Research Discoveries in April 2025

Background: Exercise is increasingly recognized as a beneficial intervention for Parkinson's disease (PD), yet the optimal type and intensity of exercise remain unclear. This study investigated the relationship between exercise intensity and neural responses in PD patients, using electroencephalography (EEG) to explore potential neural markers that could be ultimately used to guide exercise intensity.

Method: EEG data were collected from 14 PD patients (5 females) and 8 healthy controls (HC) performing stationary pedaling exercises at 60 RPM with resistance adjusted to target heart rates of 30, 40, 50, 60, and 70% of maximum heart rate. Subjects pedaled for 3 min at each intensity level in a counterbalanced order. Canonical Time-series Characteristics (Catch-22) features and Multi-set Canonical Correlation Analysis (MCCA) were utilized to identify common profiles of EEG features at increasing exercise intensity across subjects.

Results: We identified a statistically significant MCCA component demonstrating a monotonic relationship with pedaling intensity. We have discovered nine features which show significant trends across intensity (p-value<0.01), and the dominant feature in this component was Periodicity Wang (p-value<0.0001), related to the autocorrelation of the EEG. Analysis revealed a consistent trend across features: six features increased with intensity, indicating heightened rhythmic engagement and sustained neural activation, while three features decreased, suggesting reduced variability and enhanced predictability in neural responses. Notably, PD patients exhibited more rigid, consistent response patterns compared to healthy controls (HC), who showed greater flexibility and variability in their neural adaptation across intensities.

Conclusion: This study highlights the feasibility of using EEG-derived features to track exercise intensity in PD patients, identifying specific neural markers correlating with varying intensity levels. PD subjects demonstrate less inter-subject variability in motor responses to increasing intensity. Our results suggest that EEG biomarkers can be used to assess differing brain involvement with the same exercise of increasing intensity, potentially useful for guiding targeted therapeutic strategies and maximizing the neurological benefits of exercise in PD.

No abstract available

Attention networks are loosely defined as the regions of the brain which interact to control behaviour during attentional tasks, but the specific definition of attention networks varies between research programs based on task demands and modalities. The Attention Network Task was designed to exemplify three aspects of attention, alerting, orienting, and executive control, using a visual cueing paradigm. Its proponents propose a system of networks which underlies these aspects. It is debated whether there exists a unified system of networks which underlies attention independently of other cognitive and sensory processing systems. We review the evidence for an attention system within the domain of visual attention. Neuroimaging research using fMRI, EEG, MEG, and others across a variety of tasks attributed to attention, visual cueing, visual search, and divided attention, is compared. This concludes with a discussion on the limitations of an independent "attention system" for describing how the brain flexibly controls many abilities attributed to visual attention.

Purpose: Bisphosphonates (BPs) are first line agents commonly used in the management of osteoporosis. There have been two case reports that have suggested a possible link between BPs and acute angle closure (AAC). In the absence of any large epidemiologic studies, we sought to determine the risk of AAC and OAG with bisphosphonate use in patients with osteoporosis.

Methods: This was a retrospective cohort study with a case control analysis from 2008-2018. The study used the PharMetrics Plus Database (IQVIA, USA) which captures health claims for over 150 million unique patients, with fully adjudicated pharmacy and medical claims, and represents all geographic areas of the United States. 208,111 patients with osteoporosis were included in the study. AAC and OAG cases were defined by an ICD-9/10 code and had to have at least one prescription for bisphosphonate every 3 months in the year prior to the index date. The date of the first event of AAC was designated as the index date.

Results: Bisphosphonate users were more likely to develop AAC than non-users (adjusted IRR = 1.78, 95%CI [1.05-3.01]). In particular, those on risedronate were more likely to develop AAC compared to patients who used other formulations of bisphosphonates (adjusted IRRs = 2.12, 95%CI [1.05-3.01]). There was no risk for OAG with bisphosphonate use.

Conclusions: Patients with osteoporosis who used BPs were at a higher risk for AAC compared to those who did not, and those who were on risedronate were more likely to develop AAC compared to patients who used other types of bisphosphonates.

In North America, wooden honey bee hives are most often constructed from pine, but some companies also produce and sell boxes made of western red cedar (Thuja plicata) as a result of its local availability and desirable properties. However, there is debate within the beekeeping community about whether cedar is a safe hive material for bees, since resins within the wood are known to be insecticidal or insect deterrents. There is very little empirical evidence to support or refute these arguments. Here, we recorded health metrics of honey bee nucleus colonies hived in western red cedar and pine boxes (n = 10 each) to determine if the type of wood affects colony outcomes. Colonies were produced and introduced into these boxes in late July, with monitoring continued until the following spring. We found no significant differences in adult bee populations, brood areas, or Varroa mite prevalence among colonies hived in cedar versus pine boxes at either the end of summer (September 1st) or spring (April 1st) assessments. Overwintering survival was identical in the two groups at 90%. Hemolymph detoxification enzyme expression differed strongly between callow (day-old) workers and foragers but did not differ with hive material. Overall, we did not find evidence that hiving honey bee colonies in boxes constructed of western red cedar had any negative or positive effect on bee physiology or colony outcomes.

