Effectiveness of executive functioning training among heterogeneous adolescent samples: A systematic review.

The aim of the present systematic review was to discuss the reported efficacy of executive functioning training techniques among adolescents. A systematic review of the literature was conducted to retrieve and consolidate findings from articles evaluating executive functioning training techniques among adolescents. A total of 26 articles were located that examined the role of executive functioning training techniques among adolescents (age 10-19 years). Articles retrieved enabled comparison across psychiatric and medical diagnoses including attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), as well as adolescents with physical health concerns. Results revealed that among typically developing adolescents, executive functioning training was non-significant or yielded small effect size improvements in executive functioning as measured by behavioral and neuroimaging tasks among 62.5% of studies reviewed. In contrast, in those with medical conditions, ASD, ADHD, and conduct disorder, all but two studies reviewed yielded a medium to large effect size, supporting the effectiveness of EF training. Future research is needed to identify the long-term efficacy of these treatments, as well as their generalizability to real-world conditions.

Worse Physical Disability Is Associated With the Expression of PD-1 on Inflammatory T-Cells in Multiple Sclerosis Patients With Older Appearing Brains.

Background: Magnetic Resonance Imaging (MRI) analysis method "brain-age" paradigm could offer an intuitive prognostic metric (brain-predicted age difference: brain-PAD) for disability in Multiple Sclerosis (MS), reflecting structural brain health adjusted for aging. Equally, cellular senescence has been reported in MS using T-cell biomarker CD8+CD57+. Objective: Here we explored links between MRI-derived brain-age and blood-derived cellular senescence. We examined the value of combining brain-PAD with CD8+CD57+(ILT2+PD-1+) T-cells when predicting disability score in MS and considered whether age-related biological mechanisms drive disability. Methods: Brain-age analysis was applied to T1-weighted MRI images. Disability was assessed and peripheral blood was examined for CD8+CD57+ T-cell phenotypes. Linear regression models were used, adjusted for sex, age and normalized brain volume. Results: We included 179 mainly relapsing-remitting MS patients. A high brain-PAD was associated with high physical disability (mean brain-PAD = +6.54 [5.12-7.95]). CD8+CD57+(ILT2+PD-1+) T-cell frequency was neither associated with disability nor with brain-PAD. Physical disability was predicted by the interaction between brain-PAD and CD8+CD57+ILT2+PD-1+ T-cell frequency (AR 2 = 0.196), yet without improvement compared to brain-PAD alone (AR 2 = 0.206; AICc = 1.8). Conclusion: Higher frequency of CD8+CD57+ILT2+PD-1+ T-cells in the peripheral blood in patients with an older appearing brain was associated with worse disability scores, suggesting a role of these cells in the development of disability in MS patients with poorer brain health.

IFN-λ Decreases Murid Herpesvirus-4 Infection of the Olfactory Epithelium but Fails to Prevent Virus Reactivation in the Vaginal Mucosa.

Murid herpesvirus-4 (MuHV-4), a natural gammaherpesvirus of rodents, can infect the mouse through the nasal mucosa, where it targets sustentacular cells and olfactory neurons in the olfactory epithelium before it propagates to myeloid cells and then to B cells in lymphoid tissues. After establishment of latency in B cells, viral reactivation occurs in the genital tract in 80% of female mice, which can lead to spontaneous sexual transmission to co-housed males. Interferon-lambda (IFN-λ) is a key player of the innate immune response at mucosal surfaces and is believed to limit the transmission of numerous viruses by acting on epithelial cells. We used in vivo plasmid-mediated IFN-λ expression to assess whether IFN-λ could prophylactically limit MuHV-4 infection in the olfactory and vaginal mucosae. In vitro, IFN-λ decreased MuHV-4 infection in cells that overexpressed IFN-λ receptor 1 (IFNLR1). In vivo, prophylactic IFN-λ expression decreased infection of the olfactory epithelium but did not prevent virus propagation to downstream organs, such as the spleen where the virus establishes latency. In the olfactory epithelium, sustentacular cells readily responded to IFN-λ. In contrast, olfactory neurons did not respond to IFN-λ, thus, likely allowing viral entry. In the female genital tract, columnar epithelial cells strongly responded to IFN-λ, as did most vaginal epithelial cells, although with some variation from mouse to mouse. IFN-λ expression, however, failed to prevent virus reactivation in the vaginal mucosa. In conclusion, IFN-λ decreased MuHV-4 replication in the upper respiratory epithelium, likely by protecting the sustentacular epithelial cells, but it did not protect olfactory neurons and failed to block virus reactivation in the genital mucosa.

