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Aloe vera, renowned for its medicinal and food applications, offers a sustainable, scalable, and cost-effective scaffold material for cultured meat production. Our method repurposes Aloe vera parenchyma into a sustainable and innovative scaffold for CM production. These scaffolds, derived from agricultural byproducts, feature a porous structure that retains liquids and supports bovine mesenchymal stem cell (bMSC) adhesion, proliferation, and extracellular matrix formation. By incorporating oleic acid, the scaffolds enable the accumulation of fat-like tissue, creating "lipid chunks" that can enhance the texture and flavor profile of plant-based meat alternatives. Furthermore, scalability is addressed by culturing the scaffolds in a macrofluidic single-use bioreactor (MSUB), showcasing the potential for large-scale production. This work demonstrates Aloe vera scaffold's versatility as a cost-effective material and highlights its promise for sustainable protein solutions and tissue engineering applications., Competing Interests: Competing interests: The authors declare no competing interests. The funders had no role in the study’s design, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results. All authors of this publication have provided their consent for its publication. The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors., (© 2025. The Author(s).)

Liver cancer poses a global health challenge with limited therapeutic options. Notably, the limited success of current therapies in patients with primary liver cancers (PLCs) may be attributed to the high heterogeneity of both hepatocellular carcinoma (HCCs) and intrahepatic cholangiocarcinoma (iCCAs). This heterogeneity evolves over time as tumor-initiating stem cells, or cancer stem cells (CSCs), undergo (epi)genetic alterations or encounter microenvironmental changes within the tumor microenvironment. These modifications enable CSCs to exhibit plasticity, differentiating into various resistant tumor cell types. Addressing this challenge requires urgent efforts to develop personalized treatments guided by biomarkers, with a specific focus on targeting CSCs. The lack of effective precision treatments for PLCs is partly due to the scarcity of ex vivo preclinical models that accurately capture the complexity of CSC-related tumors and can predict therapeutic responses. Fortunately, recent advancements in the establishment of patient-derived liver cancer cell lines and organoids have opened new avenues for precision medicine research. Notably, patient-derived organoid (PDO) cultures have demonstrated self-assembly and self-renewal capabilities, retaining essential characteristics of their respective in vivo tissues, including both inter- and intratumoral heterogeneities. The emergence of PDOs derived from PLCs serves as patient avatars, enabling preclinical investigations for patient stratification, screening of anticancer drugs, efficacy testing, and thereby advancing the field of precision medicine. This review offers a comprehensive summary of the advancements in constructing PLC-derived PDO models. Emphasis is placed on the role of CSCs, which not only contribute significantly to the establishment of PDO cultures but also faithfully capture tumor heterogeneity and the ensuing development of therapy resistance. The exploration of PDOs' benefits in personalized medicine research is undertaken, including a discussion of their limitations, particularly in terms of culture conditions, reproducibility, and scalability., Competing Interests: Declarations. Funding: Open access funding provided by Université Paris-Saclay. This work is part of the PREMELICAN (Precision Medicine in Liver Cancer) project, supported by funding from AP-HP Carnot Institute. Conflict of interest: Julien Giron-Michel, Maël Padelli, Estelle Oberlin, Hind Guenou, and Jean-Charles Duclos-Vallée have no conflicts of interest that are directly relevant to the content of this article. Ethics approval: No ethics approval was required. Consent to participate: Not applicable. Consent for publication: Not applicable. Availability of data and materials: All data represented are available in the public domain. Code availability: Not applicable. Author contributions: J.G.M. wrote the manuscript and designed the figures; J.G.M., M.P., E.O., H.G., and J.C.D.V. edited the manuscript. All authors read and approved the final manuscript., (© 2025. The Author(s).)

