; and assessed relationships with economic indicators of vulnerability. Using the Human Mortality Database on 34 countries, excess deaths were calculated for 2020-2023 (to week 29, 2023) using 2017-2019 as reference, with weekly expected death calculations and adjustment for 5 age strata. Countries were divided into less and more vulnerable; the latter had per capita nominal GDP<$30,000, Gini>0.35 for income inequality and/or at least 2.5% of their population living in poverty. Excess deaths (as proportion of expected deaths, p%) were inversely correlated with per capita GDP (r=-0.60), correlated with proportion living in poverty (r=0.66) and modestly correlated with income inequality (r=0.45). Incidence rate ratio for deaths was 1.06 (95% confidence interval, 1.04-1.08) in the more versus less vulnerable countries. Excess deaths started deviating in the two groups after the first wave. Between-country heterogeneity diminished over time within each of the two groups. Less vulnerable countries had mean p%=-0.8% and 0.4% in 0-64 and >65 year-old strata while more vulnerable countries had mean p%=7.0% and 7.2%, respectively. Usually lower death rates were seen in children 0-14 years old during 2020-2023 versus pre-pandemic years. While the pandemic hit some countries earlier than others, country vulnerability dominated eventually the cumulative impact. Half of the analyzed countries witnessed no substantial excess deaths versus pre-pandemic levels, while the other half suffered major death tolls.

Significance Statement

Excess deaths during 2020-2023 reflect the direct and indirect effects of the COVID-19 pandemic and of the measures taken. Data from 34 countries with detailed death registration and allowing to adjust for changes in the age structure of the population over time show two groups, each with very different excess death outcomes. The 17 more vulnerable countries (those with per capita nominal GDP<$30,000, Gini>0.35 for income inequality and/or at least 2.5% of their population living in poverty) had very high excess deaths compared with 2017-2019, while the other 17 less vulnerable countries had deaths during 2020-2023 that were comparable to 2017-2019. Continuous monitoring of excess deaths helps understand how country vulnerability shapes long-term impacts.
Associations of Adipokine Levels with Levels of Remnant Cholesterol: the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Quispe Renato , Sweeney Ty , Martin Seth S. , Jones Steven R. , Allison Matthew A. , Budoff Matthew J. , Ndumele Chiadi E. , Elshazly Mohamed B. , Michos Erin D.
Published: April 2023

Background

The metabolic syndrome phenotype of individuals with obesity is characterized by elevated levels of triglyceride (TG)-rich lipoproteins and remnant particles, which have been shown to be significantly atherogenic. Understanding the association between adipokines, endogenous hormones produced by adipose tissue, and remnant cholesterol (RC) would give insight into the link between obesity and atherosclerotic cardiovascular disease.

Methods

We studied 1,791 MESA participants of an ancillary study on body composition who had adipokine levels measured (leptin, adiponectin, resistin) at either visit 2 or 3. RC was calculated as non-high density lipoprotein cholesterol minus low-density lipoprotein cholesterol (LDL-C), measured at the same visit as the adipokines, as well as subsequent visits 4 through 6. Multivariable-adjusted linear mixed effects models were used to assess the cross-sectional and longitudinal associations between adipokines and levels of RC.

Results

Mean (SD) age was 64.5±9.6 years and for body mass index (BMI) was 29.9±5.0 kg/m2; 52.0% were women. In fully adjusted models that included BMI, LDL-C and lipid-lowering therapy, for each 1-unit increment in adiponectin, there was 14.4% (12.0, 16.8) lower RC. With each 1-unit increment in leptin and resistin, there was 4.5% (2.3, 6.6) and 5.1% (1.2, 9.2) higher RC, respectively. Lower adiponectin and higher leptin were also associated with longitudinal increases in RC levels over median follow-up of 5(4-8) years.

Conclusions

Lower adiponectin and higher leptin levels were independently associated with higher levels of RC at baseline and longitudinal RC increase, even after accounting for BMI and LDL-C.

CLINICAL PERSPECTIVE

What is new?

- Among individuals without history of cardiovascular disease, adiponectin is inversely associated with cross-sectional levels of remnant cholesterol, whereas leptin and resistin are directly associated.

- Adiponectin had an inverse association with progression of remnant cholesterol levels over time.

What are the clinical implications?

- Adiponectin levels were not associated with LDL-C levels but with levels of triglyceride-rich lipoproteins, particularly remnant cholesterol.

-Incrementing adiponectin via lifestyle modification and/or pharmacological therapies (i.e. GLP-1 agonists) could be a mechanism to reduce remnant cholesterol levels and ultimately cardiovascular risk.
Transcriptome Analysis Reveals Organ-Specific Effects of 2-Deoxyglucose Treatment in Healthy Mice
Authors: Wells Ann E. , Wilson John J. , Heuer Sarah E. , Sears John D. , Wei Jian , Pandey Raghav , Costa Mauro W. , Kaczorowski Catherine C. , Roopenian Derry C. , Chang Chih-Hao , Carter Gregory W.
Published: April 2023

Objective

Glycolytic inhibition via 2-deoxy-D-glucose (2DG) has potential therapeutic benefits for a range of diseases, including cancer, epilepsy, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and COVID-19, but the systemic effects of 2DG on gene function across different tissues are unclear.

Methods

This study analyzed the transcriptional profiles of nine tissues from C57BL/6J mice treated with 2DG to understand how it modulates pathways systemically. Principal component analysis (PCA), weighted gene co-network analysis (WGCNA), analysis of variance, and pathway analysis were all performed to identify modules altered by 2DG treatment.

