bluuebunny/crossref_metadata_2025 huggingface dataset:
An alternative strategy to increasing influenza virus replication for vaccine production in chicken embryo fibroblast (DF-1) cells by inhibiting interferon alpha and beta using peptide-conjugated phosphorodiamidate morpholino oligomers
Authors: Prescott Meagan A. , Moulton Hong , Pastey Manoj K.
Published: February 2024

Introduction. Influenza is a global health issue causing substantial health and economic burdens on affected populations. Routine, annual vaccination for influenza virus is recommended for all persons older than 6 months of age. The propagation of the influenza virus for vaccine production is predominantly through embryonated chicken eggs.

Hypothesis/Gap Statement. Many challenges face the propagation of the virus, including but not limited to low yields and lengthy production times. The development of a method to increase vaccine production in eggs or cell lines by suppressing cellular gene expression would be helpful to overcome some of the challenges facing influenza vaccine production.

Aims. This study aimed to increase influenza virus titres by using a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO), an antisense molecule, to suppress protein expression of the host genes interferon alpha (IFN-α) and interferon beta (IFN-β) in chicken embryo fibroblast (DF-1) cells.

Methods. The toxicity of PPMOs was evaluated by cytotoxicity assays, and their specificity to inhibit IFN-α and IFN-β proteins was measured by ELISA. We evaluated the potential of anti-IFN-α and anti-IFN-β PPMOs to reduce the antiviral proteins in influenza virus-infected DF-1 cells and compared the virus titres to untreated controls, nonsense-PPMO and JAK/STAT inhibitors. The effects of complementation and reconstitution of IFN-α and IFN-β proteins in PPMO-treated-infected cells were evaluated, and the virus titres were compared between treatment groups.

Results. Suppression of IFN-α by PPMO resulted in significantly reduced levels of IFN-α protein in treated wells, as measured by ELISA and was shown to not have any cytotoxicity to DF-1 cells at the effective concentrations tested. Treatment of the self-directing PPMOs increased the ability of the influenza virus to replicate in DF-1 cells. Over a 2-log10 increase in viral production was observed in anti-IFN-α and IFN-β PPMO-treated wells compared to those of untreated controls at the initial viral input of 0.1 multiplicity of infection. The data from complementation and reconstitution of IFN-α and IFN-β proteins in PPMO-treated-infected cells was about 82 and 97% compared to the combined PPMO-treated but uncomplemented group and untreated group, respectively. There was a 0.5-log10 increase in virus titre when treated with anti-IFN-α and IFN-β PPMO compared to virus titre when treated with JAK/STAT inhibitors.

Conclusions. This study emphasizes the utility of PPMO in allowing cell cultures to produce increased levels of influenza for vaccine production or alternatively, as a screening tool to cheaply test targets prior to the development of permanent knockouts of host gene expression.
Statistical analysis for the development of a Deep Learning model for classification of images with TDP-43 pathology
Authors: Muñoz Azucena , Oliveira Vasco , Vallejo Marta
Published: February 2024

Diagnosing Amyotrophic Lateral Sclerosis (ALS) remains a hand challenge due to its inherent heterogeneity. Notably, the occurrence of TDP-43 cytoplasmic aggregation in approximately 95% of ALS cases has emerged as a potential indicative hallmark. In order to develop deep learning models capable of distinguishing TDP-43 proteinopathic samples from their healthy counterparts, a comprehensive understanding of the sample set becomes imperative, particularly when the sample size is limited. The samples in question encompassed images obtained via an immunofluorescence procedure, employing super high-resolution microscopy coupled with meticulous processing. A feature-extracted dataset was created to collect meaningful features from every sample to approach three different classification problems (TDP-43 Pathology, TDP-43 Pathology Grades and ALS) based on the number of red and pink pixels, signifying cytoplasmic and nuclear TDP-43 presence. A series of diverse statistical approaches were undertaken. However, definitive outcomes remained elusive, although it was suggested that a classification based on the presence of TDP-43 proteinopathy was better than the one based on the presence of ALS for training the model.

The dataset was reduced by eliminating the problematic samples through curation. Analyses were repeated using t-student tests and ANOVA, and visualisation of patient inter-variability was performed using hierarchical clustering. The TDP-43 pathology classification results showed significant differences in the number of red and pink pixels, the total amount of protein and the cytoplasmic and nuclear proportions between healthy and pathological samples between groups. These findings suggested that images classified according to the presence of TDP-43 proteinopathy are more suitable for training deep learning models.
Multi-omics Characterization of Epigenetic and Genetic Risk of Alzheimer Disease in Autopsied Brains from two Ethnic Groups
Authors: Ma Yiyi , Reyes-Dumeyer Dolly , Piriz Angel , Recio Patricia , Mejia Diones Rivera , Medrano Martin , Lantigua Rafael A. , Vonsattel Jean Paul G. , Tosto Giuseppe , Teich Andrew F. , Ciener Benjamin , Leskinen Sandra , Sivakumar Sharanya , DeTure Michael , Ranjan Duara , Dickson Dennis , Murray Melissa , Lee Edward , Wolk David A. , Jin Lee-Way , Dugger Brittany N. , Hiniker Annie , Rissman Robert A. , Mayeux Richard , Vardarajan Badri N.
Published: February 2024

Background

Both genetic variants and epigenetic features contribute to the risk of Alzheimer’s disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as the hub of both the genetic and epigenetic effects, in Hispanics decedents and generalized the findings to Non-Hispanic Whites (NHW) decedents.