Leishmania is responsible for a neglected tropical disease affecting millions of people around the world and could potentially spread more due to climate change. This disease not only leads to significant morbidity but also imposes substantial social and economic burdens on affected populations, often exacerbating poverty and health disparities. Despite the complexity and effectiveness of the immune response, the parasite has developed various strategies to evade detection and manipulates host cells in favor of its replication. These evasion strategies start at early stages of the infection by hijacking immune receptors to silence critical cellular response that would otherwise limit the pathogen's propagation. Among these receptors, Fc receptors have emerged as a significant player in the immune evasion strategies employed by microorganisms, as they could promote inhibitory pathways. This review explores the potential role of one of these immune receptors, the FcγRIIA, in leishmaniasis and how this parasite may use it and the signaling pathways downstream to evade the host immune response. By understanding the potential interactions between Leishmania and immune receptors such as FcγRIIA, we may identify novel targets for therapeutic intervention aimed to enhance the host immune response and reduce the burden of this disease., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Leishmania is the causal parasite of leishmaniasis, a neglected tropical disease affecting millions of individuals worldwide, and its dissemination is linked to climate change. Despite the complexity and effectiveness of the immune response, the parasite has developed many strategies to evade it and take control of the host cell to replicate. These evasion strategies start at early stages of infection by hijacking immune receptors to mitigate the cellular response. In this study, we examined whether Leishmania uses the Fc receptor FcγRIIA/CD32a and its downstream signaling pathways to evade the host immune response., Methods: Regarding in vivo studies, CD32a transgenic mice and the corresponding wild types were infected with Leishmania major Friedlin strain. For the in vitro experiments, BMDMs isolated from WT or CD32a transgenic mice and control or CD32a knockdown differentiated THP-1s were infected with two species of Leishmania, Leishmania major and L. tropica., Results: In vivo, expression of FcγRIIA/CD32a was found to accelerate the signs of inflammation while simultaneously preventing the formation of necrotic lesions after Leishmania infection. In infected macrophages, the presence of FcγRIIA/CD32a did not affect the secretion of proinflammatory cytokines, while the balance between ITAMa and ITAMi proteins was disturbed with improved Fyn and Lyn activation. Unexpectedly, infection with L. tropica but not L. major triggered an intracytoplasmic processing of FcγRIIA/CD32a., Conclusions: Our observations underscore the significance of FcγRIIA/CD32a in cutaneous leishmaniasis and its potential use as a therapeutic target., Competing Interests: Declarations. Consent for publication: All the authors agree and consent for publication of the results presented in this manuscript. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

There are currently 1.2 million people living with HIV (Human Immunodeficiency Virus) in the United States. Virally suppressed HIV patients commonly experience chronic inflammation which increases the risk for other chronic conditions. This inflammation can be quantified with a variety of biomarkers. Some current antiretroviral compounds bring about metabolic abnormalities and promote weight gain often associated with increases in visceral adipose tissue (VAT) and an increase in the risk of diabetes mellitus and cardiovascular disease. Sulforaphane, an isothiocyanate found in cruciferous vegetables, has shown efficacy in animal models by reducing lipid levels, lowering inflammatory markers, and decreasing fat mass. A double-blind randomized controlled pilot study with 14 virally suppressed HIV patients was conducted to evaluate the effects of 40 mg (225 μmol) of sulforaphane, once daily, over 12 weeks, followed by a 4-week washout period. There was a significant decrease in C-reactive protein compared to the control group ( p  = 0.019). Sulforaphane has been studied in a multitude of conditions and diseases, but this is the first study in a human population of patients living with HIV., 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 Giron, Smiarowski and Katz.)

Self-assembly of biological elements into biomimetic cargo carriers for targeting and delivery is a promising approach. However, it still holds practical challenges. We developed a functionalization approach of DNA origami (DO) nanostructures with neuronal growth factor (NGF) for manipulating neuronal systems. NGF bioactivity and its interactions with the neuronal system were demonstrated in vitro and in vivo models. The DO elements fabricated by molecular self-assembly have manipulated the surrounding environment through static spatially and temporally controlled presentation of ligands to the cell surface receptors. Our data showed effective bioactivity in differentiating PC12 cells in vitro. Furthermore, the DNA origami NGF (DON) affected the growth directionality and spatial capabilities of dorsal root ganglion neurons in culture by introducing a chemotaxis effect along a gradient of functionalized DO structures. Finally, we showed that these elements provide enhanced axonal regeneration in a rat sciatic nerve injury model in vivo. This study is a proof of principle for the functionality of DO in neuronal manipulation and regeneration. The approach proposed here, of an engineered platform formed out of programmable nanoscale elements constructed of DO, could be extended beyond the nervous system and revolutionize the fields of regenerative medicine, tissue engineering, and cell biology., (© 2024 The Authors. Biotechnology Journal published by Wiley‐VCH GmbH.)

Reducing production costs, known as scaling, is a significant obstacle in the advancement of cultivated meat. The cultivation process hinges on several key components, e.g., cells, media, scaffolds, and bioreactors. This study demonstrates an innovative approach, departing from traditional stainless steel or glass bioreactors, by integrating food-grade plant-based scaffolds and thermoplastic film bioreactors. While thermoplastic films are commonly used for constructing fluidic systems, conventional welding methods are cost-prohibitive and lack rapid prototyping capabilities, thus inflating research and development expenses. The developed laser welding technique facilitates contamination-free and leakproof sealing of polyethylene films, enabling the efficient fabrication of macrofluidic systems with various designs and dimensions. By incorporating food-grade plant-based scaffolds, such as rice seeded with bovine mesenchymal stem cells, into these bioreactors, this study demonstrates sterile cell proliferation on scaffolds within macrofluidic systems. This approach not only reduces bioreactor prototyping and construction costs but also addresses the need for scalable solutions in both research and industrial settings. Integrating single-use bioreactors with minimal shear forces and incorporating macro carriers such as puffed rice may further enhance biomass production in a scaled-out model. The use of food-grade plant-based scaffolds aligns with sustainable practices in tissue engineering and cultured-meat production, emphasizing its suitability for diverse applications.

