👤 Josiane Dufour

The maternal environment during gestation influences fetal development, with long-lasting effects on postnatal health and productivity. This study evaluated the effect of prenatal heat stress (PNHS) on blood DNA methylation of dairy calves immediately after birth and whether such modifications persist into early life. Holstein calves were born to dams exposed to either PNHS (n = 36, temperature-humidity index >68, access to shade of a freestall barn) or prenatal cooling (PNTN; n = 37, access to shade and evaporative cooling) during the last 54 ± 5 d of gestation. Whole-genome enzymatic DNA methyl sequencing was performed on blood samples collected at birth (d 0; n = 3 PNHS, n = 5 PNTN) and 1 wk post-weaning (d 63 of age; n = 8 PNHS, n = 8 PNTN). From birth onward, all calves were actively cooled and managed under the same conditions. At birth, 682,898 differentially methylated cytosines (DMC) were identified genome-wide. Principal component analysis using 55,304 DMC located in genes expressed in blood cells revealed a clear clustering by prenatal treatment. However, at weaning, clear clustering by treatment was no longer observed using 23,977 treatment-associated DMC in blood-expressed genes, despite 97,289 DMC persisting genome-wide from birth to weaning. Immune cell deconvolution showed only minor differences in granulocytes (d 0) and CD4/CD8 Show less

Chronic pain and opioid use disorder (OUD) are highly prevalent and frequently co-occurring conditions that pose complex treatment challenges. While opioids are effective for pain management, prolonged use significantly enhances risk of developing substance dependence. Conversely, addiction-focused therapies often fail to relieve persistent somatic pain. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has emerged as a novel adjunctive treatment with potential to address chronic pain and substance use disorders concurrently. The present investigation examines the role of intravenous ketamine infusions in cases with coexisting chronic pain and OUD. It explores pharmacological mechanisms, therapeutic applications, clinical efficacy, and safety considerations of ketamine. Ketamine primarily acts by blocking NMDA receptors, which are central to glutamatergic signaling. This inhibition reduces neural excitability and promotes neuroplastic changes, including upregulation of brain-derived neurotrophic factor (BDNF), a protein associated with synaptic remodeling and recovery within pain and addiction pathways. These mechanisms are likely to contribute to ketamine mediated dual efficacy in managing nociceptive symptoms and reducing opioid dependence. Clinical studies suggest that ketamine may reduce pain severity, decrease opioid consumption, and alleviate withdrawal symptoms in select populations. While early evidence supports ketamine's use, its side effect profile, including dissociative symptoms, sympathomimetic activity, and potential for misuse, necessitates careful patient selection, monitoring, and oversight. Evidence remains limited by inadequate sample sizes, non-standardized protocols, and short follow-up periods. Despite these limitations, ketamine remains a promising adjunct in multimodal care, especially when conventional therapies are ineffective. Ongoing research is essential to refine protocols and to explore integration with behavioral and pharmacologic addiction interventions. Show less

Severe hypertriglyceridemia (HTG) is characterized by plasma triglyceride (TG) levels >500 mg/dL (SI: 5.7 mmol/L) (reference range, <150 mg/dL [SI: <1.7 mmol/L]) and is linked to cardiovascular disease and pancreatitis risk. Treatment typically involves dietary restrictions and lipid-lowering medications. Glycerol kinase deficiency (GKD) is a rare genetic disorder that causes pseudo-HTG. In SHASTA-2, a study of patients with severe HTG, most subjects (>90%) treated with plozasiran, an apolipoprotein C-III (APOC3) small interfering RNA (siRNA), achieved TG levels <500 mg/dL (SI: 5.7 mmol/L), below the risk threshold for acute pancreatitis. We report herein a case study of a 65-year-old male apparently not responding to plozasiran. The patient was shown to carry a loss-of-function variant in the Show less

Brain metastasis occurs in up to 40% of patients with non-small cell lung cancer (NSCLC). Considerable genomic heterogeneity exists between the primary lung tumor and respective brain metastasis; however, the identity of the genes capable of driving brain metastasis is incompletely understood. Here, we carried out an in vivo genome-wide CRISPR activation screen to identify molecular drivers of brain metastasis from an orthotopic xenograft model derived from a patient with NSCLC. We found that activating expression of the Alzheimer's disease-associated beta-secretase 1 (BACE1) led to a substantial increase in brain metastases. Furthermore, genetic and pharmacological inhibition of BACE1 blocked NSCLC brain metastasis. Mechanistically, we identified that BACE1 acts through epidermal growth factor receptor to drive this metastatic phenotype. Together, our data highlight the power of in vivo CRISPR activation screening to unveil molecular drivers and potential therapeutic targets of NSCLC brain metastasis. Show less

