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Background: The invariant TCR ζ/CD247 homodimer is crucial for TCR/CD3 expression and signaling through its 3 immunoreceptor tyrosine-based activation motifs (ITAMs). Homozygous null mutations in CD247 lead to immunodeficiency, while carriers exhibit 50% reduced surface CD3. It is unclear whether carriers of other CD247 variants show dominant-negative effects., Objective: We sought to analyze and model the potential impact on T-cell receptor (TCR) expression and function of heterozygous nonsense CD247 mutations found in patients with signs of immunodeficiency or autoimmunity., Methods: Jurkat T cells, either wild-type (WT) or CRISPR/Cas9-edited CD247-deficient (ZKO), were lentivirally transduced with WT CD247 or mutations ablating 1 (Q142X), 2 (Q101X), or 3 (Q70X) ITAMs., Results: Three patients from unrelated families were studied. Two heterozygous nonsense CD247 mutations were identified (p.Y152X and p.Q101X), which affected ITAM-3 and ITAM-2 and ITAM-3, respectively. Both mutations were associated with low surface CD3 expression and normal intracellular CD247 levels using a transmembrane-specific antibody, but very low intracellular CD247 levels using an ITAM-3-specific one, suggesting the presence of truncated variants in T cells. Transduction of the mutations lacking 1, 2, or 3 ITAMs into ZKO cells could not restore normal surface CD3 expression (only 60%, 22%, and 10%, respectively), whereas in WT cells, normal surface CD3 expression was reduced (to 39%, 19%, and 9% of normal levels), and both effects were dependent on ITAM number. All 6 transfectants showed reduced CD69 induction (25% to 50%), indicating that they were unable to signal downstream properly, neither isolated nor associated with WT CD247., Conclusions: Our results suggest that CD247 variants lacking ITAMs due to nonsense, but not null, mutations are defective for normal TCR assembly and exert a dominant-negative effect on TCR expression and signaling in vitro. This, in turn, may correlate with clinical features in vivo., Competing Interests: Disclosure statement This work was supported by grants from the Ministerio de Economía y Competitividad (MINECO PID2021-125501OB-I00 and RTI2018-095673-B-I00) and Asociación Española Contra el Cáncer (AECC PROYE20084REGU). A.C.B. was supported by Complutense University scholarship (CT27/16 and CT31/21). R.F.M. and D.C.A. were supported by the Spanish Ministry of Science, Innovation and Universities (FPU19/03136 and PRE2019-088150). P.P.C. was supported by Juan de la Cierva-Incorporación fellowship (IJCI-2014-19262). Disclosure of potential conflict of interest: The authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Opnurasib (JDQ443) is a newly developed oral KRAS G12C inhibitor, with a binding mechanism distinct from the registered KRAS G12C inhibitors sotorasib and adagrasib. Phase I and II clinical trials for opnurasib in NSCLC are ongoing. We evaluated the pharmacokinetic roles of the ABCB1 (P-gp/MDR1) and ABCG2 (BCRP) efflux and OATP1 influx transporters, and of the metabolizing enzymes CYP3A and CES1 in plasma and tissue disposition of oral opnurasib, using genetically modified cell lines and mouse models. In vitro, opnurasib was potently transported by human (h)ABCB1 and slightly by mouse (m)Abcg2. In Abcb1a/b- and Abcb1a/b;Abcg2-deficient mice, a significant ∼100-fold increase in brain-to-plasma ratios was observed. Brain penetration was unchanged in Abcg2 -/- mice. ABCB1 activity in the blood-brain barrier may therefore potentially limit the efficacy of opnurasib against brain metastases. The Abcb1a/b transporter activity could be almost completely reversed by co-administration of elacridar, a dual ABCB1/ABCG2 inhibitor, increasing the brain penetration without any behavioral or postural signs of acute CNS-related toxicity. No significant pharmacokinetic roles of the OATP1 transporters were observed. Transgenic human CYP3A4 did not substantially affect the plasma exposure of opnurasib, indicating that opnurasib is likely not a sensitive CYP3A4 substrate. Interestingly, Ces1 -/- mice showed a 4-fold lower opnurasib plasma exposure compared to wild-type mice, whereas no strong effect was seen on the tissue distribution. Plasma Ces1c therefore likely binds opnurasib, increasing its retention in plasma. The obtained pharmacokinetic insights may be useful for further optimization of the clinical efficacy and safety of opnurasib, and might reveal potential drug-drug interaction risks., 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 Masson SAS.. All rights reserved.)

Cell-cell communication within the complex tumour microenvironment is critical to cancer progression. Tumor-derived extracellular vesicles (TD-EVs) are key players in this process. They can interact with immune cells and modulate their activity, either suppressing or activating the immune system. Deciphering the interactions between TD-EVs and immune cells is essential to understand immune modulation by cancer cells. Fluorescent labelling of TD-EVs is a method of choice to study such interaction. This work aims to determine the impact of EV labelling methods on the detection by imaging flow cytometry and multicolour spectral flow cytometry of EV interaction and capture by the different immune cell types within human Peripheral Blood Mononuclear Cells (PBMCs). EVs released by the triple-negative breast carcinoma cell line MDA-MB-231 were labelled either with the lipophilic dye MemGlow-488 (MG-488), Carboxyfluorescein diacetate, succinimidyl ester (CFDA-SE) or through ectopic expression of a MyrPalm-superFolderGFP reporter (mp-sfGFP), which incorporates into EVs during their biogenesis. Our results show that these labelling strategies, although analysed with the same techniques, led to diverging results. While MG-488-labelled EVs incorporate in all cell types, CFSE-labelled EVs are restricted to a minor subset of cells and mp-sfGFP-labelled EVs are mainly detected in CD14+ monocytes which are the main uptakers of EVs and other particles, regardless of the labelling method. Furthermore, our results show that the method used for EV labelling influences the detection of the different types of EV interactions with the recipient cells. Specifically, MG-488, CFSE and mp-sfGFP result in observation suggesting, respectively, transient EV-PM interaction that results in dye transfer, EV content delivery, and capture of intact EVs. Consequently, the type of EV labelling method has to be considered as they can provide complementary information on various types of EV-cell interaction and EV fate., (© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