Methods

First, we derived the dosage of the CpG site-creating allele of multiple CGSes in each 1 KB window across the genome and we conducted a sliding window association test with clinical diagnosis of AD in 7,155 Hispanics (3,194 cases and 3,961 controls) using generalized linear mixed models with the adjustment of age, sex, population structure, genomic relationship matrix, and genotyping batches. Next, using methylation and bulk RNA-sequencing data from the dorsolateral pre-frontal cortex in 150 Hispanics brains, we tested the cis- and trans-effects of AD associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we checked their enriched pathways.

Results

We identified six genetic loci in Hispanics with CGS dosage associated with AD at genome-wide significance levels:ADAM20(Score=55.2,P=4.06×10-8), betweenVRTN(Score=-19.6,P=1.47×10-8) andSYNDIG1L(Score=-37.7,P=2.25×10-9),SPG7(16q24.3) (Score=40.5,P=2.23×10-8),PVRL2(Score=125.86,P=1.64×10-9),TOMM40(Score=-18.58,P=4.61×10-8), andAPOE(Score=75.12,P=7.26×10-26). CGSes inPVRL2andAPOEwere also genome-wide significant in NHW. Except forADAM20, CGSes in all the other five loci were associated with Hispanic brain methylation levels (mQTLs) and CGSes inSPG7, PVRL2,andAPOEwere also mQTLs in NHW. Except forSYNDIG1L(P=0.08), brain methylation levels in all the other five loci affected downstream RNA expression in the Hispanics (P<0.05), and methylation atVRTNandTOMM40were also associated with RNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and synapse (FDR<0.05).

Conclusions

We identified six CpG associated genetic loci associated with AD in Hispanics, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW.
The transformation of sensory to perceptual braille letter representations in the visually deprived brain
Authors: Haupt Marleen , Graumann Monika , Teng Santani , Kaltenbach Carina , Cichy Radoslaw M.
Published: February 2024

1.

Experience-based plasticity of the human cortex mediates the influence of individual experience on cognition and behavior. The complete loss of a sensory modality is among the most extreme such experiences. Investigating such a selective, yet extreme change in experience allows for the characterization of experience-based plasticity at its boundaries.

Here, we investigated information processing in individuals who lost vision at birth or early in life by probing the processing of braille letter information. We characterized the transformation of braille letter information from sensory representations depending on the reading hand to perceptual representations that are independent of the reading hand.

Using a multivariate analysis framework in combination with fMRI, EEG and behavioral assessment, we tracked cortical braille representations in space and time, and probed their behavioral relevance.

We located sensory representations in tactile processing areas and perceptual representations in sighted reading areas, with the lateral occipital complex as a connecting “hinge” region. This elucidates the plasticity of the visually deprived brain in terms of information processing.

Regarding information processing in time, we found that sensory representations emerge before perceptual representations. This indicates that even extreme cases of brain plasticity adhere to a common temporal scheme in the progression from sensory to perceptual transformations.

Ascertaining behavioral relevance through perceived similarity ratings, we found that perceptual representations in sighted reading areas, but not sensory representations in tactile processing areas are suitably formatted to guide behavior.

Together, our results reveal a nuanced picture of both the potentials and limits of experience-dependent plasticity in the visually deprived brain.
Same Sentences, Different Grammars, Different Brain Responses: An MEG study on Case and Agreement Encoding in Hindi and Nepali Split-Ergative Structures
Authors: Chacón Dustin A. , Shrestha Subhekshya , Dillon Brian W. , Bhatt Rajesh , Almeida Diogo , Marantz Alec
Published: February 2024

At first glance, the brain’s language network appears to be universal, but languages clearly differ. How does the brain adapt to the specific details of individual grammatical systems? Here, we present an MEG study on case and agreement in Hindi and Nepali. Both languages use split-ergative case systems. However, these systems interact with verb agreement differently – in Hindi, case features conspire to determine which noun phrase (NP) the verb agrees with (subject, object, or neither), but in Nepali the verb always agrees with the subject NP. We found that left inferior frontal and left anterior temporal regions are sensitive to case features in both languages. Across case configurations, these same brain areas in Hindi participants show different patterns of activity for sentences that require masculine vs. feminine marking on the verb, before the comprehenders encounter it. Additionally, the left temporoparietal junction in Hindi shows different activity for subject and object agreement configurations. Both findings are not observed in Nepali participants. We suggest that this brain response demonstrates a unique-to-Hindi selection of an agreement controller and pre-encoding of the verb’s morphological features. This shows that brain activity reflects psycholinguistic processes that are intimately tied to grammatical features.

Highlights

The left inferior frontal lobe and the left anterior temporal lobe distinguish accusative objects versus bare object NPs in Hindi and Nepali, and pre-emptively encode gender agreement features in Hindi.

