bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Users’ Needs for Pediatric Upper Extremity Exoskeletons
Authors: Li Bai , Arcemont Sydney , Lobo Michele A.
Published: June 2024

Purpose:

Identify users’ needs for pediatric upper extremity (UE) exoskeletons and how users would like exoskeletons to serve their needs.

Methods:

Qualitative study design with semi-structured interviews performed with families who are English-speaking with a child aged 3 to 16 years with a chronic need for UE assistance to perform activities. Content analysis was conducted for the responses.

Results:

Twenty-two parents and 12 children among 21 families participated. Families identified key personal care, function and mobility, manual interaction, academic, recreational, and social activities they would like devices to support. Families rated the importance of a variety of design factors. Families using UE wearable assistive devices noted that they better met their functional needs relative to other needs. Families provided design suggestions for future exoskeletons, including preferences for attachment mechanisms, fasteners, and control systems.

Conclusions:

This study provides important information to guide the prescription and design of UE exoskeletons for pediatric populations.(Pediatr Phys Ther 2024;35:304–312)
New chronic inflammatory demyelinating polyneuropathy/Guillain–Barré syndrome guidelines – impact on clinical practise
Authors: Allen Jeffrey A.
Published: June 2024

Purpose of review

There is no diagnostic biomarker that can reliably detect Guillain–Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP). Diagnosis relies upon integrating key clinical characteristics and relevant supportive data. Consequently, misdiagnosis and delayed diagnosis are common. Diagnostic criteria have proven valuable resources to improve diagnosis, but are underutilized during routine clinical care.

Recent findings

In 2021, the EAN/PNS CIDP criteria was published, and were followed by the EAN/PNS GBS criteria in 2023. Both guidelines utilized GRADE methodology to formulate evidence-based recommendations that are intended to be used by adult and paediatric clinicians across diverse care settings to optimize diagnostic accuracy and improve patient outcomes during routine clinical care.

The EAN/PNS GBS and CIDP criteria detail specific clinical, electrophysiological, and laboratory features that raise diagnostic confidence, and call attention to diagnostic mimics. The sensitivity of EAN/PNS and other modern criteria to detect GBS and CIDP is high, but utilization during clinical practice is low. Complexity is one factor limiting widespread application. Strategies are needed to optimize criteria adoption during routine clinical care such that GBS and CIDP diagnosis can be achieved with greater speed and accuracy.
Spatial Integration of Multi-Omics Data using the novel Multi-Omics Imaging Integration Toolset
Authors: Wess Maximillian , Andersen Maria K. , Midtbust Elise , Guillem Juan Carlos Cabellos , Viset Trond , Størkersen Øystein , Krossa Sebastian , Rye Morten Beck , Tessem May-Britt
Published: June 2024

To truly understand the cancer biology of heterogenous tumors in the context of precision medicine, it is crucial to use analytical methodology capable of capturing the complexities of multiple omics levels, as well as the spatial heterogeneity of cancer tissue. Different molecular imaging techniques, such as mass spectrometry imaging (MSI) and spatial transcriptomics (ST) achieve this goal by spatially detecting metabolites and mRNA, respectively. To take full analytical advantage of such multi-omics data, the individual measurements need to be integrated into one dataset. We present MIIT (Multi-Omics Imaging Integration Toolset), a Python framework for integrating spatially resolved multi-omics data. MIIT’s integration workflow consists of performing a grid projection of spatial omics data, registration of stained serial sections, and mapping of MSI-pixels to the spot resolution of Visium 10x ST data. For the registration of serial sections, we designed GreedyFHist, a registration algorithm based on the Greedy registration tool. We validated GreedyFHist on a dataset of 245 pairs of serial sections and reported an improved registration performance compared to a similar registration algorithm. As a proof of concept, we used MIIT to integrate ST and MSI data on cancer-free tissue from 7 prostate cancer patients and assessed the spot-wise correlation of a gene signature activity for citrate-spermine secretion derived from ST with citrate, spermine, and zinc levels obtained by MSI. We confirmed a significant correlation between gene signature activity and all three metabolites. To conclude, we developed a highly accurate, customizable, computational framework for integrating spatial omics technologies and for registration of serial tissue sections.
OPTIMIZING SEGMENTATION IN OCCUPANCY MODELLING OF CAMERA-TRAP DATA
Authors: de Jager Monique , van Kuijk Marijke , Zwerts Joeri A. , Jansen Patrick A.
Published: June 2024

Accurate estimation of species’ abundances is a common challenge in conservation biology, particularly when abundances are compared in space or time. Occupancy modelling provides relative abundance estimates from camera-trapping data without the need for individual recognition. This requires segmentation of continuous records into a series of intervals with either detection or non-detection. While the segmentation method may have profound effects on the accuracy of occupancy modelling, no form of segmentation optimization is yet available.

We assessed how segmentation, defined by interval length and number, influences the accuracy of predictions by the Royle-Nichols occupancy model and how this relationship depends on species’ density, study duration, and the number of sampling points. We simulated capture data using an individual-based model in which we varied the species’ densities between study locations, and then fitted models using different segmentations. Using the simulation results, we developed a simple tool for choosing optimal segmentation and the best minimum number of intervals to use. To provide an example, we used the optimization tool on actual data from a camera-trapping study in Western Equatorial Africa and compared relative wildlife abundances between two forest management types.

