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Perturbation of thyroid hormone (T4) synthesis is known to cause numerous developmental, metabolic, and cognitive disorders in humans. Due to species differences in sensitivity to chemical exposures, there is a need for human-based in vitro approaches that recapitulate thyroid cellular architecture and T4 production when screening. To address these limitations, primary human thyrocytes, isolated from healthy adult donor tissues and cryopreserved at passage one (p’1) were characterized for cellular composition, 3D follicular architecture, and thyroglobulin (TG)/T4 expression and inhibition by prototype thyroid disrupting chemicals (TDC). Flow analysis of the post-thaw cell suspension showed >80% EpCAM-positive cells with 10%–50% CD90-positive cells. When seeded onto 96-well Matrigel®-coated plates and treated with bovine thyroid stimulating hormone (TSH), thyrocytes formed 3D microtissues during the initial 4–5 days of culture. The microtissues exhibited a stable morphology and size over a 14-day culture period. TG and T4 production were highest in microtissues when the proportion of CD90-positive cells, seeding density and thyroid stimulating hormone concentrations were between 10%–30%, 6K–12K cells per well, and 0.03–1 mIU/mL, respectively. At maximal TG and T4 production levels, average microtissue diameters ranged between 50 and 200 µm. The T4 IC50 values for two prototype TPO inhibitors, 6-propyl-2-thiouracil and methimazole, were ∼0.7 µM and ∼0.5 µM, respectively, in microtissue cultures treated between days 9 and 14. Overall, p’1 cryopreserved primary human thyrocytes in 3D microtissue culture represent a promising new model system to prioritize potential TDC acting directly on the thyroid as part of a weight-of-evidence hazard characterization.

Abstract Glaucoma is a multifactorial neurodegenerative disease characterized by the progressive and irreversible degeneration of the optic nerve and retinal ganglion cells. Despite medical advances aiming at slowing degeneration, around 40% of treated glaucomatous patients will undergo vision loss. It is thus of utmost importance to have a better understanding of the disease and to investigate more deeply its early causes. The transcriptional coactivator YAP, an important regulator of eye homeostasis, has recently drawn attention in the glaucoma research field. Here we show that Yap conditional knockout mice (Yap cKO), in which the deletion of Yap is induced in both Müller glia (i.e. the only retinal YAP-expressing cells) and the non-pigmented epithelial cells of the ciliary body, exhibit a breakdown of the aqueous-blood barrier, accompanied by a progressive collapse of the ciliary body. A similar phenotype is observed in human samples that we obtained from patients presenting with uveitis. In addition, aged Yap cKO mice harbor glaucoma-like features, including deregulation of key homeostatic Müller-derived proteins, retinal vascular defects, optic nerve degeneration and retinal ganglion cell death. Finally, transcriptomic analysis of Yap cKO retinas pointed to early-deregulated genes involved in extracellular matrix organization potentially underlying the onset and/or progression of the observed phenotype. Together, our findings reveal the essential role of YAP in preserving the integrity of the ciliary body and retinal ganglion cells, thereby preventing the onset of uveitic glaucoma-like features.

Purpose: Breast cancer is a significant global health issue, contributing to 15% of cancer-related deaths. Our laboratory has pioneered a novel approach, combining Ayurvedic principles with green nanotechnology, to develop a scientifically rigorous medical modality referred to as Nano-Ayurvedic Medicine, recently approved by the US Patents and Trademarks Office. Here in we report a new Nano-Ayurvedic medicine agent derived from gold nanoparticles encapsulated with phytochemicals from Ginkgo biloba plant (GB-AuNPs)., Methods: We have developed biocompatible gold nanoparticles using electron-rich phytochemicals from Ginkgo biloba as reducing agent cocktail. Ginkgo biloba phytochemical-encapsulated gold nanoparticles (GB-AuNPs) were fully characterized, and their anticancer activity, including immunomodulatory profiles, were evaluated against breast (MDAMB-231) cancer cell lines., Results: Characterization revealed spherical morphology for GB-AuNPs and possessed optimum in vitro stability through high zeta potential of -34 mV for optimum in vivo stability. The core size of GB-AuNPs of 19 nm allows for penetration into tumor cells through both EPR effects as well as through the receptor-mediated endocytosis. The Antitumor efficacy of this nano-ayurvedic medicine agent revealed strong antitumor effects of GB-AuNPs towards MDAMB-231. Our investigations reveal that GB-AuNPs enhance anti-tumor cytokines (IL-12, TNF-α, IFN-γ) and reduce pro-tumor cytokines (IL-10, IL-6), promoting the conversion of protumor M2 macrophages into M1-like macrophage antitumor phenotype. Cellular studies show that GB-AuNPs offer superior anti-tumor efficacy and a better safety profile against breast tumors compared to cisplatin., Conclusion: Our investigations have demonstrated that the nano-ayurvedic medicine agent, GB-AuNPs, treats cancers through an immunomodulatory mechanism facilitated by elevated levels of anti-tumor cytokines (TNF-α, IFN-γ and IL-12) with concomitant downregulation of pro-tumor cytokines expression (IL-6 and IL-10). The green nanotechnology approach for the development of nano-ayurvedic medicine agent (GB-AuNPs), as described in this paper, presents new and attractive opportunities for treating human cancers and other debilitating diseases and disorders., Competing Interests: The authors (s) report no conflicts of interest., (© 2024 Thipe et al.)

