Language experience influences audiovisual speech integration in unimodal and bimodal bilingual infants.

Infants as young as 2 months can integrate audio and visual aspects of speech articulation. A shift of attention from the eyes towards the mouth of talking faces occurs around 6 months of age in monolingual infants. However, it is unknown whether this pattern of attention during audiovisual speech processing is influenced by speech and language experience in infancy. The present study investigated this question by analysing audiovisual speech processing in three groups of 4- to 8-month-old infants who differed in their language experience: monolinguals, unimodal bilinguals (infants exposed to two or more spoken languages) and bimodal bilinguals (hearing infants with Deaf mothers). Eye-tracking was used to study patterns of face scanning while infants were viewing faces articulating syllables with congruent, incongruent and silent auditory tracks. Monolinguals and unimodal bilinguals increased their attention to the mouth of talking faces between 4 and 8 months, while bimodal bilinguals did not show any age difference in their scanning patterns. Moreover, older (6.6 to 8 months), but not younger, monolinguals (4 to 6.5 months) showed increased visual attention to the mouth of faces articulating audiovisually incongruent rather than congruent faces, indicating surprise or novelty. In contrast, no audiovisual congruency effect was found in unimodal or bimodal bilinguals. Results suggest that speech and language experience influences audiovisual integration in infancy. Specifically, reduced or more variable experience of audiovisual speech from the primary caregiver may lead to less sensitivity to the integration of audio and visual cues of speech articulation.

Leishmania infantum exploits the anti-ferroptosis effects of Nrf2 to escape cell death in macrophages.

Macrophages are major host cells for the protozoan Leishmania parasite. Depending on their activation state, they either contribute to the detection and elimination of Leishmania spp. or promote parasite resilience. Here, we report that the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages plays a pivotal role in the progression of Leishmania infantum infection by controlling inflammation and redox balance of macrophages. We also highlight the involvement of the NOX2/reactive oxygen species (ROS) axis in early Nrf2 activation and, subsequently, prostaglandin E2 (PGE2)/EP2r signaling in the sustenance of Nrf2 activation upon infection. Moreover, we establish a ferroptosis-like process within macrophages as a cell death program of L. infantum and the protective effect of Nrf2 in macrophages against L. infantum death. Altogether, these results identify Nrf2 as a critical factor for the susceptibility of L. infantum infection, highlighting Nrf2 as a promising pharmacological target for the development of therapeutic approaches for the treatment of visceral leishmaniasis.

PPARγ activation modulates the balance of peritoneal macrophage populations to suppress ovarian tumor growth and tumor-induced immunosuppression.

BACKGROUND: Ovarian adenocarcinoma (OVAD) frequently metastasizes to the peritoneal cavity and manifests by the formation of ascites, which constitutes a tumor-promoting microenvironment. In the peritoneal cavity, two developmentally, phenotypically and functionally distinct macrophage subsets, immunocompetent large peritoneal macrophages (LPM) and immunosuppressive small peritoneal macrophages (SPM), coexist. Because peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor participating in macrophage differentiation and cooperates with CCAAT/enhancer binding protein ß (C/EBPß), a transcription factor essential for SPM-to-LPM differentiation, PPARγ could be also involved in the regulation of SPM/LPM balance and could be a promising therapeutic target. METHODS: To evaluate the 15(S)-hydroxyeicosatetraenoic acid (HETE), a PPARγ endogenous ligand, impact on ovarian tumor growth, we intraperitoneally injected 15(S)-HETE into a murine ovarian cancer model. This experimental model consists in the intraperitoneally injection of ID8 cells expressing luciferase into syngeneic C57BL/6 female mice. This ID8 orthotopic mouse model is a well-established experimental model of end-stage epithelial OVAD. Tumor progression was monitored using an in vivo imaging system. Peritoneal immune cells in ascites were analyzed by flow cytometry and cell sorting. To determine whether the impact of 15(S)-HETE in tumor development is mediated through the macrophages, these cells were depleted by injection of liposomal clodronate. To further dissect how 15(S)-HETE mediated its antitumor effect, we assessed the tumor burden in tumor-bearing mice in which the PPARγ gene was selectively disrupted in myeloid-derived cells and in mice deficient of the recombination-activating gene Rag2. Finally, to validate our data in humans, we isolated and treated macrophages from ascites of individuals with OVAD. RESULTS: Here we show, in the murine experimental model of OVAD, that 15(S)-HETE treatment significantly suppresses the tumor growth, which is associated with the differentiation of SPM into LPM and the LPM residency in the peritoneal cavity. We demonstrate that C/EBPß and GATA6 play a central role in SPM-to-LPM differentiation and in LPM peritoneal residence through PPARγ activation during OVAD. Moreover, this SPM-to-LPM switch is associated with the increase of the effector/regulatory T-cell ratio. Finally, we report that 15(S)-HETE attenuates immunosuppressive properties of human ovarian tumor-associated macrophages from ascites. CONCLUSION: Altogether, these results promote PPARγ as a potential therapeutic target to restrain OVAD development and strengthen the use of PPARγ agonists in anticancer therapy.