We found that the optimum interval length for the Royle-Nichols occupancy model varied with species’ density, study duration, and the number of sampling points. By analyzing the empirical data, we found that optimal segmentation and minimum number of intervals differed substantially between species. Modelling with optimized, species-specific interval numbers and lengths yielded more conservative outcomes (i.e. fewer significant effects) than did modelling with fixed numbers and lengths. Furthermore, the choice of interval length can affect the direction of relationships.

Our results indicate that the interval length is by no means a parameter to be standardized at a given value but should be carefully chosen based on the properties of the data at hand. This study shows that the arbitrary segmentation that is commonly used in occupancy modelling may not be optimal. Our tool helps to optimize segmentation, increases the accuracy of relative abundance estimations, and thus facilitates the use of camera-trapping studies to evaluate conservation measures.
Troriluzole Rescues Glutamatergic Deficits, Amyloid and Tau Pathology, and Synaptic and Memory Impairments in 3xTg-AD Mice
Authors: Pfitzer Jeremiah , Pinky Priyanka D. , Perman Savannah , Redmon Emma , Cmelak Luca , Suppiramaniam Vishnu , Coric Vladimir , Qureshi Irfan A. , Gramlich Michael W. , Reed Miranda N.
Published: June 2024

Alzheimer’s disease (AD) is a neurodegenerative condition in which clinical symptoms are highly correlated with the loss of glutamatergic synapses. While later stages of AD are associated with markedly decreased glutamate levels due to neuronal loss, in the early stages, pathological accumulation of glutamate and hyperactivity contribute to AD pathology and cognitive dysfunction. There is increasing awareness that presynaptic dysfunction, particularly synaptic vesicle (SV) alterations, play a key role in mediating this early-stage hyperactivity. In the current study, we sought to determine whether the 3xTg mouse model of AD that exhibits both beta-amyloid (Aβ) and tau-related pathology would exhibit similar presynaptic changes as previously observed in amyloid or tau models separately. Hippocampal cultures from 3xTg mice were used to determine whether presynaptic vesicular glutamate transporters (VGlut) and glutamate are increased at the synaptic level while controlling for postsynaptic activity. We observed that 3xTg hippocampal cultures exhibited increased VGlut1 associated with an increase in glutamate release, similar to prior observations in cultures from tau mouse models. However, the SV pool size was also increased in 3xTg cultures, an effect not previously observed in tau mouse models but observed in Aβ models, suggesting the changes in pool size may be due to Aβ and not tau. Second, we sought to determine whether treatment with troriluzole, a novel 3rdgeneration tripeptide prodrug of the glutamate modulator riluzole, could reduce VGlut1 and glutamate release to restore cognitive deficits in 8-month-old 3xTg mice. Treatment with troriluzole reduced VGlut1 expression, decreased basal and evoked glutamate release, and restored cognitive deficits in 3xTg mice. Together, these findings suggest presynaptic alterations are early events in AD that represent potential targets for therapeutic intervention, and these results support the promise of glutamate-modulating drugs such as troriluzole in Alzheimer’s disease.
Differential cell-ECM interaction of rhabdomyosarcoma subtypes regulated by PAX3-FOXO1
Authors: Chronopoulos Antonios , Chavez Ivan , Vemula Chandra , Mittal Nikhil , Zamloot Victoria , Han Sangyoon J , Park JinSeok
Published: June 2024

Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma, with two subtypes: Fusion-positive RMS (FPRMS), which has the PAX3-FOXO1 fusion gene, and fusion-negative RMS (FNRMS). Despite their distinct characteristics, treatments mainly rely on conventional chemotherapies without considering these differences. This study highlights that FNRMS cells exhibit significantly heightened interaction with the extracellular matrix (ECM) compared to FPRMS cells.

Using single-cell RNA sequencing of skeletal muscle tissues and RNA sequencing of RMS samples, we identified the upregulation of genes related to cell-ECM interaction and TGFβ signaling in FNRMS compared to FPRMS. We also confirmed enhanced cell-ECM interaction stimulated by TGFβ signaling in FNRMS cells, using confocal reflection microscopy to monitor dynamic cell-ECM interaction and a live-cell sensor to quantitatively assess TGFβ signaling activity. Additionally, we discovered that the PAX3-FOXO1 fusion gene, characteristic of FPRMS, stimulated nitric oxide synthesis, which suppresses TGFβ signaling and reduces cell-ECM interaction.