The left inferior parietal lobe shows a differential sensitivity to object-agreement and subject-agreement constructions in Hindi that is absent in Nepali

MEG can reveal differences in neural activity that reflect specific requirements of different grammatical systems
Supralinear dendritic integration in murine dendrite-targeting interneurons
Authors: Griesius Simonas , Richardson Amy , Kullmann Dimitri M
Published: February 2024

Non-linear summation of synaptic inputs to the dendrites of pyramidal neurons has been proposed to increase the computation capacity of neurons through coincidence detection, signal amplification, and additional logic operations such as XOR. Supralinear dendritic integration has been documented extensively in principal neurons, mediated by several voltage-dependent conductances. It has also been reported in parvalbumin-positive hippocampal basket cells, in dendrites innervated by feedback excitatory synapses. Whether other interneurons, which support feed-forward or feedback inhibition of principal neuron dendrites, also exhibit local non-linear integration of synaptic excitation is not known. Here we use patch-clamp electrophysiology, and 2-photon calcium imaging and glutamate uncaging, to show that supralinear dendritic integration of near-synchronous spatially clustered glutamate-receptor mediated depolarization occurs in NDNF-positive neurogliaform cells and oriens-lacunosum moleculare interneurons in the mouse hippocampus. Supralinear summation was detected via recordings of somatic depolarizations elicited by uncaging of glutamate on dendritic fragments, and, in neurogliaform cells, by concurrent imaging of dendritic calcium transients. Supralinearity was abolished by blocking NMDA receptors (NMDARs) but resisted blockade of voltage-gated sodium channels. Blocking L-type calcium channels abolished supralinear calcium signalling but only had a minor effect on voltage supralinearity. Dendritic boosting of spatially clustered synaptic signals argues for previously unappreciated computational complexity in dendrite-projecting inhibitory cells of the hippocampus.
Proteostasis as a fundamental principle of Tau immunotherapy
Authors: Cruz Esteban , Nisbet Rebecca M. , Padmanabhan Pranesh , van Waardenberg Ashley J. , Graham Mark E. , Nkajja Godfrey , Tapaswi Swara , Robinson Phil , Götz Jürgen
Published: February 2024

The microtubule-associated protein Tau is a driver of neuronal dysfunction in Alzheimer’s disease and numerous other tauopathies. In this process, Tau initially undergoes subtle changes to its abundance, subcellular localisation and a vast array of post-translational modifications including phosphorylation, that progressively result in the protein’s aggregation and dysregulation of multiple Tau-dependent cellular processes.

Given the various loss- and gain-of-functions of Tau in disease and the brain-wide changes in the proteome that characterise tauopathies, we asked whether targeting Tau would restore the alterations in proteostasis observed in disease.

To this end, we generated a novel pan-Tau antibody, RNJ1, that preferentially binds human Tau and neutralises proteopathic seeding activity in multiple cell lines and benchmarked it against a clinically tested pan-Tau antibody, HJ8.5 (murine version of tilavonemab). We next evaluated both antibodies, alone and in combination, in the K3 mouse model of tauopathy, showing reduced Tau pathology and improvements in neuronal function following 14 weekly treatments, without obtaining synergistic effects for the combination treatment.

To gain insight into molecular mechanisms contributing to improvements in neuronal function, we employed quantitative proteomics and phosphoproteomics to first establish alterations in K3 mice relative to WT controls at the proteome level. This revealed 342 proteins with differential abundance in K3 mice, which are predominantly involved in metabolic and microtubule-associated processes, strengthening previously reported findings of defects in several functional domains in multiple tauopathy models. We next asked whether antibody-mediated Tau target engagement indirectly affects levels of deregulated proteins in the K3 model. Importantly, both immunotherapies, in particular RNJ1, induced abundance shifts in this protein subset towards a restoration to wild-type levels (proteostasis). A total of 257 of 342 (∼75.1%) proteins altered in K3 were closer in abundance to WT levels after RNJ1 treatment. The same analysis indicated a similar response in K3 mice treated with HJ8.5, with approximately 72.5% of these altered proteins also showing changes in the same direction as wild-type. Furthermore, analysis of the phosphoproteome showed an even stronger restoration effect with RNJ1, with ∼82.1% of altered phosphopeptides in K3 showing a shift to WT levels, and 75.4% with HJ8.5. Gene set over-representation analysis (ORA) further confirmed that proteins undergoing restoration are involved in biological pathways affected in K3 mice. Together, our study suggests that a Tau immunotherapy-induced restoration of proteostasis links target engagement and treatment efficacy.
Unveiling Tryptophan Dynamics and Functions Across Model Organisms via Quantitative Imaging
Authors: Wang Kui , Chen Tian-lun , Zhang Xin-xin , Cao Jian-bin , Wang Pengcheng , Wang Mingcang , Du Jiu-lin , Mu Yu , Tao Rongkun
Published: February 2024