The emergence of autonomous vehicles (AVs) marks a transformative leap in transportation technology. Central to the success of AVs is ensuring user safety, but this endeavor is accompanied by the challenge of establishing trust and acceptance of this novel technology. The traditional "one size fits all" approach to AVs may limit their broader societal, economic, and cultural impact. Here, we introduce the Persona-PhysioSync AV (PPS-AV). It adopts a comprehensive approach by combining personality traits with physiological and emotional indicators to personalize the AV experience to enhance trust and comfort. A significant aspect of the PPS-AV framework is its real-time monitoring of passenger engagement and comfort levels within AVs. It considers a passenger's personality traits and their interaction with physiological and emotional responses. The framework can alert passengers when their engagement drops to critical levels or when they exhibit low situational awareness, ensuring they regain attentiveness promptly, especially during Take-Over Request (TOR) events. This approach fosters a heightened sense of Human-Vehicle Interaction (HVI), thereby building trust in AV technology. While the PPS-AV framework currently provides a foundational level of state diagnosis, future developments are expected to include interaction protocols that utilize interfaces like haptic alerts, visual cues, and auditory signals. In summary, the PPS-AV framework is a pivotal tool for the future of autonomous transportation. By prioritizing safety, comfort, and trust, it aims to make AVs not just a mode of transport but a personalized and trusted experience for passengers, accelerating the adoption and societal integration of autonomous vehicles.

A program for the hematologic patient at very high risk of infections (HAR, from its initials in Spanish) was implemented, based on a multidisciplinary team and six measures intended to reduce the colonization and subsequent sepsis by multidrug-resistant organisms (MDRO). We aimed at evaluating the effectiveness of the HAR program in terms of MDRO infections mainly caused by Klebsiella pneumoniae carbapenemase-producing and multidrug-resistant Pseudomona aeruginosa , and sepsis-related mortality. We established retrospective comparisons between the pre-HAR period (2016-2018) and the post-HAR period (2018-2019), in patients who received a hematopoietic stem cell transplant (HSCT) and/or intensive chemotherapy to treat non-M3 acute myeloid leukemia (CH-AML). We included 262 patients: 176 pre-HAR and 86 post-HAR. MDRO infection was 4.6% at 30 days and 6.1% at 90 days (all the cases during the pre-HAR period). Sepsis-related mortality was 6.5%, considering a median follow-up of 608 days: 6.1% in the HSCT group and 12.4% in the CH-AML group ( p  = 0.306). Sepsis-related mortality was 8.7% in the pre-HAR period and 0% in the post-HAR period ( p  = 0.014). The implementation of this multidisciplinary program based in preventive measures and the appropriate use of antibiotics enabled a decrease in sepsis-related mortality in very high-risk hematologic patients., Competing Interests: Conflict of interestAll authors declare that they have no conflict of interest., (© Indian Society of Hematology and Blood Transfusion 2021.)

Persons living with Human immunodeficiency virus (HIV) are living longer, healthier lives due to advancements in antiretroviral therapies and access to lifelong treatment. Yet, in rural Appalachia, access to adequate medical care is complicated by factors such as geography and lack of access to resources. The purpose of this study was to explore the perceptions of advance care planning (ACP) needs of persons living with HIV (PLWH) in Appalachian Tennessee and Alabama. Using a qualitative-descriptive design, we analyzed patterns of responses to face-to-face, semi-structured interviews of 40 PLWH as part of a larger multi-site mixed method study. Data demonstrated high patient satisfaction with medical care and good relationships with providers. However, common themes arose surrounding stigma, inadequate finances, and dislike of the term "end-of-life." Findings from this study fill a gap in the extant science pertaining to the focus of ACP in the unique population of rural Appalachia.