These findings suggest that PAX3-FOXO1 determines the diminished cell-ECM interactions in FPRMS. Experimental data show higher sensitivity of FNRMS to cell-ECM interaction disruption and TGFβ inhibition. Furthermore, the diminished cell-ECM interaction in FPRMS, allowing cells to survive in the ectopic environment through circulation, may partly explain its higher metastatic potential compared to FNRMS.
Football as foraging? Movements by individual players and whole teams exhibit Lévy walk dynamics
Authors: Shpurov Ivan , Froese Tom , Ikegami Takashi
Published: June 2024

Many organisms, ranging from modern humans to extinct species, exhibit movement patterns that can be described by Lévy walk dynamics. It has been demonstrated that such behavior enables optimal foraging when resource distribution is sparse. Here, we analyze a dataset of football player trajectories, recorded during the matches of the Japanese football league to elucidate the presence of statistical signatures of Lévy walks; such as the heavy-tailed distribution of distances traveled between significant turns and the characteristic superdiffusive behavior. We conjecture that the competitive environment of a football game leads to movement dynamics reminiscent of that observed in hunter-gathering populations and more broadly in any biological organisms foraging for resources, whose exact distribution is unknown to them. Apart from analyzing individual players’ movements, we investigate the dynamics of the whole team by studying the movements of its center of mass (team’s centroid). Remarkably, the trajectory of the centroid also exhibits Lévy walk properties, marking the first instance of such type of motion observed at the group level. Our work concludes with a comparative analysis of different teams and some discussion on the relevance of our findings to sports science and science more generally.
The Comparative Genome Dashboard
Authors: Paley Suzanne , Caspi Ron , O’Maille Paul , Karp Peter D.
Published: June 2024

The Comparative Genome Dashboard is a web-based software tool for interactive exploration of the similarities and differences in gene functions between organisms. It provides a high-level graphical survey of cellular functions, and enables the user to drill down to examine subsystems of interest in greater detail. At its highest level the Comparative Dashboard contains panels for cellular systems such as biosynthesis, energy metabolism, transport, and response to stimulus. Each panel contains a set of bar graphs that plot the numbers of compounds or gene products for each organism across a set of subsystems of that panel. Users can interactively drill down to focus on subsystems of interest and see grids of compounds produced or consumed by each organism, specific GO term assignments, pathway diagrams, and links to more detailed comparison pages. For example, the dashboard enables users to compare the cofactors that a set of organisms can synthesize, the metal ions that they are able to transport, their DNA damage repair capabilities, their biofilm-formation genes, and their viral response proteins. The dashboard enables users to quickly perform comprehensive comparisons at varying levels of detail.
TransMetaSegmentation (TMS): a transcriptome-based segmentation method for spatial metabolomic data
Authors: Wang Yongheng , Bender Kayle J. , Zhang Weidi , Lin Siyu , Neumann Elizabeth K. , Wang Aijun
Published: June 2024

Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) is a powerful analytical tool that enables the visualization and comparison of relative abundances of metabolites across samples, shedding light on biological processes and disease mechanisms. Techniques such as scSpatMet enable the determination of cell boundaries and cell types through staining with 35 cell marker antibodies. Yet, distinguishing subpopulations of cells, such as astrocytes, oligodendrocytes, and neuronal clusters in the brain, remains challenging using antibodies. In this context, we introduce TransMetaSegmentation (TMS), an alternative segmentation and cell typing method that integrates MALDI MSI imagery with single-cell spatial transcriptomic analysis. This approach not only delineates cell boundaries and defines cell types based on a number of marker genes but also effectively allocates metabolites to specific cell types in a high-throughput manner. We anticipate that TMS will improve the granularity of MALDI MSI analyses, advance our understanding of metabolic alterations in diseases, and have an impact on various fields within biomedical sciences.
Missing data approaches for longitudinal neuroimaging research: Examples from the Adolescent Brain and Cognitive Development (ABCD) Study
Authors: Li Lin , Bayat Mohammadreza , Hayes Timothy B. , Thompson Wesley K. , Gard Arianna M. , Dick Anthony Steven
Published: June 2024

This paper addresses the challenges of managing missing values within expansive longitudinal neu-roimaging datasets, using the specific example of data derived from the Adolescent Brain and Cog-nitive Development (ABCD®) study. The conventional listwise deletion method, while widely used, is not recommended due to the risk that substantial bias can potentially be introduced with this method. Unfortunately, recommended alternative practices can be challenging to implement with large data sets. In this paper, we advocate for the adoption of more sophisticated statistical method-ologies, including multiple imputation, propensity score weighting, and full information maximum likelihood (FIML). Through practical examples and code using (ABCD®) data, we illustrate some of the benefits and challenges of these methods, with a review of how these advanced methodolo-gies bolster the robustness of analyses and contribute to the integrity of research findings in the field of developmental cognitive neuroscience.
Novel tools to quantify total, phospho-Ser129 and aggregated alpha-synuclein in the mouse brain
Authors: Trist Benjamin Guy , Wright Courtney Jade , Rangel Alejandra , Cottle Louise , Prasad Asheeta , Jensen Nanna Møller , Gram Hjalte , Dzamko Nicolas , Jensen Poul Henning , Kirik Deniz
Published: June 2024

Assays for quantifying aggregated and phosphorylated (S129) human α-synuclein protein are widely used to evaluate pathological burden in patients suffering from synucleinopathy disorders. Many of these assays, however, do not cross-react with mouse α-synuclein or exhibit poor sensitivity for this target, which is problematic considering the preponderance of mouse models at the forefront of pre-clinical α-synuclein research. In this project, we addressed this unmet need by reformulating two existing AlphaLISA®SureFire®UltraTMtotal and pS129 α-synuclein assay kits to yield robust and ultrasensitive (LLoQ ≤0.5pg/mL) quantification of mouse and human wild-type and pS129 α-synuclein protein. We then employed these assays, together with the BioLegend α-synuclein aggregate ELISA, to assess the relationship between α-synuclein S129 phosphorylation and aggregation in different mouse brain tissue preparations. Overall, we highlight the compatibility of these new immunoassays with rodent models and demonstrate their potential to advance knowledge surrounding α-synuclein phosphorylation and aggregation in synucleinopathies.
Neural Mechanisms of Mutualistic Fish Cleaning Behaviour: a Study in the Wild
Authors: Romeo Daniele , Ramirez-Calero Sandra , Ravasi Timothy , Rodolfo-Metalpa Riccardo , Schunter Celia
Published: June 2024