Tryptophan is an essential amino acid involved in many cellular processes in vertebrates. Systemic and quantitative measurement of tryptophan is crucial for evaluating its essential role as a precursor of serotonin and kynurenine, key neuromodulators affecting neural and immune functions. We utilized a robust and highly responsive ratiometric indicator for tryptophan (GRIT) to quantitatively measure tryptophan dynamics in bacteria, mitochondria of mammalian cell cultures, and human serum. At the cellular scale, these analyses uncovered differences in tryptophan dynamics across cell types and organelles. At the whole-organism scale, we revealed that inflammation-induced tryptophan concentration increases in zebrafish brain led to elevated tryptophan metabolites serotonin and kynurenine levels, which is associated with the prolonged sleep duration. The reduction of zebrafish plasma tryptophan was mirrored in patients with inflammation symptoms and could serve as a biochemical marker of inflammation. In summary, this study introduces GRIT as a powerful method for studying tryptophan metabolism and functions across scales and species and suggests that tryptophan metabolic processes link the immune response and animal behavior.
Ageing Biomarkers Derived From Retinal Imaging: A Scoping Review
Authors: Grimbly Michaela , Koopowitz Sheri-Michelle , Chen Alice Ruiye , Sun Zihan , Foster Paul , He Mingguang , Stein Dan J. , Ipser Jonathan , Zhu Lisa Zhuoting
Published: February 2024

Background/Aims

The emerging concept of retinal age, a biomarker derived from retinal images, holds promise in estimating biological age. The retinal age gap (RAG) represents the difference between retinal age and chronological age which serves as an indicator of deviations from normal ageing. This scoping review aims to collate studies on retinal age to determine its potential clinical utility and to identify knowledge gaps for future research.

Methods

Using the PRISMA checklist, eligible non-review, human studies were identified, selected, and appraised. Pubmed, Scopus, SciELO, PsycINFO, Google Scholar, Cochrane, CINAHL, Africa Wide EBSCO, MedRxiv, and BioRxiv databases were searched to identify literature pertaining to retinal age, the RAG, and their associations. No restrictions were imposed on publication date.

Results

Thirteen articles published between 2022 and 2023 were analysed, revealing four models capable of determining biological age from retinal images. Three models, ‘Retinal Age’, ‘EyeAge’ and a ‘convolutional network-based model,’ achieved comparable mean absolute errors (MAE): 3.55, 3.30 and 3.97 respectively. A fourth model, ‘RetiAGE’, predicting the probability of being older than 65 years, also demonstrated strong predictive ability with respect to clinical outcomes. In the models identified, a higher predicted RAG demonstrated an association with negative occurrences, notably mortality and cardiovascular health outcomes.

Conclusion

This review highlights the potential clinical application of retinal age and RAG, emphasising the need for further research to establish their generalisability for clinical use, particularly in neuropsychiatry. The identified models showcase promising accuracy in estimating biological age, suggesting its viability for evaluating health status.

Key Message

What is already known on this topic

Retinal age has emerged as a promising ageing biomarker capable of determining biological age from retinal images.

What this study adds

This study presents a comprehensive scoping review of current literature concerning retinal age and the RAG, highlighting the reproducible association between advanced retinal age gap and increased mortality and cardiovascular disease risk.

How this study might affect research, practice, or policy

The findings underscore the paucity of knowledge on this topic, advocating for further research in this area to determine the potential clinical use of retinal age as a biomarker.

Synopsis

This scoping review explores retinal age, a biological ageing marker derived from retinal images. Findings from 13 articles reveal links between advanced retinal ageing gaps and adverse outcomes, emphasizing its potential for improving health outcomes.
Trends and spatial distribution of pneumonia admissions and deaths among children <5 years, Uganda, 2013–2021
Authors: Wanyana Mercy Wendy , Migisha Richard , King Patrick , Bulage Lilian , Kwesiga Benon , Kadobera Daniel , Ario Alex Riolexus , Harris Julie R.
Published: February 2024

Background

Pneumonia is the second leading cause of hospital admissions and deaths among children <5 years old in Uganda. In 2013, Uganda adopted various interventions to protect, prevent, and improve the treatment of pneumonia under the Global Action Plan for Prevention and Control of Pneumonia and Diarrhoea (GAPPD), including the introduction of the pneumococcal conjugate vaccine (PCV) into routine immunization schedule. However, little is known about the impact of these interventions on pneumonia admissions and deaths. We described the trends and spatial distribution of pneumonia hospital admissions and mortality among children <5 years in Uganda, 2013–2021.

Methods

We analysed secondary data on pneumonia admissions and deaths from the District Health Information System version 2 during 2013–2021. Reporting rates were calculated as the percentage of expected complete monthly health facility reports submitted to the national surveillance database. The proportion of pneumonia cases admitted and case-fatality rates (CFRs) for children <5 years were calculated for children <5 years presenting at the outpatient department. At national, regional, and district levels, pneumonia mortality rates were calculated per 100,000 children <5 years. The Mann-Kendall Test was used to assess trend significance.

Results

There were 753,978 pneumonia admissions and 13,632 (2%) deaths during 2013–2021. Reporting rates ranged from 78–92%. The overall proportion of pneumonia cases admitted among children <5 years was 23%. The overall CFR was 0.41%, and the overall pneumonia mortality rate among children <5 years was 21 deaths per 100,000. From 2013 to 2021, there were declines in the proportion of pneumonia cases admitted (33% to 15%; p=0.051), mortality rates (26/100,000 to 13 per 100,000; p=0.01), and CFR (0.61% to 0.24%; p=0.01), concomitant with increasing PCV coverage. Kotido District had a persistently high proportion of pneumonia cases that were admitted (>30%) every year while Kasese District had persistently high mortality rates (68-150 deaths per 100,000 children <5 years).

