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Summary: Regulatory T (Treg) cells represent an essential component of peripheral tolerance. Given their potently immunosuppressive functions that is orchestrated by the lineage‐defining transcription factor forkhead box protein 3 (FoxP3), clinical modulation of these cells in autoimmunity and cancer is a promising therapeutic target. However, recent evidence in mice and humans indicates that Treg cells represent a phenotypically and functionally heterogeneic population. Indeed, both suppressive and non‐suppressive Treg cells exist in human blood that are otherwise indistinguishable from one another using classical Treg cell markers such as CD25 and FoxP3. Moreover, murine Treg cells display a degree of plasticity through which they acquire the trafficking pathways needed to home to tissues containing target effector T (Teff) cells. However, this plasticity can also result in Treg cell lineage instability and acquisition of proinflammatory Teff cell functions. Consequently, these dysfunctional CD4+FoxP3+ T cells in human and mouse may fail to maintain peripheral tolerance and instead support immunopathology. The mechanisms driving human Treg cell dysfunction are largely undefined, and obscured by the scarcity of reliable immunophenotypical markers and the disregard paid to Treg cell antigen‐specificity in functional assays. Here, we review the mechanisms controlling the stability of the FoxP3+ Treg cell lineage phenotype. Particular attention will be paid to the developmental and functional heterogeneity of human Treg cells, and how abrogating these mechanisms can lead to lineage instability and Treg cell dysfunction in diseases like immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, type 1 diabetes, rheumatoid arthritis and cancer. [ABSTRACT FROM AUTHOR]

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.)

Aim: To investigate the dynamics of the motor control system during walking by examining the complexity, stability, and causal relationships of leg motions. Specifically, the study focuses on gait under both bilateral and unilateral constraints induced by a passive exoskeleton designed to replicate gastrocnemius contractures., Methods: Kinematic data was collected as 10 healthy participants walked at a self-selected speed. A new Complexity-Instability Index (CII) of the leg motions was defined as a function of the Correlation Dimension and the Largest Lyapunov Exponent. Causal interactions between the leg motions are explored using Convergent Cross Mapping., Results: Normal walking is characterized by a high mutual drive of each leg to the other, where CII is lowest for both legs (complexity of each leg motion is low and stability high). The effect of the bilateral emulated contractures is a reduced drive of each leg to the other and an increased CII for both legs. With unilateral emulated contracture, the mechanically constrained leg strongly drives the unconstrained leg, and CII was significantly higher for the constrained leg compared to normal walking., Conclusion: Redundancy in limb motions is used to support causal interactions, reducing complexity and increasing stability in our leg dynamics during walking. The role of redundancy is to allow adaptability above being able to satisfy the overall biomechanical problem; and to allow the system to interact optimally. From an applied perspective, important characteristics of functional movement patterns might be captured by these nonlinear and causal variables, as well as the biomechanical aspects typically studied., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Williams, Vicinanza, Attias and Armand.)

Objective: To evaluate the efficacy of recombinant psoriasin as a novel treatment for oral candidiasis by eliminating Candida albicans growth on polymethyl methacrylate denture base., Materials and Methods: Recombinant psoriasin protein was expressed and purified from E. coli, and Candida growth was monitored in vitro with varying concentrations of psoriasin. Subsequently, denture-base polymethyl methacrylate was immersed in psoriasin's solution or voriconazole, and fungal growth on the acrylic base and in the medium was examined by scanning electron microscopy and optical density, respectively. Cellular viability of HeLa and human gingival fibroblast cells treated with psoriasin was measured by methylene blue assay., Results: The findings reveal an effective antifungal activity of psoriasin, completely inhibiting Candida albicans growth in RPMI at a protein concentration above 400 nM. Immersing the polymethyl methacrylate with 50 μM psoriasin completely eradicates fungal growth. Psoriasin has low cytotoxicity in HeLa cells at a concentration higher than 12 μM and no toxic effect on human gingival fibroblasts., Conclusions: This study marks psoriasin as an effective alternative to conventional antifungal treatments for denture stomatitis and a safe alternative to chemical antifungals in dental medicine and beyond., (© 2024 The Author(s). Oral Diseases published by John Wiley & Sons Ltd.)