Hypothalamic gonadotropin-releasing hormone (GnRH) regulates the production of gonadotropins, which control reproduction. In elasmobranchs, unlike other gnathostomes, GnRH is released into the systemic circulation to stimulate gonadotrope cells located in the ventral lobe of the pituitary. The aim of this study was to investigate the potential role of systemic GnRH in the regulation of the testis in Scyliorhinus canicula. Phylogeny and synteny analyses identified three GnRHs and four GnRH receptor (ScGnRHR-I1, -IIa1, -IIa2 and -IIb2). In vitro functional hormone-receptor interactions using synthetic ScGnRHs showed that all ScGnRHs were effective at receptors, except ScGnRHRIIa2, at femtomolar to nanomolar concentrations, with lower efficiency for ScGnRH1/ScGnRHRIIb2. Real-time PCR analyses in a wide range of tissues, including male and female reproductive tracts, showed that all three gnrh were expressed mainly in the brain and all four gnrhr were expressed in the testis, particularly during spermiogenesis. Testicular explants containing cysts with spermatids were treated with ScGnRHs and their protein content analyzed by NanoLC-ESI-MS/MS, highlighting 1677 significantly differentially expressed proteins. Among them, the growth hormone receptor (GHR) and proteins involved in cholesterol and steroid metabolism, including several HSD17bs, were upregulated. In situ hybridization showed that ghr, hsd17b3 and hsd17b12 transcripts were localized in Sertoli cells, which are the main testicular steroidogenic cells in S. canicula. Fifteen steroids were assayed in the culture media, using LC-ESI-HRMS/MS, and an increase in 17β-estradiol concentrations was observed, consistent with hsd17b expressions. Furthermore, proteins involved in transcription and DNA structure were downregulated in response to GnRHs. In conclusion, this study showed that ScGnRHs may play a direct role in the regulation of elasmobranch testes by promoting spermiogenesis and modulating steroidogenesis. Show less

In this functional magnetic resonance imaging study, we investigated whether language production and understanding recruit similar phoneme-specific networks. We did so by comparing the brain's response to different phoneme categories in minimal pairs: Bilabial-initial words (eg "monkey") were contrasted to alveolar-initial words (eg "donkey") in 37 participants performing both language production and comprehension tasks. Individual-specific region-of-interest analyses showed that the same sensorimotor networks were activated across the language modalities. In motor regions, word production and comprehension elicited the same phoneme-specific topographical activity patterns, with stronger haemodynamic activations for alveolar-initial words in the tongue cortex and stronger activations for bilabial-initial words in the lip cortex. In the posterior and middle superior temporal cortex, production and comprehension likewise resulted in similar activity patterns, with enhanced activations to alveolar- compared to bilabial-initial words. These results disagree with the classical asymmetry between language production and understanding in neurobiological models of language, and instead advocate for a cortical organization where phonology is carried by similar topographical activations in motor cortex and distributed activations in temporal cortex across the language modalities. Show less

An emerging approach in surgery is to propose prehabilitation programs to strengthen the patient's functional abilities before surgical interventions, thus helping them cope better with its consequences. In drug-resistant language-dominant temporal lobe epilepsy (LdTLE), surgical treatment carries a risk of increasing cognitive deficits, notably word-finding difficulties (anomia) and verbal memory difficulties that negatively impact personal, social, and occupational activities. In this study, we invited 15 LdTLE patients to enroll in a speech and language prehabilitation program adapted to the specifics of their difficulties, organized daily during the preoperative period. Naming performance (for trained and untrained words) was studied twice before prehabilitation, during prehabilitation, and 1 week and 6 months after surgery. Results were analyzed using a generalized linear mixed effects model. We found a significant effect of prehabilitation on trained items before surgery. Postoperatively, trained items showed a slight and nonsignificant performance increase compared to baseline, whereas untrained items showed a significant decline in the same comparison. We conclude that trained words were better protected from postsurgical decline than untrained words. Our research can contribute to patient support during surgical decision-making; ultimately, prehabilitation might be considered as part of individualized care. These encouraging results lay the groundwork for more detailed or powerful examinations of the protective effect of prehabilitation on language skills. Show less