Conclusion

Pneumonia admissions, mortality, and case fatality among children <5 years declined during 2013–2021 in Uganda after the introduction of PCV. However, with these trends it is unlikely that Uganda will meet the 2025 GAPPD targets. There is therefore a need to review implementation of existing interventions, identify gaps in order to highlight priority actions to further accelerate declines.
Prevalence of Mendelian kidney disease among patients with high-riskAPOL1genotypes undergoing commercial genetic testing in the United States
Authors: Francisco Ronaldo da Silva , Punj Sumit , Vincent Lisa , Sanapareddy Nina , Bhalla Vivek , Chertow Glenn M. , Keen-Kim Dianne , Charu Vivek
Published: February 2024

Background

Among individuals with high-riskAPOL1genotypes, the lifetime risk of developing kidney failure is ∼15%, indicating that other genetic variants or non-genetic modifiers likely contribute substantially to an individual patient’s risk of progressive kidney disease. Here we estimate the prevalence and distribution of molecularly diagnosed Mendelian kidney diseases among patients with high-riskAPOL1genotypes undergoing commercial genetic testing in the United States.

Methods

We analyzed clinical exome sequencing data from 15,181 individuals undergoing commercial genetic testing for Mendelian kidney disease in the United States from 2020-2021. We identified patients with high-riskAPOL1genotypes by the presence of G1/G1, G1/G2, or G2/G2 alleles. Patients carrying single riskAPOL1alleles were identified as G1/G0, G2/G0; the remainder of patients were G0/G0. We estimated the prevalence and distribution of molecularly diagnosed Mendelian kidney disease stratified byAPOL1genotype.

Results

Of 15,181 patients, 3119 had genetic testing results consistent with a molecular diagnosis of Mendelian kidney disease (20.5%). 1035 (6.8%) had high-riskAPOL1genotypes. The prevalence of molecularly diagnosed Mendelian kidney diseases was lower in individuals with high-riskAPOL1genotypes (9.2%; n=95/1035) compared to single riskAPOL1allele carriers (14.4%; n=243/1687) and those with G0/G0APOL1genotypes (22.3%; n=2781/12459). The distribution of molecularly diagnosed Mendelian kidney diseases was broadly similar among patients with and without high-riskAPOL1genotypes.

Conclusions

Among patients undergoing clinical genetic testing, we found a relatively high rate of molecularly diagnosed Mendelian kidney disease in patients with high-riskAPOL1genotypes. Mendelian kidney disease may contribute to wide variation in rates of progression observed among patients with high-riskAPOL1genotypes.
Investigating the relationship of serum vitamin D levels with blood pressure and hypertension risk in The HUNT Study: Using traditional observational and Mendelian randomization approaches
Authors: Jiang Lin , Sun Yi-Qian , Denos Marion , Brumpton Ben Michael , Chen Yue , Malmo Vegard , Sanderson Eleanor , Mai Xiao-Mei
Published: February 2024

Background

Limited studies have triangulated the relationship between serum vitamin D [25(OH)D] levels and systolic blood pressure (SBP), diastolic blood pressure (DBP) or hypertension risk using traditional observational and Mendelian randomization (MR) approaches.

Methods and results

Data were obtained from the Norwegian Trøndelag Health Study (HUNT). A cross-sectional study was performed among 5854 participants from HUNT2. Among them, 3592 participants were followed over 11 years for a prospective analysis. Furthermore, a one-sample MR was conducted with 86,324 participants from HUNT. An externally weighted genetic risk score based on 19 genetic variants for 25(OH)D was used as instrument and the Wald ratio method was applied to evaluate causal associations. Additionally, two-sample MR were performed using updated publicly available data. Our cross-sectional analyses showed a 25 nmol/L increase in 25(OH)D was associated with a 1.73 mmHg decrease in SBP (95 % CI -2.46 to -1.01), a 0.91 mmHg decrease in DBP (95% CI - 1.35 to -0.47) and 19% lower prevalence of hypertension (OR 0.81, 95% CI 0.74 to 0.90) after adjusting for important confounders. However, these associations disappeared in prospective analyses. Both one-sample and two-sample MR results suggested no causal associations.

Conclusions

Cross-sectional findings of inverse associations between serum 25(OH)D levels and blood pressure or hypertension were not supported by results from the prospective and MR analyses, suggesting no causal links.

Clinical Perspective What Is New?

We triangulated the potential relationships of serum 25(OH)D with blood pressure and hypertension using several observational methods such as cross-sectional, prospective cohort, one-sample and two-sample Mendelian randomization (MR) approaches.

What Are the Clinical Implications?

The consistency across the prospective, one-sample MR and two-sample MR analyses enhanced the robustness of the findings of no causal association between vitamin D and blood pressure or hypertension.

Clinicians should be cautious when recommending vitamin D supplementation to the general population for the prevention of cardiovascular diseases.
Association of Mobile Stroke Unit Care and Spending, Utilization, and Mortality in New York City
Authors: Khullar Dhruv , Navi Babak B. , Mir Saad , Fink Matthew E. , Tinapay Luisa , Asaeda Glenn , Kaushal Rainu , Pareek Eshani , Bond Amelia M.
Published: February 2024

Background

Transport by mobile stroke units (MSUs), which provide access to computed tomography scanning and intravenous blood pressure medications and thrombolytics, reduces time to treatment and may improve short-term functional outcomes for patients with acute stroke. The longer-term clinical and financial impacts remain incompletely understood.