The World Health Organization (WHO) recommends multidrug therapy (MDT) for the treatment of paucibacillary and multibacillary forms of leprosy, also known as Hansen's disease (HD). MDT combinations of dapsone, rifampin, and clofazimine have reduced the prevalence of the disease but are not without adverse effects impacting regimen adherence. Hence, an urgent need exists to consider alternative MDT regimens with an improved safety profile that promotes treatment adherence. Herein, we described a case series of 10 patients with HD (nine patients with multibacillary leprosy and one with pure neural leprosy) treated with monthly rifampin, moxifloxacin, and minocycline (RMM). The United States National Hansen's Disease Program (NHDP) diagnosed and treated patients across US institutions. All patients received a regimen of 12-24 months of RMM. We reviewed the clinical outcomes, adherence, rate of completion, and adverse events of patients treated with monthly RMM from January 2019 to August 2022. Nine patients had multibacillary leprosy, with some having type-2 reactions. One patient had pure neural leprosy with a reversal reaction. In this case series, we identified that all patients completed the RMM regimen without treatment interruptions. None of the patients experienced any skin hyperpigmentation or any significant side effects. All patients tolerated the monthly RMM regimen with rapid improvement of skin lesions and without logistic hurdles. Based on previous clinical evidence and the results of this case series, the NHDP and other programs should consider the RMM regimen as first-line therapy., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Henao-Martínez reported receiving a K12-clinical trial award as a co-principal investigator for the Expanded Access IND Program (EAP) to provide the Yellow Fever vaccine (Stamaril) to persons in the United States outside the submitted work. The Editor-in-Chief of Therapeutic Advances in Infectious Disease is an author of this paper, therefore, the peer review process was managed by alternative members of the Board and the submitting Editor had no involvement in the decision-making process. No other disclosures were reported., (© The Author(s), 2022.)

The International Classification of Functionality (CIF) defines mobility as the possibility of "moving by changing the position or location of the body or moving from one place to another, transporting, moving or manipulating objects, walking, running or climbing, and using various forms of transport". Physical therapy focuses on the assessment and management of movement problems. Determining mobility status is a central component of the health assessment of older adults since it is an important marker of physical abilities and independence, and a predictor of morbidity and mortality. However, to date we did not have scales that represent the degree of mobility of the patient with some type of visual image that facilitates its documentation quickly and reliably by any health professional who works in the field of hospitalization. For these reasons, we developed an intuitive, icon-based mobility scale that is easy to administer in hospitalized patients in different settings. The ProMover mobility scale provides health professionals with a unified tool for evaluating the mobility of hospitalized patients, in order to unify a common language. This is a simple, practical, reliable and objective tool and commonly used by all health professionals.

Manipulating sensory and motor cues can cause an illusionary perception of ownership of a fake body part. Presumably, the illusion can work as long as the false body part's position and appearance are anatomically plausible. Here, we introduce an illusion that challenges past assumptions on body ownership. We used virtual reality to switch and mirror participants' views of their hands. When a participant moves their physical hand, they see the incongruent virtual hand moving. The result is an anatomically implausible configuration of the fake hand. Despite the hand switch, participants reported significant body ownership sensations over the virtual hands. In the first between-group experiment, we found that the strength of body ownership over the incongruent hands was similar to that of congruent hands. Whereas, in the second within-group experiment, anatomical incongruency significantly decreased body ownership. Still, participants reported significant body ownership sensations of the switched hands. Curiously, we found that perceived levels of agency mediate the effect of anatomical congruency on body ownership. These findings offer a fresh perspective on the relationship between anatomical plausibility and assumed body ownership. We propose that goal-directed and purposeful actions can override anatomical plausibility constraints and discuss this in the context of the immersive properties of virtual reality., 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 © 2021 Yizhar, Giron, Wenger, Chetrit, Ostrin, Friedman and Amedi.)

Chronic kidney disease (CKD), secondary to renal fibrogenesis, is a public health burden. The activation of interstitial myofibroblasts and excessive production of extracellular matrix (ECM) proteins are major events leading to end-stage kidney disease. Recently, interleukin-15 (IL-15) has been implicated in fibrosis protection in several organs, with little evidence in the kidney. Since endogenous IL-15 expression decreased in nephrectomized human allografts evolving toward fibrosis and kidneys in the unilateral ureteral obstruction (UUO) model, we explored IL-15's renoprotective role by pharmologically delivering IL-15 coupled or not with its soluble receptor IL-15Rα. Despite the lack of effects on myofibroblast accumulation, both IL-15 treatments prevented tubulointerstitial fibrosis (TIF) in UUO as characterized by reduced collagen and fibronectin deposition. Moreover, IL-15 treatments inhibited collagen and fibronectin secretion by transforming growth factor-β (TGF-β)-treated primary myofibroblast cultures, demonstrating that the antifibrotic effect of IL-15 in UUO acts, in part, through a direct inhibition of ECM synthesis by myofibroblasts. In addition, IL-15 treatments resulted in decreased expression of monocyte chemoattractant protein 1 (MCP-1) and subsequent macrophage infiltration in UUO. Taken together, our study highlights a major role of IL-15 on myofibroblasts and macrophages, two main effector cells in renal fibrosis, demonstrating that IL-15 may represent a new therapeutic option for CKD.