One crucial interaction for the health of fish communities in coral reefs is performed by the cleaner fish by removing ectoparasites and other particles from the body of other fish, so called clients. Studying the underlying mechanisms of this behaviour is essential to understanding how species react to social stimuli and defining the drivers of mutualism. Here, we pinpoint the neural molecular mechanisms in the cleaning behaviour ofLabroides dimidiatusin the wild through anin-situinteraction experiment at a coral reef in New Caledonia. Five cleaners and clients (Abudefduf saxatilis) were placed into underwater aquaria to interact, while five were not presented with a client. The brain transcriptomes revealed 291 differentially expressed genes in cleaners that were interacting with a client. Among these genes,grin2d, npy, slc6a3and immediate early genes (fosb;fosl1;nr4a1)were related to learning and memory, glutamate and dopamine pathways, which confirm molecular pathways observed in laboratory studies. However, a new potential mechanism was found withnpy(Neuropeptide Y) as a driver of feeding behaviour. These results show that in-situ experiments are essential for corroborating interpretations inferred from experiments in captivity and identify drivers of interspecific interactions.
Targeting Molecular Collagen Defects from the Initiation of Knee Osteoarthritis
Authors: Huang Kui , Qiu Rongmao , Fang Yijie , Zhu Dantian , Li Xiaojing , Lv Zhongyang , Jia Taoyu , Fei Yuxiang , Zhou Daoning , Wu Wenjun , Huang Yongjie , Zhao Suwen , Zhu Yongqiao , Li Shaolin , Shi Dongquan , Li Yang
Published: June 2024

Knee osteoarthritis (OA) is the most prevalent degenerative joint disease. When morphological changes become apparent on radiographs, no approved treatment can reverse the disease process. Early diagnosis is an unmet need demanding new molecular and imaging biomarkers to define OA from the earliest stages. In this context, we focus on collagen, the most basic building block of all joint tissues, and interrogate how OA development affects collagen’s molecular folding, a previously underexplored area. Here, through whole-joint mapping with a peptide that recognizes unfolded collagen molecules, we report the discovery of collagen denaturation in cartilage before proteolysis and major histopathological degeneration in animal models and patients. Mechanistically, we reveal that such molecular collagen defects can be driven by mechanical overloading without collagenase degradation and are intimately associated with glycosaminoglycan loss. We showcase the advantages of using collagen denaturation as an early-stage OA hallmark for in vivo therapeutic evaluation and molecular magnetic resonance imaging (MRI) of subtle joint defects that are challenging to detect with conventional morphology-based MRI. These results highlight biomolecular integrity as a crucial dimension for characterizing joint degeneration and a molecular foundation for diagnosing early-stage OA and beyond.
Beyond the numbers: A phenomenological analysis of women’s childbirth experiences in Spain’s evolving healthcare system
Authors: Palau-Costafreda Roser , Nar-Devi Sonia , Gil-Poisa Maria , Pajares Manso Amaia , Vela Ana España , Gutiérrez Noemí Obregón , Escuriet Ramon , Julià Mireia , Graells-Sans Ariadna
Published: June 2024

Background

Childbirth is a transformative experience, yet a considerable percentage of women worldwide encounter negative birth events, affecting maternal wellbeing and mental health. The choice of birth setting significantly impacts outcomes, with midwifery-led units often associated with lower intervention rates and higher satisfaction levels. The recent introduction of midwifery-led units in Spain presents a unique opportunity to explore the impact of this model within a medicalized healthcare context.

Aim

To capture the depth and diversity of women’s voices, understanding factors influencing their perceptions of childbirth experiences following the introduction of the first midwifery-led unit in the Spanish Healthcare System.

Methods

A qualitative study with a phenomenological approach within the constructivist paradigm. Four focus groups were conducted including nineteen women who gave birth in a hospital with both an obstetric and a midwifery-led unit.

Findings

Three main themes were identified; ‘Shaping birth expectations’, highlighting the influence of cultural and social contexts on women’s childbirth expectations; ‘The childbirth essentials’, incorporating fundamental characteristics related to the model of care; and ‘Navigating the protective factors’, considering the pivotal role of midwives in delivering compassionate and respectful care.