Endosymbionts (Symbiodiniaceae) play a vital role in the health of corals. Seawater pollution can harm these endosymbionts and dispersants used during oil spill cleanup can be extremely toxic to these organisms. Here, we examined the impact of oil and a specific dispersant, Corexit-9500, on two representative endosymbionts - Symbiodinium and Cladocopium - from the Southwestern endemic coral Mussismilia braziliensis. The survival and photosynthetic potential of the endosymbionts decreased dramatically after exposure to the dispersant and oil by ~25 % after 2 h and ~50 % after 7 days. Low concentrations of dispersant (0.005 ml/l) and dispersed oil (Polycyclic Aromatic Hydrocarbons, 1132 μg/l; Total Petroleum Hydrocarbons, 595 μg/l) proved highly toxic to both Symbiodinium and Cladocopium. These levels triggered a reduction in growth rate, cell size, and cell wall thickness. After a few hours of exposure, cellular organelles were damaged or destroyed. These acute toxic effects underline the fragile nature of coral endosymbionts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Immune checkpoint inhibitors (ICIs) have been a breakthrough in cancer therapy, inducing durable remissions in responding patients. However, they are associated with variable outcomes, spanning from disease hyperprogression to complete responses with the onset of immune-related adverse events. The consequences of checkpoint inhibition on Foxp3 + regulatory T (T reg ) cells remain unclear but could provide key insights into these variable outcomes. In this review, we first cover the mechanisms that underlie the development of hot and cold tumour microenvironments, which determine the efficacy of immunotherapy. We then outline how differences in tumour-intrinsic immunogenicity, T-cell trafficking, local metabolic environments and inhibitory checkpoint signalling differentially impair CD8 + T-cell function in tumour microenvironments, all the while promoting T reg -cell suppressive activity. Finally, we focus on the mechanisms that enable the induction of polyfunctional CD8 + T-cells upon checkpoint blockade and discuss the role of ICI-induced T reg -cell reactivation in acquired resistance to treatment., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Mollusc rearing is a relevant global socioeconomic activity. However, this activity has faced severe problems in the last years in southeast Brazil. The mariculture scallop production dropped from 51,2 tons in 2016 to 10,2 tons in 2022 in the Baia da Ilha Grande (BIG; Rio de Janeiro). However, the possible causes of this collapse are unknown. This study aimed to analyze decadal trends of water quality in Nodipecten nodosus spat and adult production in BIG. We also performed physical-chemical and biological water quality analyses of three scallop farms and two nearby locations at BIG in 2022 to evaluate possible environmental stressors and risks. Scallop spat production dropped drastically in the last five years (2018-2022: mean ± stdev: 0.47 ± 0.45 million). Spat production was higher in colder waters and during peaks of Chlorophyll a in the last 13 years. Reduction of Chlorophyll a coincided with decreasing spat production in the last five years. Warmer periods (>27 °C) of the year may hamper scallop development. Counts of potentially pathogenic bacteria (Vibrios) and Escherichia coli were significantly higher in warmer periods which may further reduce scallop productivity. Shotgun metagenomics of seawater samples from the five studied corroborated these culture-based counts. Vibrios and fecal indicator bacteria metagenomic sequences were abundant across the entire study area throughout 2022. The results of this study suggest the collapse of scallop mariculture is the result of a synergistic negative effect of global warming and poor seawater quality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The Leadership in Emergencies learning programme, launched in 2019, was designed to strengthen the competencies of World Health Organization (WHO) and Member State staff in teamwork, decision-making and communication, key skills required to lead effectively in emergencies. While the programme was initially used to train 43 staff in a workshop setting, the COVID-19 pandemic required a new remote approach. An online learning environment was developed using a variety of digital tools including WHO's open learning platform, OpenWHO.org. The strategic use of these technologies enabled WHO to dramatically expand access to the programme for personnel responding to health emergencies in fragile contexts and increase participation among key groups that were previously underserved.