The circadian clock coordinates biological and physiological functions to day/night cycles. The perturbation of the circadian clock increases cancer risk and affects cancer progression. Here, we studied how BMAL1 knockdown (BMAL1-KD) by shRNA affects the epithelial-mesenchymal transition (EMT), a critical early event in the invasion and metastasis of colorectal carcinoma (CRC). In corresponding to a gene set enrichment analysis, which showed a significant enrichment of EMT and invasive signatures in BMAL1_high CRC patients as compared to BMAL1_low CRC patients, our results revealed that BMAL1 is implicated in keeping the epithelial-mesenchymal equilibrium of CRC cells and influences their capacity of adhesion, migration, invasion, and chemoresistance. Firstly, BMAL1-KD increased the expression of epithelial markers (E-cadherin, CK-20, and EpCAM) but decreased the expression of Twist and mesenchymal markers (N-cadherin and vimentin) in CRC cell lines. Finally, the molecular alterations after BMAL1-KD promoted mesenchymal-to-epithelial transition-like changes mostly appeared in two primary CRC cell lines (i.e., HCT116 and SW480) compared to the metastatic cell line SW620. As a consequence, migration/invasion and drug resistance capacities decreased in HCT116 and SW480 BMAL1-KD cells. Together, BMAL1-KD alerts the delicate equilibrium between epithelial and mesenchymal properties of CRC cell lines, which revealed the crucial role of BMAL1 in EMT-related CRC metastasis and chemoresistance.

Dysregulation of the circadian timing system (CTS) frequently appears during colorectal cancer (CRC) progression. In order to better understand the role of the circadian clock in CRC progression, this study evaluated in vitro how knockdown of a core circadian protein BMAL1 (BMAL1-KD) influenced the behavior of two primary human CRC cell lines (HCT116 and SW480) and a metastatic CRC cell line (SW620).Unexpectedly, BMAL1-KD induced CRC cell-type specific responses rather than the same phenomenon throughout. First, BMAL1-KD increased AKT/mTOR activation in each CRC cell line, but to different extents. Second, BMAL1-KD-induced P53 activation varied with cell context. In a wild type P53 background, HCT116 BMAL1-KD cells quickly underwent apoptosis after shBMAL1 lentivirus transduction, while surviving cells showed less P53 but increased AKT/mTOR activation, which ultimately caused higher proliferation. In the presence of a partially functional mutant P53, SW480 BMAL1-KD cells showed moderate P53 and mTOR activation simultaneously with cell senescence. With a moderate increased AKT but unchanged mutant P53 activation, SW620 BMAL1-KD cells grew faster.Thus, under different CRC cellular pathological contexts, BMAL1 knockdown induced relatively equal effects on AKT/mTOR activation but different effects on P53 activation, which finally triggered different CRC cell fates.

Long noncoding RNA molecules (lncRNAs) are estimated to account for the majority of eukaryotic genomic transcripts, and have been associated with multiple diseases in humans. However, our understanding of their structure-function relationships is scarce, with structural evidence coming mostly from indirect biochemical approaches or computational predictions. Here we describe direct visualization of the lncRNA HOTAIR (HOx Transcript AntIsense RNA) using atomic force microscopy (AFM) in nucleus-like conditions at 37°. Our observations reveal that HOTAIR has a discernible, although flexible, shape. Fast AFM scanning enabled the quantification of the motion of HOTAIR, and provided visual evidence of physical interactions with genomic DNA segments. Our report provides a biologically plausible description of the anatomy and intrinsic properties of HOTAIR, and presents a framework for studying the structural biology of lncRNAs., (© 2020 Spokoini-Stern et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Background: Normal aging is associated with balance, mobility and working memory decline that increase fall risk and influence activity of daily living functions. Mounting evidence suggests that physical activity is beneficial for decreasing aging effects. Previous studies have focused on land-based physical activity. Research concerning the aquatic environment is scarce. The primary objectives of this three arm intervention pilot study were to examine the effects of an aquatic physical intervention program on balance, gait, fall risk and working memory among community-dwelling older individuals. The secondary objective was to examine the effects of an aquatic physical intervention program on safety of street-crossing among community-dwelling older individuals., Methods: Forty-two healthy participants aged 65 or older were enrolled into one of three intervention groups: aquatic physical intervention (API) (N = 13), on-land physical intervention (OLPI) (N = 14) or non-physical intervention (NPI) (N = 15). The intervention took place from 2018 until 2019 at Tel-Aviv University, Sheba medical center and Reich Center. The protocol included 30-min sessions twice a week for 12 weeks. Balance, gait and fall risk were assessed by the Tinneti test, working memory abilities were assessed by digit span and Corsi blocks tests and simulated safe streets-crossing was assessed by the hazard perception test for pedestrians. Testing and data collection was conducted at baseline, after six weeks and 12 weeks of intervention. All members of the professional team involved in evaluating participants were blind to the intervention group to which participants were allocated., Results: The differences in Tinetti balance (F (2, 39)=10.03, p < 0.01), fall risk (F (2, 39)=5.62, p0 > .05), digit span forward (F (2, 39)=8.85, p < 0.01) and Corsi blocks forward (F (2, 39)=3.54, p < 0.05) and backward (F (2, 39)=6.50, p < 0.05) scores after 12 weeks between the groups were significant. The API group showed improved scores. The differences in hazard perception test for pedestrians scores after 12 weeks of intervention between the groups were marginally significant (F (2, 39)=3.13, p = 0.055). The API group showed improved scores., Conclusions: These findings may affect experts working with the elderly population when making decisions concerning therapeutic prevention interventions for the deficiencies of elderly patients. Older adults practicing aquatic physical activity could contribute to their increased safety., Trial Registration: Trial registration number: ClinicalTrials.gov Registry NCT03510377. Date of registration: 10/31/2017.