Conclusion

These findings offer valuable insights into childbirth experiences, advocating for a transformation of the medicalized healthcare system in Spain through the integration of midwifery-led units. By prioritising women’s voices and addressing systemic inequalities, healthcare policymakers can enhance maternal care practices and foster positive childbirth experiences for all women.
A genome-wide cross-trait analysis identifies causal relationship and shared loci of food preference with obesity
Authors: Yao Shi , Wu Hao , Bao Peng , Qian Long , Han Ji-Zhou , Wang Yan , Feng Si-Fan , Cai Yu-Jie , Guo Jing , Ke Xin , Shi Wei , Ma Fu-Bin , Liang Qiu-Hao , Dong Shan-Shan , Guo Yan , Zhu Dong-Li , Cui Li-Li
Published: June 2024

Food preferences play a pivotal role in dietary choices and body weight regulation, yet the causal relationships and complex pathways linking food liking to obesity remain elusive. Here, we employed a two-sample Mendelian randomization (MR) analysis and pleiotropic analysis to explore the causalities and shared loci between 187 food preferences (N=161,625) and five obesity-related phenotypes (N=100,716 to 322,154). MR analysis revealed a causal association between two food-liking phenotypes and increased body mass index (BMI), specifically, onion liking (β, 0.286; 95% CI, 0.185 to 0.387;P= 2.80×10−8), and highly palatable food liking (β, 0.266; 95% CI, 0.140 to 0.391;P= 3.31×10−5). Multivariable MR analysis indicated that the impact of onion liking on BMI persisted even after conditioning on actual onion intake, suggesting a degree of independence in dietary preferences’ influence. Pleiotropic analysis under a composite null hypothesis detected 32 pleiotropic loci and six colocalized loci in these two trait pairs. Candidate pleiotropic genes associated with onion liking-BMI highlighted biological pathways primarily involved in the sensory perception of smell. These findings enhance our comprehension of the intricate relationship between food preferences and obesity.
Voluntary Medical Male Circumcision’s (VMMC) Strategy for HIV prevention in Sub-Saharan Africa, prevalence, risks, costs, benefits and best practice: A scoping review of progress and unfolding insights
Authors: Maibvise Charles , Munangatire Takaedza , Tomas Nector , Ashipala Daniel O. , Dlamini Priscilla S.
Published: June 2024

Campaigns to scale up Voluntary Medical Male Circumcision (VMMC) for the prevention of HIV transmission has been going on for years in selected Southern African countries, following recommendations from the World Health Organisations. Despite significant strides made in the initiative and its proven benefits, controversies surrounding the strategy have never ceased, and its future remains uncertain especially as some countries near their initial targets. Over the years, as the campaigns unfolded, a lot of insights have been generated in favour of continuing the VMMC campaigns, while some insights portray the impression that the strategy is not worthy the risks and effort required, or enough has been done, as the targets have been achieved. This article proposes a scoping review that aims at synthesizing and consolidating that evidence into a baseline for a further systematic review aimed at developing sound recommendations for the future of the VMMC strategy for HIV prevention. The scoping review will target all scientific literature published on the Web of Science, Cochrane Library, Scopus, Science Direct, PubMed as well as WHO Institutional Repository for Information Sharing (IRIS) since 2011. The review shall be guided by Arksey and O’Malley’s (2005) framework for scoping reviews, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) checklist shall be followed. Discussion of the findings is envisioned to yield evidence that can be further analysed to give insights about risk/cost-benefits ratios of the strategy at this point in time as well best clinical practices for the VMMC procedure, to inform the future of the strategy.
Do silver-chitosan nanocomposites promote bacterial resistance to silver or common antibiotics?
Authors: Sihtmäe Mariliis , Laanoja Jüri , Otsus Maarja , Vija Heiki , Kahru Anne , Kasemets Kaja
Published: June 2024

Silver-containing nanomaterials are versatile antimicrobials for slowing down the rapid increase of nosocomial infections caused by antibiotic-resistant bacteria. However, silver can also promote resistance in bacteria to both silver itself and conventional antibiotics. Despite this, the topic is still poorly studied.

Silver-chitosan nanocomposites (nAgCSs) with a primary size of ∼50 nm and weight ratios of 1:1 (nAgCS-1) and 1:3 (nAgCS-3) were synthesised and studied for potential antimicrobials, such as wound dressings, antimicrobial coatings. These nAgCSs exhibited antibacterial efficacy at level of 6.25–14.6 mg Ag/L level (minimal inhibitory concentration, MIC) againstEscherichia coliandStaphylococcus aureusbeing comparable to the efficiency of AgNO3(MIC 3.13–7.29 mg Ag/L) or benzalkonium chloride (MIC 0.91–6.25 mg/L). Low molecular weight chitosan also demonstrated antibacterial activity againstS. aureus(MIC 25 mg/L), though it was less effective againstE. coli(MIC 70 mg/L). Notably, nAgCS-3 was almost as efficient as AgNO3againstS. aureus(MIC 6.25–7.29 mg/L) and benzalkonium chloride againstE. coli(MIC 6. mg/L). Confocal laser scanning microscopy revealed a noticeable aggregation ofS. aureuscells caused by exposure to nAgCS-3, an effect that was less pronounced inE. coli.