Tumor cells educate mesenchymal stromal cells to release chemoprotective and immunomodulatory factors.

Factors released by surrounding cells such as cancer-associated mesenchymal stromal cells (CA-MSCs) are involved in tumor progression and chemoresistance. In this study, we characterize the mechanisms by which naïve mesenchymal stromal cells (MSCs) can acquire a CA-MSCs phenotype. Ovarian tumor cells trigger the transformation of MSCs to CA-MSCs by expressing pro-tumoral genes implicated in the chemoresistance of cancer cells, resulting in the secretion of high levels of CXC chemokine receptors 1 and 2 (CXCR1/2) ligands such as chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, and interleukin 8 (IL-8). CXCR1/2 ligands can also inhibit the immune response against ovarian tumor cells. Indeed, through their released factors, CA-MSCs promote the differentiation of monocytes towards M2 macrophages, which favors tumor progression. When CXCR1/2 receptors are inhibited, these CA-MSC-activated macrophages lose their M2 properties and acquire an anti-tumoral phenotype. Both ex vivo and in vivo, we used a CXCR1/2 inhibitor to sensitize ovarian tumor cells to carboplatin and circumvent the pro-tumoral effects of CA-MSCs. Since high concentrations of CXCR1/2 ligands in patients' blood are associated with chemoresistance, CXCR1/2 inhibition could be a potential therapeutic strategy to revert carboplatin resistance.

Circulating CD14high CD16low intermediate blood monocytes as a biomarker of ascites immune status and ovarian cancer progression.

BACKGROUND: Besides the interest of an early detection of ovarian cancer, there is an urgent need for new predictive and prognostic biomarkers of tumor development and cancer treatment. In healthy patients, circulating blood monocytes are typically subdivided into classical (85%), intermediate (5%) and non-classical (10%) populations. Although these circulating monocyte subsets have been suggested as biomarkers in several diseases, few studies have investigate their potential as a predictive signature for tumor immune status,tumor growth and treatment adaptation. METHODS: In this study, we used a homogeneous cohort of 28 chemotherapy-naïve patients with ovarian cancer to evaluate monocyte subsets as biomarkers of the ascites immunological status. We evaluated the correlations between circulating monocyte subsets and immune cells and tumor burden in peritoneal ascites. Moreover, to validate the use of circulating monocyte subsets tofollow tumor progression and treatment response, we characterized blood monocytes from ovarian cancer patients included in a phase 1 clinical trial at baseline and following murlentamab treatment. RESULTS: We demonstrate here a robust expansion of the intermediate blood monocytes (IBMs) in ovarian cancer patients. We establish a significant positive correlation between IBM percentage and tumor-associate macrophages with a CCR2high/CD163high/CD206high/CD86lowprofile. Moreover, IBM expansion is associated with a decreased effector/regulatory T-cell ratio in ascites and with the presence of soluble immunosuppressive mediators. We also establish that IBM proportion positively correlates with the peritoneum tumor burden. Finally, the study of IBMs in patients with ovarian cancer under immunotherapy during the phase clinical trial supports IBMs to follow the evolution of tumor development and the treatment adaptation. CONCLUSIONS: This study, which links IBM level with immunosuppression and tumor burden in peritoneum, identifies IBMs as apotential predictive signature of ascites immune status and as a biomarker ofovarian cancer development and treatment response. TRIAL REGISTRATION NUMBER: EudraCT: 2015-004252-22 NCT02978755.

Impact of Language Experience on Attention to Faces in Infancy: Evidence From Unimodal and Bimodal Bilingual Infants.

Faces capture and maintain infants' attention more than other visual stimuli. The present study addresses the impact of early language experience on attention to faces in infancy. It was hypothesized that infants learning two spoken languages (unimodal bilinguals) and hearing infants of Deaf mothers learning British Sign Language and spoken English (bimodal bilinguals) would show enhanced attention to faces compared to monolinguals. The comparison between unimodal and bimodal bilinguals allowed differentiation of the effects of learning two languages, from the effects of increased visual communication in hearing infants of Deaf mothers. Data are presented for two independent samples of infants: Sample 1 included 49 infants between 7 and 10 months (26 monolinguals and 23 unimodal bilinguals), and Sample 2 included 87 infants between 4 and 8 months (32 monolinguals, 25 unimodal bilinguals, and 30 bimodal bilingual infants with a Deaf mother). Eye-tracking was used to analyze infants' visual scanning of complex arrays including a face and four other stimulus categories. Infants from 4 to 10 months (all groups combined) directed their attention to faces faster than to non-face stimuli (i.e., attention capture), directed more fixations to, and looked longer at faces than non-face stimuli (i.e., attention maintenance). Unimodal bilinguals demonstrated increased attention capture and attention maintenance by faces compared to monolinguals. Contrary to predictions, bimodal bilinguals did not differ from monolinguals in attention capture and maintenance by face stimuli. These results are discussed in relation to the language experience of each group and the close association between face processing and language development in social communication.