Virulence of apicomplexan parasites is based on their ability to divide rapidly to produce significant biomass. The regulation of their cell cycle is therefore key to their pathogenesis. Phosphorylation is a crucial posttranslational modification that regulates many aspects of the eukaryotic cell cycle. The phosphatase PP1 is known to play a major role in the phosphorylation balance in eukaryotes. We explored the role of TgPP1 during the cell cycle of the tachyzoite form of the apicomplexan parasite Toxoplasma gondii. Using a conditional mutant strain, we show that TgPP1 regulates many aspects of the cell cycle including the proper assembly of the daughter cells' inner membrane complex (IMC), the segregation of organelles, and nuclear division. Unexpectedly, depletion of TgPP1 also results in the accumulation of amylopectin, a storage polysaccharide that is usually found in the latent bradyzoite form of the parasite. Using transcriptomics and phospho-proteomics, we show that TgPP1 mainly acts through posttranslational mechanisms by dephosphorylating target proteins including IMC proteins. TgPP1 also dephosphorylates a protein bearing a starch-binding domain. Mutagenesis analysis reveals that the targeted phospho-sites are linked to the ability of the parasite to regulate amylopectin steady-state levels. Therefore, we show that TgPP1 has pleiotropic roles during the tachyzoite cell cycle regulation, but also regulates amylopectin accumulation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Khelifa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Many citizen scientists are highly motivated to help address the current extinction crisis. Their work is making valuable contributions to protecting species by raising awareness, identifying species occurrences, assessing population trends, and informing direct management actions, such as captive breeding. However, clear guidance is lacking about how to use existing citizen science data sets and how to design effective citizen science programs that directly inform extinction risk assessments and resulting conservation actions based on the International Union for Conservation of Nature (IUCN) Red List criteria. This may be because of a mismatch between what citizen science can deliver to address extinction risk and the reality of what is needed to inform threatened species listing based on IUCN criteria. To overcome this problem, we examined each IUCN Red List criterion (A-E) relative to the five major types of citizen science outputs relevant to IUCN assessments (occurrence data, presence-absence observations, structured surveys, physical samples, and narratives) to recommend which outputs are most suited to use when applying the IUCN extinction risk assessment process. We explored real-world examples of citizen science projects on amphibians and fungi that have delivered valuable data and knowledge for IUCN assessments. We found that although occurrence data are routinely used in the assessment process, simply adding more observations of occurrence from citizen science information may not be as valuable as inclusion of more nuanced data types, such as presence-absence data or information on threats from structured surveys. We then explored the characteristics of citizen science projects that have already delivered valuable data to support assessments. These projects were led by recognized experts who champion and validate citizen science data, thereby giving greater confidence in its accuracy. We urge increased recognition of the value of citizen science data within the assessment process., (© 2024 The Author(s). Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)