The development of bacterial resistance to nAgCSs and AgNO3and cross-resistance to 14 conventional antibiotics upon continuous exposure (up to 5 weeks) to sub-inhibitory concentrations (EC20) of the studied silver compounds was examined. No resistance development was observed for the studied silver compounds and antibiotics in eitherE. coliorS. aureus. Thus, silver-chitosan nanocomposites show promise as efficient and not AMR-inducing compounds for antimicrobial applications, such as wound dressings and surfaces.
Mitochondrial oxidant stress promotes α-synuclein aggregation and spreading in mice with mutated glucocerebrosidase
Authors: Vitola Pietro La , Szegö Eva M , Pinto-Costa Rita , Rollar Angela , Harbachova Eugenia , Schapira Anthony HV , Ulusoy Ayse , Di Monte Donato A
Published: June 2024

Mutations of the glucocerebrosidase-encoding gene,GBA1, are common risk factors for Parkinson’s disease. Although only a minority of mutation-carrying individuals develops the disease, the mechanisms of neuronal vulnerability predisposing to pathology conversion remain largely unclear. In this study, heterozygous expression of a common glucocerebrosidase variant, namely the L444P mutation, was found to exacerbate α-synuclein aggregation and spreading in a mouse model of Parkinson-like pathology targeting neurons of the medullary vagal system. These neurons are primary sites of α-synuclein lesions in Parkinson’s disease and were shown here to become more vulnerable to oxidative stress after L444P expression. Nitrative burden paralleled the enhanced formation of reactive oxygen species within vagal neurons expressing mutated glucocerebrosidase, as indicated by pronounced accumulation of nitrated α-synuclein. A causal relationship linked mutation-induced oxidative stress to enhanced α-synuclein pathology that could indeed be rescued by neuronal overexpression of the mitochondrial antioxidant enzyme superoxide dismutase 2. Further evidence supported a key involvement of mitochondria as sources of reactive oxygen species as well as targets of oxidative and nitrative damage within L444P-expressing neurons. Scavenging of oxygen species by superoxide dismutase 2 effectively counteracted deleterious nitrative reactions and prevented nitrated α-synuclein burden. Taken together, these findings support the conclusion that enhanced vulnerability to mitochondrial oxidative stress conferred by glucocerebrosidase mutations should be considered an important mechanism predisposing to Parkinson’s disease pathology, particularly in brain regions targeted by α-synuclein aggregation and involved in α-synuclein spreading.
The L,D-transpeptidation pathway is inhibited by antibiotics of the β-lactam class in Clostridioides difficile
Authors: Paiva Ana M. Oliveira , Courtin Pascal , Charpentier Glenn , Soutourina Olga , Chapot-Chartier Marie-Pierre , Peltier Johann
Published: June 2024

The resistance ofClostridioides difficileto the β-lactam antibiotics cephalosporins, which target the peptidoglycan (PG) assembly, is a leading contributor to the development ofC. difficileinfections.C. difficilehas an original PG structure with a predominance of 3→3 cross-links generated by L,D-transpeptidases (LDTs).C. difficileforms spores and we show that the spore cortex PG contains exclusively 3→3 cross-links. PG and spore cortex ofC. difficilecells were largely unaffected by the deletion of the three predicted LDTs, revealing the implication of a new family of LDTS. The D,D-carboxypeptidases producing the essential LDT substrate were inactivated by cephalosporins, resulting in the inhibition of the L,D-transpeptidation pathway. In contrast, the participation of penicillin-binding proteins (PBPs) to PG cross-linking increased in the presence of the antibiotics. Our findings highlight that cephalosporin resistance is not primarily mediated by LDTs and illustrate the plasticity of the PG biosynthesis machinery inC. difficile.
Notch induces transcription by stimulating release of paused RNA Pol II without increasing chromatin accessibility
Authors: Rogers Julia M , Mimoso Claudia A , Martin Benjamin JE , Martin Alexandre P , Aster Jon C , Adelman Karen , Blacklow Stephen C
Published: June 2024

Notch proteins undergo ligand-induced proteolysis to release a nuclear effector that influences a wide range of cellular processes by regulating transcription. Despite years of study, however, how Notch induces the transcription of its target genes remains unclear. Here, we comprehensively examined the response to human Notch1 across a time course of activation using high-resolution genomic assays of chromatin accessibility and nascent RNA production. Our data reveal that Notch induces target gene transcription primarily by releasing paused RNA polymerase II (RNAPII). Moreover, in contrast to prevailing models suggesting that Notch acts by promoting chromatin accessibility, we found that open chromatin was established at Notch-responsive regulatory elements prior to Notch signal induction, through SWI/SNF-mediated remodeling. Together, these studies show that the nuclear response to Notch signaling is dictated by the pre-existing chromatin state and RNAPII distribution at the time of signal activation.
The developing Human Connectome Project fetal functional MRI release: Methods and data structures
Authors: Karolis Vyacheslav R. , Cordero-Grande Lucilio , Price Anthony N. , Hughes Emer , Fitzgibbon Sean P. , Kyriakopoulou Vanessa , Uus Alena , Harper Nicholas , Prokopenko Denis , Bridglal Devi , Moore Jucha Willers , Wilson Sian , Pietsch Maximilian , Christiaens Daan , Deprez Maria , Williams Logan Z.J. , Robinson Emma C. , Makropoulos Antonis , Farahibozorg Seyedeh-Rezvan , O’Muircheartaigh Jonathan , Rutherford Mary A. , Rueckert Daniel , Edwards A. David , Arichi Tomoki , Smith Stephen M. , Duff Eugene , Hajnal Joseph V.
Published: June 2024

