The Montreal Neurological Institute-Hospital (MNI), also known as Montreal Neuro or The Neuro, is a research and medical centre dedicated to neuroscience, training and clinical care, located in the city's downtown core of Montreal, Quebec, Canada. It is part of the McGill University Health Centre network and it is situated on the southern slope of Mount Royal along the east side of University Street, just north of Pine Avenue. It was founded in 1934 by neurosurgeon Wilder Penfield, who developed the Montreal procedure there for the treatment of epilepsy.
Plastic products have been progressively integrated into every aspect of human life, and they are susceptible to fragmentation, leading to the release of micro- and nanoplastics (MNPs) to the surroundings. Not only are these persistent particles ubiquitous in the environment, but they have also been detected in food, beverages and ambient air, placing them in close contact with humans. Consequently, concerns have been raised on their potential impacts on human health. A growing number of studies have been reporting MNPs detection in various human tissues. Some have attempted to explore the correlation to impacts on human health, gaining significant societal attention. Whilst it is widely accepted that MNPs can enter humans via ingestion and inhalation, accurate identification and quantification have not been without challenges, and their fate in the human body is largely unknown. The objective of this review is to critically assess the potential for translocation of MNPs through the lens of human physiology. Here, we present a comprehensive synthesis of human cell studies, in vivo studies, biological pathways and the current state of human biomonitoring studies, to evaluate how MNPs migrate from entry points to systemic circulation and cross key physiological barriers. Our analysis highlights that larger microplastics are more easily detected with current techniques, though characterisation and quantification-oriented studies often lack adequate consideration for biological plausibility and physiological limits behind reported results. Studies that utilise thermal degradation mass spectrometric analysis are highly susceptible to matrix interference-induced inflated reports of MNP concentrations. Conversely, nanoplastics – sizes most likely to translocate and hence pose the greatest risk – remain underexplored due to analytical challenges, particularly the resolution limitations of spectroscopic techniques. This review provides a critical bridge between empirical detection and physiological relevance – a perspective that is largely absent from current research. We argue that such an integrated approach is essential to advance understanding of the behaviour and fate of MNPs in humans and more robust scientific evidence is needed to form a strong foundation for future research of plastics effects on human health.
Recent research suggests that humans use language-like mental representations for many stimuli, from auditory sequences to visual shapes. However, evidence has been largely indirect, relying on stimulus compression as a proxy for internal representation. Using constituency tests, we probed representational structure in the domain of geometry more directly. Across three preregistered experiments (n= 136), we find robust evidence for tree structure in human adults’ shape representations. First, the same shape can receive different structural representations depending on how a preceding animation organizes it. Second, subparts of shapes are easier to detect when they belong to the same subtree than when spanning different subtrees. Third, shape fragments are easier to reconfigure the higher in the tree they are split. Unlike humans, state-of-the-art deep networks show no syntactic effects whatsoever. Thus, humans—and so far only humans—encode geometric shapes in hierarchical structures, mirroring the representations used in natural language processing.
The brain is a complex network of neuronal populations interconnected by white matter tracts. The composition of these white matter connections (SC) shapes inter-regional signaling dynamics giving rise to spatial patterns of synchronous functional connectivity (FC). Several modeling approaches have proven useful for studying the mechanisms underlying the relationship between SC and FC. However, despite being a major component of white matter connectivity, the myelination of white matter tracts is not accounted for by conventional SC networks and has therefore largely been excluded from models of FC. Here, we expand structure-function brain modeling by integrating a multi-feature white matter SC network. We use multi-modal MRI to compute an SC network with connections (edges) weighted by the caliber, myelination, and length of white matter tracts. We investigate the relationship of this multi-feature SC network with both haemodynamic and electromagnetic FC. Edge myelin was strongly predictive of FC in a pattern that was heterogeneous across brain regions and timescales of neural function. Edge myelin showed strong, frequency-specific interactions with both edge caliber and length suggesting a modulatory role for white matter myelin in structure-function coupling. This was further supported by antagonistic gradients of white matter myelin and structure-function coupling along the sensory-association axis. We describe in detail the individual and joint relationships between these major white matter features and multi-frequency FC. These results illustrate the advantage of a more comprehensive characterization of white matter in structure-function models and establish how white matter myelin-known for roles in conduction velocity, plasticity, and metabolic support at the microscale-shapes brain function at the systems-level.
BACKGROUND:Multiple sclerosis (MS) treatment response varies significantly, hindering effective management and necessitating better predictive biomarkers. Pharmacogenomics offers a promising avenue to identify genetic markers that, combined with clinico-demographic predictors, could enhance personalized therapeutic decisions. OBJECTIVES:This multi-center study investigated genetic determinants of response to interferon-beta (IFN-β) and glatiramer acetate (GA) in European ancestry patients with relapsing-remitting MS (RRMS). METHODS:After harmonization and quality control, we tested over 6 million genetic variants. We used negative binomial regression, meta-analysis, and gene-set enrichment to link variants, genes, and biological pathways to treatment response. RESULTS:In 679 GA and 1614 IFN-β patients, the top GA variant was rs2053696A in MAP3 K1 (p = 3.97*10-9), involved in key signaling pathways. Another significant GA signal was in WWOX. For IFN-β, no genome-wide significant variants were found, but suggestive signals emerged near ZMIZ1, ZCCHC7, and other genes linked to immune function and interferon signaling. Gene-set analysis revealed IL-17 regulation for GA and ion channel pathways for IFN-β. CONCLUSION:This study identified novel genetic variants for GA response, implicating genes in crucial pathways. For IFN-β, suggestive signals point to immune and interferon-related genes. These findings enhance our understanding of genetic influences on RRMS treatment response, while highlighting pharmacogenomic research challenges.
Efforts to translate advances in immunology into anti-cancer immunotherapies have progressed rapidly in recent years. Six antibodies acting on programmed death ligand 1 or programmed death 1 pathways were approved in 75 cancer indications between 2015 and 2021. Several of these therapies were granted accelerated approval for specific cancer indications based on evidence from single-arm phase II clinical trials. In the absence of randomization, however, patient prognosis for progression-free and overall survival may not have been studied under standard chemotherapies for PD-1 and PD-L1 biomarker subpopulations. In 2021, two immunotherapies were withdrawn from accelerated approval applications for treatment of metastatic urothelial carcinoma after randomized phase III trials failed to demonstrate evidence for survival advantage over standard of care. This re-analysis uses digitized data to quantify PD-L1 heterogeneity in chemotherapy response, extending prior meta-analyses by incorporating digitized data and design simulation. The findings of the IMvigor210 (NCT02108652) and IMvigor211 (NCT02302807) trials of atezolizumab are reviewed to elucidate the statistical implications of PD-L1 subpopulation heterogeneity. To place the findings into the context of external evidence, digitization software is used to combine results from journal articles of eleven trials that assigned metastatic urothelial carcinoma patients to the same chemotherapy agents administered in the IMvigor211 control arm. This article defines the extent to which PD-L1 IC2/3 subpopulations appeared to outperform historical expectations in the IMvigor211 study based on external evidence from digitized data. Given the extent of PD-L1 heterogeneity suggested by this analysis, trial simulation is applied to define the probability that IMvigor211 would have resulted in a positive trial based on its actual design and alternative designs that enrolled more IC2/3 patients or had longer durations.