As people age, there is a natural decline in cognitive functioning and brain structure. However, the relationship between brain function and cognition in older adults is neither straightforward nor uniform. Instead, it is complex, influenced by multiple factors, and can vary considerably from one person to another. Reserve, compensation, and maintenance mechanisms may help explain why some older adults can maintain high levels of performance while others struggle. These mechanisms are often studied concerning memory and executive functions that are particularly sensitive to the effects of aging. However, language abilities can also be affected by age, with changes in production fluency. The impact of brain changes on language abilities needs to be further investigated to understand the dynamics and patterns of aging, especially successful aging. We previously modeled several compensatory profiles of language production and lexical access/retrieval in aging within the Lexical Access and Retrieval in Aging (LARA) model. In the present paper, we propose an extended version of the LARA model, called LARA-Connectivity (LARA-C), incorporating recent evidence on brain connectivity. Finally, we discuss factors that may influence the strategies implemented with aging. The LARA-C model can serve as a framework to understand individual performance and open avenues for possible personalized interventions., (© 2024 The Authors. Topics in Cognitive Science published by Wiley Periodicals LLC on behalf of Cognitive Science Society.)

Vascular endothelial dysfunction is a major risk factor in the development of renal diseases. Recent studies pointed out a major interest for the inter-endothelial junction protein CD146, as its expression is modulated during renal injury. Indeed, some complex mechanisms involving this adhesion molecule and its multiple ligands are observed in a large number of renal diseases in fundamental or clinical research. The purpose of this review is to summarize the most recent literature on the role of CD146 in renal pathophysiology, from experimental nephropathy to clinical trials., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Obstructive sleep apnea-hypopnea (OSAH) is common in MS patients and is associated with fatigue. We recently published a randomized, controlled trial (RCT) of active vs sham continuous positive airway pressure (CPAP) treatment in MS patients with fatigue, poor sleep quality, and (OSAH) (Mult Scl J 2022;28:82-92). Our aim was to evaluate the long-term effects of CPAP treatment on fatigue (Fatigue Severity Scale, FSS, primary outcome) and other clinical outcomes in MS patients with OSAH., Methods: Following the RCT, participants were offered treatment with CPAP and participation in an open label study. Patients were re-evaluated with RCT outcome measures at least 6 months after completion of the RCT., Results: Twenty-eight of 34 (82 %) RCT-completers participated in this study a mean of 2.7 years after the RCT. Sixteen (57 %) patients were treated with CPAP (mean use 5.4 ± 1.0 h/night during the 6 months prior to follow-up visit), while the other 12 patients declined CPAP use and received no other OSAH treatments. Baseline clinical characteristics, including MS related disability and sleep outcomes, were not significantly different between CPAP-treated vs non-CPAP treated patients. Patients using CPAP at follow-up (n = 16) demonstrated significant improvements from RCT baseline in FSS (p = 0.005), Fatigue Scale for Motor and Cognitive Functions (p = 0.008, p = 0.012), Pittsburgh Sleep Quality Index (p = 0.016), Center of Epidemiological Studies-Depression Scale (p = 0.05), and Multiple Sclerosis Quality of Life-54 (MSQOL-54) physical and mental component scores (p = 0.012, p = 0.023), but no improvements in Epworth Sleepiness Scale, Pain Visual Analog Scale, or Expanded Disability Status Scale. Patients not using CPAP (n = 12) had no significant improvements in outcome measures. Using a linear mixed model, FSS (p = 0.03), morning fatigue (p = 0.048), and MSQOL-54 physical component score (p = 0.02) improved significantly in CPAP treated patients compared with non-CPAP treated patients from RCT baseline., Conclusion: In this post-RCT open label study, long-term CPAP use was associated with improved fatigue (FSS, our primary outcome) and physical quality of life in MS patients with OSAH., Competing Interests: Declaration of Competing Interest The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MM, SK PD, YL, AB, KM, ER, AB-O, and GL have nothing to disclose. RJK received and receives operating research support from the Multiple Sclerosis Society of Canada, the Canadian Institutes of Health Research, the Fonds de Recherche du Québec-Santé, and in-kind research support from VitalAire Inc. and Philips Respironics. VJ declares that the Sleep Laboratory where he works has received non-restrictive research grants from Biron and Pradair Laboratories. MK reports Advisory Committee membership at Biron Soins du Sommeil, and research support from Philips, the Canadian Institute of Health Research and the Weston Brain Institute. DAT received operating research support from the Multiple Sclerosis Society of Canada and in-kind research support from VitalAire Inc. and Philips Respironics., (Copyright © 2023. Published by Elsevier B.V.)