Renal tubulointerstitial fibrosis is the final common pathway in end-stage renal disease and is characterized by aberrant accumulation of extracellular matrix (ECM) components secreted by myofibroblasts. Tubular type 2 EMT, induced by TGF- β , plays an important role in renal fibrosis, by participating directly or indirectly in myofibroblasts generation. TGF- β 1-induced apoptosis and fibrosis in experimental chronic murine kidney diseases are concomitantly associated with an intrarenal decreased expression of the IL-15 survival factor. Since IL-15 counteracts TGF- β 1 effects in different cell models, we analyzed whether (1) human chronic inflammatory nephropathies evolving towards fibrosis could be also characterized by a weak intrarenal IL-15 expression and (2) IL-15 could inhibit epithelial-mesenchymal transition (EMT) and excess matrix deposition in human renal proximal tubular epithelial cells (RPTEC). Our data show that different human chronic kidney diseases are characterized by a strong decreased expression of intrarenal IL-15, which is particularly relevant in diabetic nephropathy, in which type 2 tubular EMT plays an important role in fibrosis. Moreover, primary epithelial tubular cultures deprived of growth supplements rapidly produce active TGF- β 1 inducing a "spontaneous" EMT process characterized by the loss of membrane-bound IL-15 (mbIL-15) expression. Both "spontaneous" EMT and recombinant human (rh) TGF- β 1-induced EMT models can be inhibited by treating RPTEC and HK2 cells with rhIL-15. Through a long-lasting phospho-c-jun activation, IL-15 inhibits rhTGF- β 1-induced Snail1 expression, the master inducer of EMT, and blocks TGF- β 1-induced tubular EMT and downstream collagen synthesis. In conclusion, our data suggest that intrarenal IL-15 could be a natural inhibitor of TGF- β in human kidney able to guarantee epithelial homeostasis and to prevent EMT process. Thus, both in vivo and in vitro an unbalance in intrarenal IL-15 and TGF- β 1 levels could render RPTEC cells more prone to undergo EMT process. Exogenous IL-15 treatment could be beneficial in some human nephropathies such as diabetic nephropathy.

Background: Iodinated and gadolinium-based contrast media (ICM; GBCM) induce immediate hypersensitivity (IH) reactions. Differentiating allergic from non-allergic IH is crucial; allergy contraindicates the culprit agent for life. We studied frequency of allergic IH among ICM or GBCM reactors., Methods: Patients were recruited in 31 hospitals between 2005 and 2009. Clinical symptoms, plasma histamine and tryptase concentrations and skin tests were recorded. Allergic IH was diagnosed by intradermal tests (IDT) with the culprit CM diluted 1:10, "potentially allergic" IH by positive IDT with pure CM, and non-allergic IH by negative IDT., Findings: Among 245 skin-tested patients (ICM = 209; GBCM = 36), allergic IH to ICM was identified in 41 (19.6%) and to GBCM in 10 (27.8%). Skin cross-reactivity was observed in 11 patients with ICM (26.8%) and 5 with GBCM (50%). Allergy frequency increased with clinical severity and histamine and tryptase concentrations (p < 0.0001). Cardiovascular signs were strongly associated with allergy. Non-allergic IH was observed in 152 patients (62%) (ICM:134; GBCM:18). Severity grade was lower (p < 0.0001) and reaction delay longer (11.6 vs 5.6 min; p < 0.001). Potentially allergic IH was diagnosed in 42 patients (17.1%) (ICM:34; GBCM:8). The delay, severity grade, and mediator release were intermediate between the two other groups., Interpretation: Allergic IH accounted for < 10% of cutaneous reactions, and > 50% of life-threatening ones. GBCM and ICM triggered comparable IH reactions in frequency and severity. Cross-reactivity was frequent, especially for GBCM. We propose considering skin testing with pure contrast agent, as it is more sensitive than the usual 1:10 dilution criteria.