Recent advances in fetal fMRI present a new opportunity for neuroscience to study functional human brain connectivity at the time of its emergence. Progress in the field however has been hampered by the lack of openly available datasets that can be exploited by researchers across disciplines to develop methods that would address the unique challenges associated with imaging and analysing functional brain in utero, such as unconstrained head motion, dynamically evolving geometric distortions, or inherently low signal-to-noise ratio. Here we describe the developing Human Connectome Project’s release of the largest open access fetal fMRI dataset to date, containing 275 scans from 255 fetuses and spanning the period of 20.86 to 38.29 post-menstrual weeks. We present a systematic approach to its pre-processing, implementing multi-band soft SENSE reconstruction, dynamic distortion corrections via phase unwrapping method, slice-to-volume reconstruction and a tailored temporal filtering model, with attention to the prominent sources of structured noise in the in utero fMRI. The dataset is accompanied with an advanced registration infrastructure, enabling group-level data fusion, and contains outputs from the main intermediate processing steps. This allows for various levels of data exploration by the imaging and neuroscientific community, starting from the development of robust pipelines for anatomical and temporal corrections to methods for elucidating the development of functional connectivity in utero. By providing a high-quality template for further method development and benchmarking, the release of the dataset will help to advance fetal fMRI to its deserved and timely place at the forefront of the efforts to build a life-long connectome of the human brain.
Examining heterogeneity in dementia using data-driven unsupervised clustering of cognitive profiles
Authors: Kumar Sayantan , Oh Inez Y. , Schindler Suzanne E. , Ghoshal Nupur , Abrams Zachary , Payne Philip R.O.
Published: June 2024

Dementia is characterized by a decline in memory and thinking that is significant enough to impair function in activities of daily living. Patients seen in dementia specialty clinics are highly heterogenous with a variety of different symptoms that progress at different rates. Recent research has focused on finding data-driven subtypes for revealing new insights into dementia’s underlying heterogeneity, compared to analyzing the entire cohort as a single homogeneous group. However, current studies on dementia subtyping have the following limitations: (i) focusing on AD-related dementia only and not examining heterogeneity within dementia as a whole, (ii) using only cross-sectional baseline visit information for clustering and (iii) predominantly relying on expensive imaging biomarkers as features for clustering. In this study, we seek to overcome such limitations, using a data-driven unsupervised clustering algorithm named SillyPutty, in combination with hierarchical clustering on cognitive assessment scores to estimate subtypes within a real-world clinical dementia cohort. We use a longitudinal patient data set for our clustering analysis, instead of relying only on baseline visits, allowing us to explore the ongoing temporal relationship between subtypes and disease progression over time. Results showed that subtypes with very mild or mild dementia were more heterogenous in their cognitive profiles and risk of disease progression.
The C-terminal activating domain promotes Panx1 channel opening
Authors: Henze Erik , Ehrlich Jacqueline J. , Robertson Janice L. , Kawate Toshimitsu
Published: June 2024

Pannexin 1 (Panx1) constitutes a large pore channel responsible for the release of ATP from apoptotic cells. Strong evidence indicates that caspase-mediated cleavage of the C-terminus promotes the opening of the Panx1 channel by unplugging the pore. However, this simple pore- plugging mechanism alone cannot account for the observation that a Panx1 construct ending before the caspase cleavage site remains closed. Here, we show that a helical region located immediately before the caspase cleavage site, referred to as the "C-terminal activating domain (CAD)," plays a pivotal role in facilitating Panx1 activation. Electrophysiology and mutagenesis studies uncovered that two conserved leucine residues within the CAD plays a pivotal role. Cryo- EM analysis of the construct ending before reaching the CAD demonstrated that the N-terminus extends into an intracellular pocket. In contrast, the construct including the CAD revealed that this domain occupies the intracellular pocket, causing the N-terminus to flip upward within the pore. Analysis of electrostatic free energy landscape in the closed conformation indicated that the intracellular side of the ion permeation pore may be occupied by anions like ATP, creating an electrostatic barrier for anions attempting to permeate the pore. When the N-terminus flips up, it diminishes the positively charged surface, thereby reducing the drive to accumulate anions inside the pore. This dynamic change in the electrostatic landscape likely contributes to the selection of permeant ions. Collectively, these experiments put forth a novel mechanism in which C-terminal cleavage liberates the CAD, causing the repositioning of the N-terminus to promote Panx1 channel opening.
Comparative connectomics of two distantly related nematode species reveals patterns of nervous system evolution
Authors: Cook Steven J , Kalinski Cristine A , Loer Curtis M , Memar Nadin , Majeed Maryam , Stephen Sarah Rebecca , Bumbarger Daniel J , Riebesell Metta , Schnabel Ralf , Sommer Ralf J , Hobert Oliver
Published: June 2024