Sex-Specific Differences in Fat Storage, Development of Non-Alcoholic Fatty Liver Disease and Brain Structure in Juvenile HFD-Induced Obese Ldlr-/-.Leiden Mice.

BACKGROUND: Sex-specific differences play a role in metabolism, fat storage in adipose tissue, and brain structure. At juvenile age, brain function is susceptible to the effects of obesity; little is known about sex-specific differences in juvenile obesity. Therefore, this study examined sex-specific differences in adipose tissue and liver of high-fat diet (HFD)-induced obese mice, and putative alterations between male and female mice in brain structure in relation to behavioral changes during the development of juvenile obesity. METHODS: In six-week-old male and female Ldlr-/-.Leiden mice (n = 48), the impact of 18 weeks of HFD-feeding was examined. Fat distribution, liver pathology and brain structure and function were analyzed imunohisto- and biochemically, in cognitive tasks and with MRI. RESULTS: HFD-fed female mice were characterized by an increased perigonadal fat mass, pronounced macrovesicular hepatic steatosis and liver inflammation. Male mice on HFD displayed an increased mesenteric fat mass, pronounced adipose tissue inflammation and microvesicular hepatic steatosis. Only male HFD-fed mice showed decreased cerebral blood flow and reduced white matter integrity. CONCLUSIONS: At young age, male mice are more susceptible to the detrimental effects of HFD than female mice. This study emphasizes the importance of sex-specific differences in obesity, liver pathology, and brain function.

Species Specificity of Type III Interferon Activity and Development of a Sensitive Luciferase-Based Bioassay for Quantitation of Mouse Interferon-λ.

The type III interferon (IFN-λ) family includes 4 IFN-λ subtypes in man. In the mouse, only the genes coding for IFN-λ2 and -λ3 are present. Unlike mouse and human type I IFNs (IFN-α/ß), which exhibit strong species specificity, type III IFNs were reported to act in a cross-specific manner. We reexamined the cross-specificity and observed that mouse and human IFN-λ exhibit some species specificity, although much less than type I IFNs. Mouse IFN-λ3 displayed clear species specificity, being 25-fold less active in human cells than the closely related mouse IFN-λ2. This specificity likely depends on amino acids in α helices A and F that diverged from other IFN-λ sequences. Human IFN-λ4, in contrast, retained high activity in mouse cells. We next developed a firefly luciferase-based reporter cell line, named Fawa-λ-luc, to detect IFN-λ in biological fluids with high specificity and sensitivity. Fawa-λ-luc cells, derived from mouse epithelial cells that are responsive to IFN-λ, were made nonresponsive to type I IFNs by inactivation of the Ifnar2 gene and strongly responsive to IFN-λ by overexpression of the mouse IFNLR1. This bioassay was as sensitive as a commercially available enzyme-linked immunosorbent assay in detecting mouse IFN-λ in cell culture supernatant, as well as in serum and bronchoalveolar lavage samples of virus-infected mice. The assay also enabled the sensitive detection of human IFN-λ activity, including that of the divergent IFN-λ4 with a bias, however, due to variable activity of IFN-λ subtypes.

Interferon lambda (IFN-λ) efficiently blocks norovirus transmission in a mouse model.

Human noroviruses are highly efficient in person to person transmission thus associated with explosive outbreaks of acute gastroenteritis. Outbreak control is limited to disinfection and isolation measures. Strategies to control the spread of noroviruses should be developed and models to study norovirus transmission will greatly facilitate this. Here, a mouse-to-mouse transmission model, in which mice develop acute murine norovirus (MNV)-induced diarrhea, was used to explore the role of interferon lambda (IFN-λ) in the control of a norovirus infection. Sentinel AG129 mice [deficient in IFN-α/ß and IFN-γ receptors] that were co-housed with MNV-infected mice shedding high amounts of virus in their stool, developed a MNV-infection with associated diarrhea. Inoculation of such sentinel mice with an IFN-λ expression plasmid resulted in the production of circulating IFN-λ and upregulation of the expression of IFN-stimulated genes (ISGs) of the gut. Injection of the IFN-λ-expressing plasmid to sentinels prevents MNV-induced disease upon exposure to MNV-infected mice, as well as MNV replication in the small intestine, the associated signs of inflammation and the mounting of a specific IgG-based immune response. This demonstrates that IFN-λ can alone mediate protection against transmission of norovirus. The development of a simple delivery method for IFN-λ could be explored as a strategy to control norovirus outbreaks and protect vulnerable populations such as the elderly and immunocompromised.

Neurotropism of Saffold virus in a mouse model.