Human cells consist of a complex hierarchy of components, many of which remain unexplored^1,2. Here we construct a global map of human subcellular architecture through joint measurement of biophysical interactions and immunofluorescence images for over 5,100 proteins in U2OS osteosarcoma cells. Self-supervised multimodal data integration resolves 275 molecular assemblies spanning the range of 10^-8 to 10^-5 m, which we validate systematically using whole-cell size-exclusion chromatography and annotate using large language models³. We explore key applications in structural biology, yielding structures for 111 heterodimeric complexes and an expanded Rag-Ragulator assembly. The map assigns unexpected functions to 975 proteins, including roles for C18orf21 in RNA processing and DPP9 in interferon signalling, and identifies assemblies with multiple localizations or cell type specificity. It decodes paediatric cancer genomes⁴, identifying 21 recurrently mutated assemblies and implicating 102 validated new cancer proteins. The associated Cell Visualization Portal and Mapping Toolkit provide a reference platform for structural and functional cell biology.

Cryptococcus neoformans, an invasive basidiomycete fungal pathogen, causes one of the most prevalent, life-threatening diseases in immunocompromised individuals and accounts for ~19% of AIDS-associated deaths. Therefore, understanding the pathogenesis of C. neoformans and its interactions with the host immune system is critical for developing therapeutics against cryptococcosis. Previous studies demonstrated that C. neoformans cells lacking polyphosphate (polyP), an immunomodulatory polyanionic storage molecule, display altered cell surface architecture but unimpaired virulence in a murine model of cryptococcosis. However, the relevance of cell surface changes and the role of hyperaccumulation of polyP in the virulence of C. neoformans remain unclear. Here we show that mutants with abundant polyP due to loss of the polyphosphatases Xpp1 and Epp1 are attenuated for virulence. The double mutant differed from the wild type during disease by demonstrating a higher fungal burden in disseminated organs at the experimental endpoint and by provoking an altered immune response. An analysis of triple mutants lacking the polyphosphatases and the Vtc4 protein for polyP synthesis also caused attenuated virulence in mice, thus suggesting an influence of Xpp1 and/or Epp1 independent of polyP levels. A more detailed characterization revealed that Xpp1 and Epp1 play multiple roles by contributing to the organization of the cell surface, virulence factor production, the response to stress, and mitochondrial function. Overall, we conclude that polyphosphatases have additional functions in the pathobiology of C. neoformans beyond an influence on polyP levels.IMPORTANCECryptococcus neoformans causes one of the most prevalent fungal diseases in people with compromised immune systems and accounts for ~19% of AIDS-associated deaths worldwide. The continual increase in the incidence of fungal infections and limited treatment options necessitate the development of new antifungal drugs and improved diagnostics. Polyphosphate (polyP), an under-explored biopolymer, functions as a storage molecule, modulates the host immune response, and contributes to the ability of some fungal and bacterial pathogens to cause disease. However, the role of polyP in cryptococcal disease remains unclear. In this study, we report that the polyphosphatase enzymes that regulate polyP synthesis and turnover contribute to the virulence of C. neoformans in a mouse model of cryptococcosis. The polyphosphatases influenced the survival of C. neoformans in macrophages and altered the host immune response. In addition, the mutants lacking the enzymes have changes in cell surface architecture and size, as well as defects in both mitochondrial function and the stress response. By using mutants defective in the polyphosphatases and polyP synthesis, we demonstrate that many of the phenotypic contributions of the polyphosphatases are independent of polyP.

Objectives: This study aimed to develop best practice recommendations for physiotherapists providing telerehabilitation to First Nations people.

Design: Modified Delphi study.

Participants: Eighteen experts from four groups were selected: (a) physiotherapists who provide telerehabilitation to First Nations people, (b) Carrier Sekani Family Services leaders (CSFS, First Nations-led health organization/research partners), (c) telehealth experts from British Columbia (BC), Canada, and (d) First Nations individuals (end users) with experience in telerehabilitation.

Methods: Panelists rated recommendations on telehealth best practices in two rounds using an online questionnaire. Recommendations were synthesized from a scoping review and two qualitative studies. Each statement was rated on a four-point Likert scale indicating whether it was essential, useful, not useful, or unnecessary for inclusion in the best practices. Statements endorsed by ≥80% of panel members were considered for inclusion in the final document.

Results: Following the Delphi process, 77 recommendations covering foundational components, information technology utilization, professional expertise, therapeutic relationships, cultural safety, and the telehealth visit were validated for inclusion in the policy document. Participants also validated the methodology.

Conclusion: The recommendations offer a valuable resource for continuing education and professional development, empowering physiotherapists to enhance their skills and competencies in delivering culturally competent telerehabilitation to the First Nations population. The adoption of these best practices ensures that First Nations people are getting the best standard of care, potentially enhancing uptake and experiences with telehealth. It also enables healthcare organizations and policymakers to monitor adherence to established standards and identify areas for improvement.