Speech input like [byt] has been shown to facilitate not only the subsequent processing of an identical target word /byt/ but also that of a target word /tyb/ that contains the same phonemes in a different order. In the TISK model of spoken word recognition (Hannagan et al., Frontiers in psychology, 4, 563, 2013), this transposed-phoneme priming effect could result from the activation of shared position-independent phonemes (i.e., a sublexical effect) or pre-activation of the lexical representation corresponding to the transposed-phoneme target word by the prime (i.e., a lexical effect). In this study, we aimed to distinguish sublexical and lexical contributions to transposed-phoneme priming effects by (1) manipulating the lexical status of primes, and (2) examining if transposed-phoneme effects occur when targets are nonwords. An inhibitory transposed-phoneme priming effect was observed when target nonwords (e.g., /tad/) were preceded by transposed-phoneme word primes (e.g., /dat/). In contrast, there was a small non-significant facilitatory priming effect when target nonwords (e.g., /nuk/) were preceded by transposed-phoneme nonword primes (/kun/). These findings point to a greater contribution of lexical representations than sublexical representations in driving transposed-phoneme priming effects. Show less

Current guidelines recommend avoiding activities with the risk of contact during pregnancy, despite a lack of empirical data to support this recommendation. As a result, individuals who participate in contact and collision sports such as football or rugby are often confronted with difficult decisions and, in the absence of clear guidance, may resort to making choices based on personal experience, limited advice, or fear. We aimed to examine the impact of continued participation in contact sport during pregnancy on maternal and fetal health outcomes. We conducted an online survey study of individuals (≥ 18 years of age) who participated in contact or collision sports during pregnancy. The survey collected self-reported information on participant demographics, sport participation (type, hours, and contact exposure) from pre-conception to postpartum, maternal and infant health outcomes, feelings towards continuing/stopping participation in sport, and medical advice received during the perinatal period. Odds ratios or relative risk ratios with 95% confidence intervals were calculated for all categorical outcomes using regression adjusted for relevant covariates to compare outcomes in individuals who stopped participating in contact sport ≤ 12 weeks and > 12 weeks gestation as well as individuals who did and did not sustain a hit (contact) during pregnancy. Between September 2023 and February 2024, 395 participants (age 34.6 ± 5.0, months postpartum 27.2 ± 34.3; primarily from Australia, Canada, the UK, and the USA) were recruited to participate in the survey. Participants participated in contact sports for an average of 12.8 ± 6.4 weeks of pregnancy with 84 individuals sustaining hard hits and 114 individuals sustaining cumulative low impact contact. Participants reported partaking in a total of 11,687.2 h of contact exposure during pregnancy and the rate of adverse events was 1.11 per 1000 h of exposure. Overall, continued participation in contact sport during pregnancy was associated with better mental health status. Over half of participants stated that they had concerns about participating in contact sports during their pregnancy; however, 90% felt "happy" or "very happy" about continuing their sport during pregnancy. Pregnant individuals continue to participate in contact sports during pregnancy. Participants who continued participating in contact sports were more likely to report decreased depression. Continued participation in contact activities was not associated with the odds of other maternal or fetal complications during pregnancy or the postpartum period. Further investigation is required to direct safe participation in contact sports during pregnancy. Show less

Accentuation is encoded by both durational and pitch cues in French. While previous research agrees that the sole presence of pitch cues is sufficient to encode accentuation in French, the role of durational cues is less clear. In four cue-weighting accent perception experiments, we examined the role of pitch and durational cues in French listeners' perception of accentuation. French listeners were tested on acoustic continua ranging from an unaccented first syllable [depla'se] "moved" to an accented first syllable ['de] [pla'se] "a dice placed." The continua were obtained by manipulating pitch and durational cues either separately or conjointly. In Experiments 1 and 2, participants identified each step of the continuum by choosing between two possible segmentations while in Experiments 3 and 4, participants performed an AX discrimination task on two adjacent steps. Results indicate that participants' performance was better when pitch cues were varied compared to when durational cues were varied in both the identification and discrimination tasks. In addition, while participants always benefited from the additional presence of pitch cues, participants did not consistently benefit from the additional presence of durational cues. Together, these results suggest that pitch cues are a better marker of French accentuation than durational cues. Show less

We used a novel nonword detection task to examine the lexical competition principle postulated in most models of spoken word recognition. To do so, in Experiment 1 we presented sequences of spoken words with half of the sequences containing a nonword, and the target nonword (i.e., press a response key whenever you detect a nonword in the sequence) could either be phonologically related (a phonological neighbor) or unrelated to the immediately preceding word. We reasoned that the reactivation of a phonological neighbor during target nonword processing should delay the moment at which a nonword decision can be made. Contrary to our hypothesis, participants were faster at detecting nonwords when they were preceded by a phonological neighbor compared with an unrelated word. In Experiment 2, an inhibitory effect of phonological relatedness on nonword decisions was observed in a classic priming situation using the same set of related and unrelated word-nonword pairs. We discuss the implications of these findings in regard to the main models of spoken word recognition, and conclude that our specific experimental set-up with phonological neighbors embedded in spoken sentences is more sensitive to cooperative interactions between co-activated sublexical representations than lexical competition between co-activated lexical representations, with the latter being modulated by whether or not the words compete for the same slot in time. Show less