Objective

Determine whether MSU care is associated with better health, utilization, and spending outcomes for patients with suspected acute stroke.

Design

Retrospective, observational study of Medicare patients transported by MSUs versus traditional ambulances in New York City, from October 2016 to December 2019.

Eligibility

167 Medicare patients with suspected acute stroke transported by MSU and 2,518 propensity-score matched controls.

Main Outcomes

Primary outcomes included length of stay and discharge destination at index hospitalization, as well as risk of repeat hospitalization, number of emergency department visits, total costs of care, and mortality at 1 year.

Results

Of 167 patients (mean age, 79.9 years;56.3% women) transported by a MSU for suspected acute stroke, 61.1% had an ischemic stroke/TIA, 7.8% had an intracerebral hemorrhage, and 31.1% had a stroke mimic or other diagnosis. Compared to propensity-score matched control patients, MSU patients experienced similar lengths of stay (5.9 vs 6.7 days,p=0.13) and were similarly likely to be discharged to a skilled nursing facility (15.6% vs 15.1%,p=0.86). They had clinically but marginally significant lower rates of mortality at 1 year (21.6% vs 28.4%; difference, 6.8 percentage points [95% CI -13.3 to 0.3,p=0.058). They had similar rates of any repeat hospitalization (24% vs 23.2%,p=0.82) and ED visits without hospitalization (14% vs 12%,p=0.86), and there were no significant differences in total spending or specific types of spending.

Conclusions

In this study of patients presenting with suspected acute stroke in New York City, transport by MSUs, compared with traditional ambulances, was associated with a trend toward lower mortality at 1 year. Prospective trials and replication in other regions are warranted.
Investigating 3D microbial community dynamics in the rhizosphere using complex-field and fluorescence microscopy
Authors: Zhang Oumeng , Alcalde Reinaldo E. , Zhou Haowen , Yin Siyuan , Newman Dianne K. , Yang Changhuei
Published: February 2024

Microbial interactions in the rhizosphere contribute to soil health. Understanding these interactions thus has the potential to advance sustainable agriculture, ecosystem management, and environmental stewardship. Yet it is difficult to understand what we cannot see; amongst the limitations in rhizosphere imaging are challenges associated with rapidly and non-invasively imaging microbial cells over field depths relevant to plant roots. Here, we present a novel bimodal imaging technique called Complex-field and Fluorescence microscopy using the Aperture Scanning Technique (CFAST) that begins to address these limitations by integrating quantitative phase and 3D fluorescence imaging. We showcase CFAST’s practicality and versatility in two ways. First, by harnessing its depth of field of more than 100 microns, we significantly reduce the number of captures required for 3D imaging of plant roots and bacteria in the rhizoplane, thereby minimizing potential photobleaching and phototoxicity. Second, by leveraging CFAST’s phase sensitivity and fluorescence specificity, we track early bacterial aggregate development, bacterial competition, and gene expression under varying environmental conditions. Specifically, we resolve bacterial growth dynamics of mixed populations at the early stages of colonization without the need for genetically labeling environmental isolates. Moreover, we find that the expression of genes of interest to rhizosphere chemistry (e.g. representative genes involved in phosphorus-sensing and antibiotic production) varies spatiotemporally within microbial populations that are surface-attached and appears distinct from their expression in planktonic cultures. Together, CFAST’s attributes overcome commercial imaging platform limitations and enable new insights to be gained into microbial behavioral dynamics in experimental systems of relevance to the rhizosphere.
Task-guided Generative Adversarial Networks for Synthesizing and Augmenting Structural Connectivity Matrices for Connectivity-Based Prediction
Authors: Yamamoto Tatsuya , Sugiura Tomoki , Hiroyasu Tomoyuki , Hiwa Satoru
Published: February 2024

Recent machine learning techniques have improved connectome-based predictions by modelling complex dependencies between brain connectivity and cognitive traits. However, they typically require large datasets that are costly and time-consuming to collect. To address this, we propose Task-guided GAN II, a novel data augmentation method that uses generative adversarial networks (GANs) to expand sample sizes in connectome-based prediction tasks. Our method incorporates a task-guided branch within the Wasserstein GAN framework, specifically designed to synthesize structural connectivity matrices and improve prediction accuracy by capturing task-relevant features. We evaluated Task-guided GAN II on the prediction of fluid intelligence using the NIMH Health Research Volunteer Dataset. Results showed that data augmentation improved prediction accuracy. To further assess whether augmentation can substitute for increasing real-world sample sizes, we conducted additional validation using the HCP WU-Minn S1200 dataset. Task-guided GAN II improved prediction performance with limited real data, with gains of up to twofold augmentation observed. However, excessive augmentation did not result in further improvements, suggesting that augmentation complements, but does not fully replace, real data augmentation. These results suggest that Task-guided GAN II is a promising tool for harnessing small datasets in human connectomics research, improving predictive modelling where large-scale data collection is impractical.
A new paradigm considering multicellular adhesion, repulsion and attraction represents diverse cellular tile patterns
Authors: Carrillo Jose A. , Murakawa Hideki , Sato Makoto , Wang Miaoxing
Published: February 2024