Huntington disease (HD) is a progressive and devastating neurodegenerative disease caused by expansion of a glutamine-coding CAG tract in the huntingtin (HTT) gene above a critical threshold of ~ 35 repeats resulting in expression of mutant HTT (mHTT). A promising treatment approach being tested in clinical trials is HTT lowering, which aims to reduce levels of the mHTT protein. Target engagement of these therapies in the brain are inferred using antibody-based assays that measure mHTT levels in the cerebrospinal fluid (CSF). These levels are typically reported as the absolute concentration of mHTT concentration, derived from a standard curve generated using a single protein standard. However, patient biofluids are a complex milieu containing different mHTT protein species, suggesting that absolute quantitation is challenging. As a result, a single recombinant protein standard may not be sufficient to interpret assay signal as molar mHTT concentration. In this study, we used immunoprecipitation and flow cytometry (IP-FCM) to investigate different factors that influence mHTT detection assay signal. Our results show that HTT protein fragmentation, protein-protein interactions, affinity tag positioning, oligomerization and polyglutamine tract length affect assay signal intensity. These findings indicate that absolute HTT quantitation in heterogeneous biological samples is not possible with current technologies using a single standard protein. We also explore the binding specificity of the MW1 anti-polyglutamine antibody, commonly used in these assays as a mHTT-selective reagent and demonstrate that mHTT binding is preferred but not specific. Furthermore, we find that MW1 depletion of mHTT for quantitation of wildtype HTT is not only incomplete, leaving residual mHTT, but also non-specific, resulting in pull down of some wildtype HTT protein. Based on these observations, we recommend that mHTT detection assays report only relative mHTT quantitation using normalized arbitrary units of assay signal intensity, rather than molar concentrations, in the assessment of central nervous system HTT lowering in ongoing clinical and preclinical studies. Further, we recommend that MW1-depletion not be used as a method for quantifying wildtype HTT protein and that detergent be consistently added to samples during testing.

In a recent debate piece, Livingstone, Orben and Odgers (Child and Adolescent Mental Health, 2023, 28, 150) asked whether and when it is advisable for academics researching youth mental health to collaborate with digital companies. Such collaborations arise when researchers seek to identify risks and opportunities associated with youth digital engagement or to develop research-based interventions that leverage digital technologies to improve young people's mental health. However, young people's digital experiences, the associated data records and the prospects of testing interventions in situ are often under the control of digital providers and inaccessible to researchers. There is growing optimism that collaboration with companies may allow independent researchers access to proprietary resources along with opportunities to test and scale up beneficial digital interventions. Understandably, such optimism is tempered by scepticism about the processes, trust, and interests at stake during collaboration between researchers and companies. Given these often opposed positions, it is clear that professional guidance is required for academics so they understand the potential costs and benefits of choosing to enter into such collaborations and the terms on which this is advisable. This article highlights what information already exists for researchers and what guidance is needed to ensure that youth mental health researchers can successfully collaborate with digital companies.

Hyaluronan (HA) in the extracellular matrix promotes epithelial-to-mesenchymal transition (EMT) and metastasis; however, the mechanism by which the HA network constructed by cancer cells regulates cancer progression and metastasis in the tumor microenvironment (TME) remains largely unknown. In this study, inter-alpha-trypsin inhibitor heavy chain 2 (ITIH2), an HA-binding protein, was confirmed to be secreted from mesenchymal-like lung cancer cells when co-cultured with cancer-associated fibroblasts. ITIH2 expression is transcriptionally upregulated by the EMT-inducing transcription factor ZEB1, along with HA synthase 2 (HAS2), which positively correlates with ZEB1 expression. Depletion of ITIH2 and HAS2 reduced HA matrix formation and the migration and invasion of lung cancer cells. Furthermore, ZEB1 facilitates alternative splicing and isoform expression of CD44, an HA receptor, and CD44 knockdown suppresses the motility and invasiveness of lung cancer cells. Using a deep learning-based drug-target interaction algorithm, we identified an ITIH2 inhibitor (sincalide) that inhibited HA matrix formation and migration of lung cancer cells, preventing metastatic colonization of lung cancer cells in mouse models. These findings suggest that ZEB1 remodels the HA network in the TME through the regulation of ITIH2, HAS2, and CD44, presenting a strategy for targeting this network to suppress lung cancer progression.

Tracking and intercepting a moving object requires predicting its trajectory, an ability that depends on the reliability of the available motion information. We investigated two common sources that limit the reliability (certainty) of visual motion information during laboratory object interception: how long an object is shown and how long it is occluded. A simulated flyball was shown briefly on a screen and then occluded before it entered a hit zone. Observers tracked the trajectory of the ball with their eyes and intercepted it in the hit zone with a rapid pointing movement. In a two-part experiment, we either varied the presentation of the ball or occlusion duration. Short presentation duration produced a strong center bias in hand movements, but long occlusion duration yielded only a weak center bias. Whereas the center bias merely improved with long presentation durations, it was fully resolved when occlusion duration was short. These findings indicate that sensorimotor decisions under uncertainty might have to rely more on priors when an object is presented briefly versus when it is occluded for longer periods. Eye and hand movement accuracy were correlated across levels of uncertainty, confirming that predictive processes guiding these effectors share a common readout of motion information.