Results

PCA revealed that samples clustered predominantly by tissue, suggesting that 2DG affects each tissue uniquely. Unsupervised clustering and WGCNA revealed six distinct tissue-specific modules significantly affected by 2DG, each with unique key pathways and genes. 2DG predominantly affected mitochondrial metabolism in the heart, while in the small intestine, it affected immunological pathways.

Conclusions

These findings suggest that 2DG has a systemic impact that varies across organs, potentially affecting multiple pathways and functions. The study provides insights into the potential therapeutic benefits of 2DG across different diseases and highlights the importance of understanding its systemic effects for future research and clinical applications.
Regulation of adaptive growth decisions via phosphorylation of the TRAPPII complex in Arabidopsis
Authors: Wiese Christian , Abele Miriam , Al Benjamin , Altmann Melina , Steiner Alexander , Kalbfuß Nils , Strohmayr Alexander , Ravikumar Raksha , Park Chan Ho , Brunschweiger Barbara , Meng Chen , Facher Eva , Ehrhardt David W. , Falter-Braun Pascal , Wang Zhi-Yong , Ludwig Christina , Assaad Farhah F.
Published: April 2023

Plants often adapt to adverse or stress conditions via differential growth. The trans-Golgi Network (TGN) has been implicated in stress responses, but it is not clear in what capacity it mediates adaptive growth decisions. In this study, we assess the role of the TGN in stress responses by exploring the interactome of the Transport Protein Particle II (TRAPPII) complex, required for TGN structure and function. We identified physical and genetic interactions between TRAPPII and shaggy-like kinases (GSK3/AtSKs). Kinase assays and pharmacological inhibition providedin vitroandin vivoevidence that AtSKs target the TRAPPII-specific subunit AtTRS120/TRAPPC9. GSK3/AtSK phosphorylation sites in AtTRS120/TRAPPC9 were mutated, and the resulting AtTRS120 phosphovariants subjected to a variety of single and multiple stress conditionsin planta. The non-phosphorylatable TRS120 mutant exhibited enhanced adaptation to multiple stress conditions and to osmotic stress whereas the phosphomimetic version was less resilient. Higher order inducibletrappii atskmutants had a synthetically enhanced defect in root gravitropism. Our results suggest that the TRAPPII phosphostatus mediates adaptive responses to abiotic cues. AtSKs are multifunctional kinases that integrate a broad range of signals. Similarly, the TRAPPII interactome is vast and considerably enriched in signaling components. An AtSK-TRAPPII interaction would integrate all levels of cellular organization and instruct the TGN, a central and highly discriminate cellular hub, as to how to mobilize and allocate resources to optimize growth and survival under limiting or adverse conditions.
Genomes from 25 historicalDrosophila melanogasterspecimens illuminate adaptive and demographic changes across more than 200 years of evolution
Authors: Shpak Max , Ghanavi Hamid R. , Lange Jeremy D. , Pool John E. , Stensmyr Marcus C.
Published: April 2023

The ability to perform genomic sequencing on long-dead organisms is opening new frontiers in evolutionary research. These opportunities are especially profound in the case of museum collections, from which countless documented specimens may now be suitable for genomic analysis. Here, we report 25 newly sequenced genomes from museum specimens of the model organismDrosophila melanogaster, including the oldest extant specimens of this species. By comparing historical samples ranging from the early 1800s to 1933 against modern day genomes, we document evolution across thousands of generations, including time periods that encompass the species’ initial occupation of northern Europe and an era of rapidly increasing human activity. At the genome-wide level, we find that historical flies from the same time and place show much greater evidence for relatedness than flies from modern collections, and some show evidence of inbreeding as well, potentially reflecting either much smaller local population sizes in the past or else the specific circumstances of the collections. We also find that the Lund, Sweden population underwent local genetic differentiation during the early 1800s to 1933 interval (potentially due to accelerated drift) but then became more similar to other European populations thereafter (potentially due to increased migration). Within each time period, our temporal sampling allows us to document compelling candidates for recent natural selection. In some cases, we gain insights regarding previously implicated selection candidates, such asChKov1, for which our inferred timing of selection favors the hypothesis of antiviral resistance over insecticide resistance. Other candidates are novel, such as the circadian-related geneAhcy, which yields a selection signal that rivals that of the DDT resistance geneCyp6g1. These insights deepen our understanding of recent evolution in a model system, and highlight the potential of future museomic studies.
Monoterpene glucosides accumulated inEustoma grandiflorumroots promote hyphal branching in arbuscular mycorrhizal fungi
Authors: Tominaga Takaya , Ueno Kotomi , Saito Hikaru , Egusa Mayumi , Yamaguchi Katsushi , Shigenobu Shuji , Kaminaka Hironori
Published: April 2023

Host plant-derived strigolactones trigger hyphal branching in arbuscular mycorrhizal (AM) fungi, initiating a symbiotic interaction between land plants and AM fungi. However, our previous studies revealed that gibberellin-treatedEustoma grandiflorum(Gentianaceae) activates rhizospheric hyphal branching in AM fungi using unidentified molecules other than strigolactones. In this study, we analyzed independent transcriptomic data ofE. grandiflorumand found that the gentiopicroside (GPS) and swertiamarin (SWM), which are characteristic monoterpene glucosides in Gentianaceae, were highly biosynthesized in gibberellin-treatedE. grandiflorumroots. Moreover, these metabolites considerably promoted hyphal branching in the Glomeraceae AM fungiRhizophagus irregularisandR. clarus. GPS treatment also enhancedR. irregulariscolonization of the monocotyledonous cropAllium schoenoprasum. Interestingly, these metabolites did not provoke the germination of the root parasitic plantOrobanche minor. Altogether, our study unveiled the crucial role of GPS and SWM in activating the symbiotic relationship between AM fungi andE. grandiflorum.