Cell sorting by differential adhesion is one of the basic mechanisms explaining spatial organization of neurons in early stage brain development of fruit flies. The columnar arrangements of neurons determine the large scale patterns in the fly visual center. Experimental studies indicate that hexagonal configurations regularly appear while tetragonal configurations can be induced in mutants. Mathematical models based on macroscopic approximations of agent based models (ARA models) are shown to produce a similar behavior changing from hexagonal to tetragonal steady configurations when medium range repulsion and longer-range attraction between individuals is incorporated in previous successful models for cell sorting based on adhesion and volume constraints. We analyse the angular configurations of these patterns based on angle summary statistics and compare between experimental data and parameter fitted ARA models showing that intermediate patterns between hexagonal and tetragonal configuration are common in experimental data as well as in our ARA mathematical model. Our studies indicate an overall qualitative agreement of ARA models in tile patterning and pave the way for their quantitative studies.

2010 MSC

92C17, 92C37, 35Q92
The Lab Streaming Layer for Synchronized Multimodal Recording
Authors: Kothe Christian , Shirazi Seyed Yahya , Stenner Tristan , Medine David , Boulay Chadwick , Grivich Matthew I. , Mullen Tim , Delorme Arnaud , Makeig Scott
Published: February 2024

Accurately recording the interactions of humans or other organisms with their environment or other agents requires synchronized data access via multiple instruments, often running independently using different clocks. Active, hardware-mediated solutions are often infeasible or prohibitively costly to build and run across arbitrary collections of input systems. The Lab Streaming Layer (LSL) offers a software-based approach to synchronizing data streams based on per-sample time stamps and time synchronization across a common LAN. Built from the ground up for neurophysiological applications and designed for reliability, LSL offers zero-configuration functionality and accounts for network delays and jitters, making connection recovery, offset correction, and jitter compensation possible. These features ensure precise, continuous data recording, even in the face of interruptions. The LSL ecosystem has grown to support over 150 data acquisition device classes as of Feb 2024, and establishes interoperability with and among client software written in several programming languages, including C/C++, Python, MATLAB, Java, C#, JavaScript, Rust, and Julia. The resilience and versatility of LSL have made it a major data synchronization platform for multimodal human neurobehavioral recording and it is now supported by a wide range of software packages, including major stimulus presentation tools, real-time analysis packages, and brain-computer interfaces. Outside of basic science, research, and development, LSL has been used as a resilient and transparent backend in scenarios ranging from art installations to stage performances, interactive experiences, and commercial deployments. In neurobehavioral studies and other neuroscience applications, LSL facilitates the complex task of capturing organismal dynamics and environmental changes using multiple data streams at a common timebase while capturing time details for every data frame.
Developmental emergence of quiescent-like neural progenitor cells in the zebrafish embryonic brain
Authors: Liu Yuanyuan , Lembke Carla-Sophie , Paridaen Judith TML
Published: February 2024

The mature brain is made up of differentiated neurons and glial cells that are produced by embryonic neural stem and progenitor cells (collectively called neural stem cells (NSCs)) during brain development. In contrast, adult NSCs generate only a limited number of neuronal and glial cell types. Moreover, in contrast to embryonic NSCs, adult NSCs spend most of their time in a non-dividing resting phase called quiescence. In the adult brain, the quiescent NSCs are activated at a low frequency to divide and produce new cells to replace lost or damaged mature cells.

Previous studies have demonstrated that about halfway through mammalian brain development, a subset of the embryonic NSCs population slows down their division rate and slowly transition into adult quiescent NSCs (qNSCs). However, the molecular mechanisms that underlie the emergence of the pre-adult SCs remain largely unknown.

Here, we explored single-cell transcriptomes from several embryonic stages of zebrafish development in order to determine at what developmental stage transcriptional signatures typical of adult quiescent NSCs first emerge. We identified a subpopulation of embryonic NSCs with a distinct transcriptional profile from other embryonic NSCs. This population shares transcriptional similarities with adult qNSCs including genes known to maintain quiescence. We propose that this population constitute slower cycling embryonic NSCs that may transition into the adult qNSCs of the adult zebrafish brain.
Individual differences in the boldness of female zebrafish are associated with alterations in serotonin function
Authors: Beigloo Fatemeh , Davidson Cameron J. , Gjonaj Joseph , Perrine Shane A. , Kenney Justin W.
Published: February 2024