Recovery of function is among a patient's main expectations when undergoing total knee arthroplasty (TKA). However, normal gait knee function is not always completely restored, which can affect patient satisfaction and quality of life. Computer-assisted surgery (CAS) allows surgeons to evaluate passive knee kinematics intra-operatively. Understanding associations between knee kinematics measured during surgery and during daily activities, such as walking, could help define criteria for success based on knee function and not only on the correct alignment of the implant or the leg. This preliminary study compared passive knee kinematics measured during surgery with active kinematics measured during walking. Eight patients underwent a treadmill gait analysis using the KneeKG™ system both before surgery and three months afterwards. Knee kinematics were measured during CAS both before and after TKA implantation. The anatomical axes of the KneeKG™ and CAS systems were homogenised using a two-level, multi-body kinematics optimisation with a kinematic chain based on the calibration measured during CAS. A Bland-Altman analysis was performed before and after TKA for adduction-abduction angle, internal-external rotation, and anterior-posterior displacement over the whole gait cycle, at the single stance phase and at the swing phase. Homogenising the anatomical axes between CAS and treadmill gait led to limited median bias and limits of agreement (post-surgery -0.6 ± 3.6 deg, -2.7 ± 3.6 deg, and -0.2 ± 2.4 mm for adduction-abduction, internal-external rotation and anterior-posterior displacement, respectively). At the individual level, correlations between the two systems were mostly weak (R2 < 0.3) over the whole gait cycle, indicating low kinematic consistency between the two measurements. However, correlations were better at the phase level, especially the swing phase. The multiple sources of differences did not enable us to conclude whether they came from anatomical and biomechanical differences or from measurement system errors., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Hermes Miozzari is an associate editor for EFORT Open Reviews and a board member of Swiss Orthopaedics. Stéphane Armand is a member of the editorial board of EFORT Open Reviews. There are no competing interests associated with this research., (Copyright: © 2023 Gasparutto 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.)

Breast cancer (BCa) is the most prevalent cancer in females and has a high rate of mortality, especially due to increased metastasis to skeletal and non-skeletal sites. Despite the marked clinical accomplishment of immune checkpoint inhibitor (CPI) therapy in patients with several cancers, it has had limited success in luminal subtypes of BCa. Accordingly, recent efforts have focused on combination therapy with CPI, including epigenetic modulators, to increase response rates of CPI in luminal BCa. We have previously shown that S-adenosylmethionine (SAM), the ubiquitous methyl donor, has strong anti-cancer effects in various cancers, including all subtypes of BCa. In the current study, we took a novel approach and examined the effect of CPI alone and in combination with SAM on tumor growth and metastasis in a syngeneic mouse model of luminal B BCa. We showed that SAM decreases cell proliferation, colony-formation (survival), and invasion of luminal B BCa cell lines (Eo771, R221A) in vitro. In in vivo studies, in Eo771 tumor-bearing mice, either SAM or anti-PD-1 antibody treatment alone significantly reduced tumor growth and progression, while the SAM+anti-PD-1 combination treatment had the highest anti-cancer efficacy of all groups. The SAM+anti-PD-1 combination reduced the percentage of animals with lung metastasis, as well as total metastatic lesion area, compared to control. Additionally, the SAM+anti-PD-1 combination significantly reduced the skeletal lesion area and protected tibial integrity to a greater extent than the monotherapies in an Eo771 bone metastasis model. Transcriptome analysis of Eo771 primary tumors revealed significant downregulation of pro-metastatic genes, including Matrix metalloproteinases (MMPs) and related pathways. On the other hand, CD8 + T cell infiltration, CD8 + T cell cytotoxicity (elevated granzymes), and immunostimulatory genes and pathways were significantly upregulated by the combination treatment. The results presented point to a combination of SAM with CPI as a possible treatment for luminal B BCa that should be tested in clinical studies.