Understanding the evolution of the bilaterian brain requires a detailed exploration of the precise nature of cellular and subcellular differences between related brains. To define the anatomical substrates of evolutionary change in the nervous system, we undertook an electron micrographic reconstruction of the brain of the predatory nematode Pristionchus pacificus. A comparison with the brain of Caenorhabditis elegans, which diverged at least 100 million years ago, reveals a conserved nematode core connectome and a wide range of specific substrates of evolutionary change. These changes include differences in neuronal cell death, neuronal cell position, axo-dendritic projection patterns and many changes in synaptic connectivity of homologous neurons that display no obvious changes in overall neurite morphology and projection patterns. Differences in connectivity are distributed throughout the nervous system arguing against specific hot spots of evolutionary change and extend to differences in neuro/glia connectivity. We observed examples of apparent circuit drift, where changes in morphology and connectivity of a neuron do not appear to alter its behavioral output. In conclusion, our comprehensive comparison of distantly related nematode species provides novel vistas on patterns of conservation as well as the substrates of evolutionary change in the brain that span multiple organizational levels.
Single-Mitochondrion Sequencing Uncovers Distinct Mutational Patterns and Heteroplasmy Landscape in Mouse Astrocytes and Neurons
Authors: Kadam Parnika S , Yang Zijian , Lu Youtao , Zhu Hua , Atiyas Yasemin , Shah Nishal , Fisher Stephen , Nordgren Erik , Kim Junhyong , Issadore David , Eberwine James
Published: June 2024

Background

Mitochondrial (mt) heteroplasmy can cause adverse biological consequences when deleterious mtDNA mutations accumulate disrupting ‘normal’ mt-driven processes and cellular functions. To investigate the heteroplasmy of such mtDNA changes we developed a moderate throughput mt isolation procedure to quantify the mt single-nucleotide variant (SNV) landscape in individual mouse neurons and astrocytes In this study we amplified mt-genomes from 1,645 single mitochondria (mts) isolated from mouse single astrocytes and neurons to 1. determine the distribution and proportion of mt-SNVs as well as mutation pattern in specific target regions across the mt-genome, 2. assess differences in mtDNA SNVs between neurons and astrocytes, and 3. Study cosegregation of variants in the mouse mtDNA.

Results

1. The data show that specific sites of the mt-genome are permissive to SNV presentation while others appear to be under stringent purifying selection. Nested hierarchical analysis at the levels of mitochondrion, cell, and mouse reveals distinct patterns of inter- and intra-cellular variation for mt-SNVs at different sites. 2. Further, differences in the SNV incidence were observed between mouse neurons and astrocytes for two mt-SNV 9027:G>A and 9419:C>T showing variation in the mutational propensity between these cell types. Purifying selection was observed in neurons as shown by the Ka/Ks statistic, suggesting that neurons are under stronger evolutionary constraint as compared to astrocytes. 3. Intriguingly, these data show strong linkage between the SNV sites at nucleotide positions 9027 and 9461. f

Conclusion

This study suggests that segregation as well as clonal expansion of mt-SNVs is specific to individual genomic loci, which is important foundational data in understanding of heteroplasmy and disease thresholds for mutation of pathogenic variants.
Months-long stability of the head-direction system
Authors: Carrasco Sofia Skromne , Viejo Guillaume , Peyrache Adrien
Published: June 2024

Spatial orientation is a universal ability that allows animals to navigate their environment. In mammals, the head-direction (HD) system is an essential component of the brain’s navigation system, yet the stability of its underlying neuronal code remains unclear. Here, by longitudinally tracking the activity of the same HD cells in freely moving mice, we show that the internal organization of population activity in the HD system was preserved for several months. Furthermore, the HD system developed a unique mapping between its internal organization and spatial orientation in each environment. This was not affected by visits to other environments and was stabilized with experience. These findings demonstrate that stable neuronal code supports the sense of direction and forms long-lasting orientation memories.
Genotypic and Phenotypic Analyses ShowRalstonia solanacearumCool Virulence is a Quantitative Trait Not Restricted to “Race 3 biovar 2”
Authors: Dewberry Ronnie J. , Sharma Parul , Prom Jessica L. , Kinscherf Noah A. , Lowe-Power Tiffany , Mazloom Reza , Zhang Xuemei , Liu Haijie , Arif Mohammad , Stulberg Michael , Heath Lenwood S. , Eversole Kellye , Beattie Gwyn A. , Vinatzer Boris A. , Allen Caitilyn
Published: June 2024

MostRalstonia solanacearumspecies complex strains cause bacterial wilts in tropical or subtropical zones, but the group known as Race 3 biovar 2 (R3bv2) is cool virulent and causes potato brown rot at lower temperatures. R3bv2 has invaded potato-growing regions around the world but is not established in the United States. Phylogenetically, R3bv2 corresponds to a subset of theR. solanacearumphylotype IIB clade, but little is known about the distribution of the cool virulence phenotype within phylotype IIB. Therefore, genomes of 76 potentially cool virulent phylotype IIB strains and 30 public genomes were phylogenetically analyzed. A single clonal lineage within the sequevar 1 subclade of phylotype IIB that originated in South America has caused nearly all brown rot outbreaks worldwide. To correlate genotypes with relevant phenotypes, we quantified virulence of tenRalstoniastrains on tomato and potato at both 22°C and 28°C. Cool virulence on tomato did not predict cool virulence on potato. We found that cool virulence is a quantitative trait. Strains in the sequevar 1 pandemic clonal lineage caused the most disease, while other R3bv2 strains were only moderately cool virulent. However, some non-R3bv2 strains were highly cool virulent and aggressively colonized potato tubers. Thus, cool virulence is not consistently correlated with strains historically classified as R3bv2 group. To aid detection of sequevar 1 strains, this group was genomically delimited in the LINbase web server and a sequevar 1 diagnostic primer pair was developed and validated. We discuss implications of these results for the R3bv2 definition.