One of the most prevalent axes of behavioral variation in both humans and animals is risk taking, where individuals that are more willing to take risk are characterized as bold while those that are more reserved as shy. Brain monoamines (i.e., serotonin, dopamine, and norepinephrine) have been found to play a role in a variety of behaviors related to risk taking. Genetic variation related to monoamine function have also been linked to personality in both humans and animals. Using zebrafish, we investigated the relationship between monoamine function and boldness behavior during exploration of a novel tank. We found a sex-specific correlation between serotonin metabolism (5-HIAA:5-HT ratio) and boldness that was limited to female animals; there were no relationships between boldness and dopamine or norepinephrine. To probe differences in serotonergic function, we administered a serotonin reuptake inhibitor, escitalopram, to bold and shy fish, and assessed their exploratory behavior. We found that escitalopram had opposing effects on thigmotaxis in female animals with bold fish spending more time near the center of the tank and shy fish spent more time near the periphery. Taken together, our findings suggest that variation in serotonergic function makes sex-specific contributions to individual differences in risk taking behavior.
Dissecting the contribution of vagal subcircuits in sepsis-induced brain dysfunctions
Authors: Bourhy Lena , Moigneu Carine , Dupin Alice , Hecquet Estéban , Levy Jarod , Sharshar Tarek , Lledo Pierre-Marie , Lepousez Gabriel
Published: February 2024

Sepsis, a life-threatening syndrome caused by a dysregulated host response to infection, induces a range of acute effects on the brain, including sickness behaviour and sepsis-associated encephalopathy. In addition, sepsis can lead to durable changes in neuronal circuits, resulting in long-term impairments such as post-traumatic stress disorder (PTSD). These brain dysfunctions are not directly caused by brain infection but result from peripheral inflammatory signals relayed to the brain via neural and humoral pathways. The vagal complex in the brainstem, composed of the nucleus of the solitary tract (NTS) and the area postrema, plays a crucial role in sensing and relaying these signals. Notably, the activation of the vagal complex triggers neurovegetative, neuroendocrine, and behavioural responses to infection. Chronic electrical vagus nerve stimulation has been used clinically to treat various brain disorders and is being investigated for its potential to alleviate inflammation and immune diseases through the anti-inflammatory reflex. However, a deeper understanding of the involvement of the vagus nerve and downstream brain circuits in sepsis-induced brain activation and dysfunction is needed to optimize therapeutic strategies.

To investigate the role of the vagal complex in sepsis-induced brain dysfunction, various techniques were employed to manipulate vagus nerve activity and downstream circuits in a rodent model of sepsis by caecal ligation and puncture. Subdiaphragmatic vagotomy and pharmacogenetic manipulation of NTS and nodose (i.e. vagus sensory neurons) were implemented, revealing that vagotomy effectively reduced acute brain activation, inflammatory responses, and sickness behaviour triggered by sepsis. Additionally, transient activation of NTS neurons had a significant impact on inflammatory responses, sickness behaviour, and long-term PTSD-like consequences. This study underscores the complex interplay among the vagus nerve, brain circuits, and systemic inflammation during sepsis, emphasizing the critical importance of understanding these interactions in the development of targeted therapeutic interventions.
TheDrosophilahistone methyl-transferase SET1 coordinates multiple signaling pathways in regulating male germline stem cell maintenance and differentiation
Authors: Vidaurre Velinda , Song Annabelle , Li Taibo , Ku Wai Lim , Zhao Keji , Qian Jiang , Chen Xin
Published: February 2024

Many cell types come from tissue-specific adult stem cells that maintain the balance between proliferation and differentiation. Here, we study how the H3K4me3 methyltransferase, Set1, regulates early-stage male germ cell proliferation and differentiation inDrosophila. Early-stage germline-specific knockdown ofset1results in a temporally progressed defects, arising as germ cell loss and developing to overpopulated early-stage germ cells. These germline defects also impact the niche architecture and cyst stem cell lineage in a non-cell-autonomous manner. Additionally, wild-type Set1, but not the catalytically inactive Set1, could rescue theset1knockdown phenotypes, highlighting the functional importance of the methyl-transferase activity of the Set1 enzyme. Further, RNA-seq experiments reveal key signaling pathway components, such as the JAK-STAT pathway genestat92Eand the BMP pathway genemad, that are upregulated uponset1knockdown. Genetic interaction assays support the functional relationships betweenset1and JAK-STAT or BMP pathways, as mutations of both thestat92Eandmadgenes suppress theset1knockdown phenotypes. These findings enhance our understanding of the balance between proliferation and differentiation in an adult stem cell lineage. The germ cell loss followed by over-proliferation phenotypes when inhibiting a histone methyl-transferase raise concerns about using their inhibitors in cancer therapy.
Physics-informed neural networks for predicting the asymptotic outcome of fast neutrino flavor conversions
Authors: Abbar Sajad , Wu Meng-Ru , Xiong Zewei
Published: February 2024

In the most extreme astrophysical environments, such as core-collapse supernovae (CCSNe) and neutron star mergers (NSMs), neutrinos can undergo fast flavor conversions (FFCs) on exceedingly short scales. Intensive simulations have demonstrated that FFCs can attain equilibrium states in certain models. In this study, we utilize physics-informed neural networks (PINNs) to predict the asymptotic outcomes of FFCs, by specifically targeting the first two moments of neutrino angular distributions. This makes our approach suitable for state-of-the-art CCSN and NSM simulations. Through effective feature engineering and the incorporation of customized loss functions that penalize discrepancies in the predicted total number of νe and ν¯e, our PINNs demonstrate remarkable accuracies, with an error margin of ≲3%. Our study represents a substantial leap forward in the potential incorporation of FFCs into simulations of CCSNe and NSMs, thereby enhancing our understanding of these extraordinary astrophysical events.

Published by the American Physical Society
2024