The administration of ex vivo -expanded Natural Killer (NK) cells in leukemia therapy is still challenging, in part due to the difficulty to generate in sufficient quantities fully mature and functional NK cells and Identification of surface markers indicative of NK maturation and functionality is therefore needed. Here, based on the analysis of surface receptors of ex vivo -expanded NK cells, we identified CD94 as a surface marker correlating with high lytic potential against leukemic cell lines and immunological synapse formation. CD94-positive ex vivo -expanded NK cells displayed higher expression of NKG2 receptors and the adhesion molecule LFA-1, as compared with their CD94-negative counterparts. We also tested the in vivo anti-leukemic capacity of ex vivo -expanded NK cells against patient-derived acute myeloid leukemia cells. Although no anti-leukemic effect was detected, we noticed that only CD94-positive ex vivo -expanded NK cells were detected in leukemic mice at the end of the 2-week treatment. Moreover, flow cytometry analysis showed a subpopulation harboring CD94 (NK) and CD34 (leukemic cells) double staining, indicative of conjugate formation. Therefore surface expression of CD94 on ex vivo -differentiated NK cells emerged as an indicator of in vitro and in vivo killer cell functionality.

The ability to form relational categories for objects that share few features in common is a hallmark of human cognition. For example, anything that can play a preventative role, from a boulder to poverty, can be a "barrier." However, neurobiological research has focused solely on how people acquire categories defined by features. The present functional magnetic resonance imaging study examines how relational and feature-based category learning compare in well-matched learning tasks. Using a computational model-based approach, we observed a cluster in left rostrolateral prefrontal cortex (rlPFC) that tracked quantitative predictions for the representational distance between test and training examples during relational categorization. Contrastingly, medial and dorsal PFC exhibited graded activation that tracked decision evidence during both feature-based and relational categorization. The results suggest that rlPFC computes an alignment signal that is critical for integrating novel examples during relational categorization whereas other PFC regions support more general decision functions., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose: An esthetically pleasing smile is one of our patients' main goals. However, it is not always clear that the esthetic perceptions of patients and clinicians are the same. The purpose of this study was to evaluate and quantify the discrepancies in the esthetic perception of maxillary incisor torque among professionals, and between professionals and the general public., Materials and Methods: A photograph of a 30-year-old woman was digitally manipulated to obtain nine smile images and nine full-profile images with various maxillary incisor torques, while maintaining the overjet. The images were evaluated in an online survey by three different groups: laypersons (LP, n = 21), orthodontists (OR, n = 20), and specialists in dental esthetics (SDE, n = 19)., Results: From among the smile images, the LP group preferred the 80-degree option (the angle that forms the tangent between the crown of the maxillary incisor and the functional occlusal plane), the SDE group preferred the 75-degree option, and the OR group preferred the 70-degree option. From among the full-profile images, both the LP and the SDE groups preferred the 80-degree option, while the OR group preferred the 75-degree option. To analyze the data and verify or reject the hypotheses of normality and homoscedasticity, ANOVA and Kruskal-Wallis tests were used., Conclusions: The LP and SDE groups coincided, in contrast to the OR group, which preferred more protrusive torques and was less tolerant of retroclined maxillary incisors.

Melanoma is a particularly virulent human cancer, due to its resistance to conventional treatments and high frequency of metastasis. Melanomas contain a fraction of cells, the melanoma-initiating cells (MICs), responsible for tumor propagation and relapse. Identification of the molecular pathways supporting MICs is, therefore, vital for the development of targeted treatments. One factor produced by melanoma cells and their microenvironment, insulin-like growth factor-1 (IGF- 1), is linked to epithelial-mesenchymal transition (EMT) and stemness features in several cancers.We evaluated the effect of IGF-1 on the phenotype and chemoresistance of B16-F10 cells. IGF-1 inhibition in these cells prevented malignant cell proliferation, migration and invasion, and lung colony formation in immunodeficient mice. IGF-1 downregulation also markedly inhibited EMT, with low levels of ZEB1 and mesenchymal markers (N-cadherin, CD44, CD29, CD105) associated with high levels of E-cadherin and MITF, the major regulator of melanocyte differentiation. IGF-1 inhibition greatly reduced stemness features, including the expression of key stem markers (SOX2, Oct-3/4, CD24 and CD133), and the functional characteristics of MICs (melanosphere formation, aldehyde dehydrogenase activity, side population). These features were associated with a high degree of sensitivity to mitoxantrone treatment.In this study, we deciphered new connections between IGF-1 and stemness features and identified IGF-1 as instrumental for maintaining the MIC phenotype. The IGF1/IGF1-R nexus could be targeted for the development of more efficient anti-melanoma treatments. Blocking the IGF-1 pathway would improve the immune response, decrease the metastatic potential of tumor cells and sensitize melanoma cells to conventional treatments.