Saffold virus (SAFV) is a highly seroprevalent human Cardiovirus discovered recently. No clear association between SAFV infection and human disease has been established. Rare infection cases, however, correlated with neurological symptoms. To gain insight into the pathogenesis potential of the virus, we performed experimental mouse infection with SAFV strains of genotypes 2 and 3 (SAFV-2 and SAFV-3). After intraperitoneal infection, both strains exhibited a typical Cardiovirus tropism. Viral load was most prominent in the pancreas. Heart, spleen, brain and spinal cord were also infected. In IFN-receptor 1 deficient (IFNAR-KO) mice, SAFV-3 caused a severe encephalitis. The virus was detected by immunohistochemistry in many parts of the brain and spinal cord, both in neurons and astrocytes, but astrocyte infection was more extensive. In vitro, SAFV-3 also infected astrocytes better than neurons in mixed primary cultures. Astrocytes were, however, very efficiently protected by IFN-α/ß treatment.

Successful vitrification and autografting of baboon (Papio anubis) ovarian tissue.

STUDY QUESTION: Can a vitrification protocol using an ethylene glycol/dimethyl sulphoxide-based solution and a cryopin successfully cryopreserve baboon ovarian tissue? SUMMARY ANSWER: Our results show that baboon ovarian tissue can be successfully cryopreserved with our vitrification protocol. WHAT IS KNOWN ALREADY: Non-human primates have already been used as an animal model to test vitrification protocols for human ovarian tissue cryopreservation. STUDY DESIGN, SIZE, DURATION: Ovarian biopsies from five adult baboons were vitrified, warmed and autografted for 5 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: After grafting, follicle survival, growth and function and also the quality of stromal tissue were assessed histologically and by immunohistochemistry. The influence of the vitrification procedure on the cooling rate was evaluated by a computer model. MAIN RESULTS: After vitrification, warming and long-term grafting, follicles were able to grow and maintain their function, as illustrated by Ki67, anti-Müllerian hormone (AMH) and growth differentiation factor-9 (GDF-9) immunostaining. Corpora lutea were also observed, evidencing successful ovulation in all the animals. Stromal tissue quality did not appear to be negatively affected by our cryopreservation procedure, as demonstrated by vascularization and proportions of fibrotic areas, which were similar to those found in fresh ungrafted ovarian tissue. LIMITATIONS, REASONS FOR CAUTION: Despite our promising findings, before applying this technique in a clinical setting, we need to validate it by achieving pregnancies. WIDER IMPLICATIONS OF THE FINDINGS: In addition to encouraging results obtained with our vitrification procedure for non-human ovarian tissue, this study also showed, for the first time, expression of AMH and GDF-9 in ovarian follicles. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the Fonds National de la Recherche Scientifique de Belgique (grant Télévie No. 7.4507.10, grant 3.4.590.08 awarded to Marie-Madeleine Dolmans), Fonds Spéciaux de Recherche, Fondation St Luc, Foundation Against Cancer, and Department of Mechanical Engineering at Louisiana State University (support to Ram Devireddy), and donations from Mr Pietro Ferrero, Baron Frère and Viscount Philippe de Spoelberch. None of the authors has any competing interests to declare.

Broad-spectrum suppression of innate immunity is required for colonization of Arabidopsis roots by the fungus Piriformospora indica.

Piriformospora indica is a root-colonizing basidiomycete that confers a wide range of beneficial traits to its host. The fungus shows a biotrophic growth phase in Arabidopsis (Arabidopsis thaliana) roots followed by a cell death-associated colonization phase, a colonization strategy that, to our knowledge, has not yet been reported for this plant. P. indica has evolved an extraordinary capacity for plant root colonization. Its broad host spectrum encompasses gymnosperms and monocotyledonous as well as dicotyledonous angiosperms, which suggests that it has an effective mechanism(s) for bypassing or suppressing host immunity. The results of our work argue that P. indica is confronted with a functional root immune system. Moreover, the fungus does not evade detection but rather suppresses immunity triggered by various microbe-associated molecular patterns. This ability to suppress host immunity is compromised in the jasmonate mutants jasmonate insensitive1-1 and jasmonate resistant1-1. A quintuple-DELLA mutant displaying constitutive gibberellin (GA) responses and the GA biosynthesis mutant ga1-6 (for GA requiring 1) showed higher and lower degrees of colonization, respectively, in the cell death-associated stage, suggesting that P. indica recruits GA signaling to help establish proapoptotic root cell colonization. Our study demonstrates that mutualists, like pathogens, are confronted with an effective innate immune system in roots and that colonization success essentially depends on the evolution of strategies for immunosuppression.