In this EEG study, we examined the ability of French listeners to perceive and use the position of stress in a discrimination task. Event-Related-Potentials (ERPs) were recorded while participants performed a same-different task. Different stimuli diverged either in one phoneme (e.g., /ʒy'ʁi/-/ʒy'ʁɔ̃/) or in stress position (e.g., /ʒy'ʁi/-/'ʒyʁi/). Although participants reached 93% of correct responses, ERP results indicated that a change in stress position was not detected while a change in one phoneme elicited a MisMatchNegativity (MMN) response. It results that in the early moments of speech processing, stimuli that are phonemically identical but that differ in stress position are perceived as being strictly similar. We concluded that the good performance observed in behavioral responses on stress position contrasts are due to attentional/decisional processes linked to discrimination tasks, and not to automatic and unconscious processes involved in stress position processing. Show less

Benign prostatic hyperplasia is a nonmalignant enlargement of the prostate that commonly occurs in older men. We show that liver X receptor (Lxr)-α knockout mice (lxrα(-/-)) develop ventral prostate hypertrophy, correlating with an overaccumulation of secreted proteins in prostatic ducts and an alteration of vesicular trafficking in epithelial cells. In the fluid of the lxrα(-/-) prostates, spermine binding protein is highly accumulated and shows a 3000-fold increase of its mRNA. This overexpression is mediated by androgen hypersensitivity in lxrα(-/-) mice, restricted to the ventral prostate. Generation of chimeric recombinant prostates demonstrates that Lxrα is involved in the establishment of the epithelial-mesenchymal interactions in the mouse prostate. Altogether these results point out the crucial role of Lxrα in the homeostasis of the ventral prostate and suggest lxrα(-/-) mice may be a good model to investigate the molecular mechanisms of benign prostatic hyperplasia. Show less

Liver X receptor (LXR) α and LXRβ belong to the nuclear receptor superfamily. For many years, they have been called orphan receptors, as no natural ligand was identified. In the last decade, the LXR natural ligands have been shown to be oxysterols, molecules derived from cholesterol. While these nuclear receptors have been abundantly studied for their roles in the regulation of lipid metabolism, it appears that they also present crucial activities in reproductive organs such as testis and epididymis, as well as prostate. Phenotypic analyses of mice lacking LXRs (lxr-/-) pointed out their physiological activities in the various cells and organs regulating reproductive functions. This review summarizes the impact of LXR-deficiency in male reproduction, highlighting the novel information coming from the phenotypic analyses of lxrα-/-, lxrβ-/- and lxrα;β-/- mice. This article is part of a Special Issue entitled: Translating nuclear receptor from health to disease. Show less

Nonalcoholic fatty liver disease is associated with hepatic insulin resistance and type 2 diabetes mellitus. Whether this association has a genetic basis is unknown. In 95 healthy Asian Indian men, a group known to have a high prevalence of nonalcoholic fatty liver disease, we genotyped two single-nucleotide polymorphisms (SNPs) in the gene encoding apolipoprotein C3 (APOC3) that are known to be associated with hypertriglyceridemia (rs2854116 [T-455C] and rs2854117 [C-482T]). Plasma apolipoprotein C3 concentrations, insulin sensitivity, and hepatic triglyceride content were measured. We also measured plasma triglyceride concentrations and retinyl fatty acid ester absorption as well as plasma triglyceride clearance after oral and intravenous fat-tolerance tests. Liver triglyceride content and APOC3 genotypes were also assessed in a group of 163 healthy non-Asian Indian men. Carriers of the APOC3 variant alleles (C-482T, T-455C, or both) had a 30% increase in the fasting plasma apolipoprotein C3 concentration, as compared with the wild-type homozygotes. They also had a 60% increase in the fasting plasma triglyceride concentration, an increase by a factor of approximately two in the plasma triglyceride and retinyl fatty acid ester concentrations after an oral fat-tolerance test, and a 46% reduction in plasma triglyceride clearance. The prevalence of nonalcoholic fatty liver disease was 38% among variant-allele carriers and 0% among wild-type homozygotes (P<0.001). The subjects with nonalcoholic fatty liver disease had marked insulin resistance. A validation study involving non-Asian Indian men confirmed the association between APOC3 variant alleles and nonalcoholic fatty liver disease. The polymorphisms C-482T and T-455C in APOC3 are associated with nonalcoholic fatty liver disease and insulin resistance. Show less