We report a new type of brain-machine interface enabling a human operator to control nanometer-size robots inside a living animal by brain activity. Recorded EEG patterns are recognized online by an algorithm, which in turn controls the state of an electromagnetic field. The field induces the local heating of billions of mechanically-actuating DNA origami robots tethered to metal nanoparticles, leading to their reversible activation and subsequent exposure of a bioactive payload. As a proof of principle we demonstrate activation of DNA robots to cause a cellular effect inside the insect Blaberus discoidalis, by a cognitively straining task. This technology enables the online switching of a bioactive molecule on and off in response to a subject's cognitive state, with potential implications to therapeutic control in disorders such as schizophrenia, depression, and attention deficits, which are among the most challenging conditions to diagnose and treat.

Chronic kidney disease, secondary to renal fibrogenesis, is a burden on public health. There is a need to explore new therapeutic pathways to reduce renal fibrogenesis. To study this, we used unilateral ureteral obstruction (UUO) in mice as an experimental model of renal fibrosis and microarray analysis to compare gene expression in fibrotic and normal kidneys. The cannabinoid receptor 1 (CB1) was among the most upregulated genes in mice, and the main endogenous CB1 ligand (2-arachidonoylglycerol) was significantly increased in the fibrotic kidney. Interestingly, CB1 expression was highly increased in kidney biopsies of patients with IgA nephropathy, diabetes, and acute interstitial nephritis. Both genetic and pharmacological knockout of CB1 induced a profound reduction in renal fibrosis during UUO. While CB2 is also involved in renal fibrogenesis, it did not potentiate the role of CB1. CB1 expression was significantly increased in myofibroblasts, the main effector cells in renal fibrogenesis, upon TGF-β1 stimulation. The decrease in renal fibrosis during CB1 blockade could be explained by a direct action on myofibroblasts. CB1 blockade reduced collagen expression in vitro. Rimonabant, a selective CB1 endocannabinoid receptor antagonist, modulated the macrophage infiltrate responsible for renal fibrosis in UUO through a decrease in monocyte chemoattractant protein-1 synthesis. Thus, CB1 has a major role in the activation of myofibroblasts and may be a new target for treating chronic kidney disease.

Intrarenal interleukin-15 (IL-15) participates to renal pathophysiology, but the role of its different membrane-bound isoforms remains to be elucidated. In this study, we reassess the biology of membrane-bound IL-15 (mb-IL-15) isoforms by comparing primary cultures of human renal proximal tubular epithelial cells (RPTEC) to peritumoral (ptumTEC), tumoral (RCC), and cancer stem cells (CSC/CD105(+)). RPTEC express a 14 to 16 kDa mb-IL-15, whose existence has been assumed but never formally demonstrated and likely represents the isoform anchored at the cell membrane through the IL-15 receptor α (IL-15Rα) chain, because it is sensitive to acidic treatment and is not competent to deliver a reverse signal. By contrast, ptumTEC, RCC, and CSC express a novel N-hyperglycosylated, short-lived transmembrane mb-IL-15 (tmb-IL-15) isoform around 27 kDa, resistant to acidic shock, delivering a reverse signal in response to its soluble receptor (sIL-15Rα). This reverse signal triggers the down-regulation of the tumor suppressor gene E-cadherin in ptumTEC and RCC but not in CSC/CD105(+), where it promotes survival. Indeed, through the AKT pathway, tmb-IL-15 protects CSC/CD105(+) from non-programmed cell death induced by serum starvation. Finally, both mb-IL-15 and tmb-IL-15 are sensitive to metalloproteases, and the cleaved tmb-IL-15 (25 kDa) displays a powerful anti-apoptotic effect on human hematopoietic cells. Overall, our data indicate that both mb-IL-15 and tmb-IL-15 isoforms play a complex role in renal pathophysiology downregulating E-cadherin and favoring cell survival. Moreover, "apparently normal" ptumTEC cells, sharing different properties with RCC, could contribute to organize an enlarged peritumoral "preneoplastic" environment committed to favor tumor progression., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Modified melanoma B16 cells inhibited in their IGF-1 expression (B16MOD), on the contrary to the IGF-1 fully expressed parental wild-type (B16WT) counterpart, were shown to stimulate humoral as well as cellular immune responses. Among humoral components, the neutralizing and complement-fixing antibodies of IgM and essentially IgG2 (a+b) isotypes exhibited in vitro and in vivo effects upon tumour growth, while the IgG1 antibody isotype promoted enhanced tumour proliferation. As for the cellular immunity, it was found that the T CD8(+) lymphocyte subpopulation remained the main potent and long lasting immune active effector regulating tumour growth., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)