The human αβ T-cell receptor (TCR) is composed of a variable heterodimer (TCRαβ) and three invariant dimers (CD3γε, CD3δε, and ζζ/CD247 2 ). The role of each invariant chain in the stepwise interactions among TCR chains along the assembly is still not fully understood. Despite the high sequence homology between CD3γ and CD3δ, the clinical consequences of the corresponding immunodeficiencies (ID) in humans are very different (mild and severe, respectively), and mouse models do not recapitulate findings in human ID. To try to understand such disparities, we stably knocked down (KD) CD3D or CD3G expression in the human Jurkat T-cell line and analyzed comparatively their impact on TCRαβ assembly, transport, and surface expression. The results indicated that TCR ensembles were less stable and CD3ε levels were lower when CD3γ, rather than CD3δ, was scarce. However, both defective TCR ensembles were strongly retained in the ER, lacked ζζ/CD247 2 , and barely reached the T-cell surface (<11% of normal controls) in any of the CD3 KD cells. This is in sharp contrast to human CD3γ ID, whose mature T cells express higher levels of surface TCR (>30% vs. normal controls). CD3 KD of human T-cell progenitors followed by mouse fetal thymus organ cultures showed high plasticity in emerging immature polyclonal T lymphocytes that allowed for the expression of significant TCR levels which may then signal for survival in CD3γ, but not in CD3δ deficiency, and explain the immunological and clinical disparities of such ID cases., 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 Garcillán, Fuentes, Marin, Megino, Chacon-Arguedas, Mazariegos, Jiménez-Reinoso, Muñoz-Ruiz, Laborda, Cárdenas, Fernández-Malavé, Toribio and Regueiro.)

This article describes the experience of the MEF's impact evaluation management as one of the RBB instruments and documents the design and results obtained from three impact evaluations of the most emblematic government social programs. The Service of Visiting Families (SAF) of the National Program "Cuna Mas", conditional cash transfer Program "JUNTOS" and National Program "Pension 65" focusing on objective population's health the outcomes. Among the main results, it was found the SAF generated improvements in cognitive and communication development in children, but had no impact on mothers' child care practices or children's nutritional status. In the case of JUNTOS, there were increases in per capita spending, food expenditure, decreases in severity and poverty gap, increases in school attendance and reductions of school dropout. However, no significant results were found in most indicators of prenatal health, child health, or chronic malnutrition. In the case of Pension 65, there were increases in household consumption and improvements in elderly's emotional health (depression, self valoration); but there was no evidence of increases in the use of health services by the elderly or improvements in their physical health. Therefore, it is recommended that such programs boost their designs and inter-sectoral coordination with MINSA and subnational institutions, in order to improve contents of healthy practices and child care, and optimize the provision of health and education services, in order to meet the demands of their users.

Diagnostic testing was performed between 2000 and 2012 to determine the distribution of infectious pancreatic necrosis virus (IPNV) in the main states of the Mexican Republic with freshwater Rainbow Trout Oncorhynchus mykiss (Walbaum) farms. This virus was positively identified from Rainbow Trout farms in seven of the eight states assessed. Due to nonnormal data distribution, a logistic regression model was applied for statistical analysis, the results of which indicated that virus prevalence was variable between states, with moderate but significant differences. Regarding the time periods evaluated, IPNV prevalence was higher during the first years of the study. The susceptible, infected, removed model was used to examine this phenomenon, which indicated that the decreased prevalence during the latter years of the study could be associated with a real elimination of the infection. The information of the cases analyzed also suggests a relationship with the irregularity in the submission of samples to the laboratory and emphasizes other factors that have contributed to the transmission of IPNV throughout the country. Received November 10, 2014; accepted December 5, 2015.

Wilson's Disease (WD) (also known as hepatolenticular degeneration) is a rare inherited autosomal recessive disorder of abnormal copper metabolism, with an estimated prevalence of approximately 1 in 30,000. The clinical features associated with WD are highly varied. However, subtypes generally reflect neurological, hepatic, and psychiatric symptoms. The present case study reports two brothers with a recent diagnosis of WD. Neurological symptoms and cognitive deficits were exhibited in one brother (BL) in the form of extrapyramidal features, while the other brother (AL) only exhibited hepatic symptoms. Extensive neuropsychological testing was conducted on both siblings to compare cognitive profiles. Results for BL indicated significantly impaired motor functioning and information processing speed, which impacted him significantly at school. Aspects of executive dysfunction were also apparent in addition to reduced visual and verbal memory, working memory, and attention. Results for AL revealed evidence of verbal memory difficulties and aspects of executive dysfunction. Comparison is made of the distinct and common cognitive characteristics of the cases presented in terms of implications for early intervention and management of cognitive difficulties.

People with schizophrenia who experience auditory-verbal hallucinations experience difficulty in determining the source (self vs. other) of verbal information, and those with visual hallucinations experience a conceptually similar problem with visual information. In this study, we examined whether such source monitoring deficits extend to olfaction for olfactory hallucinators and whether they are selective to the modality in which the hallucination is experienced. To test these claims, three groups were formed: normal controls (NC), people with schizophrenia who experience olfactory hallucinations (OH), and people with schizophrenia who experience auditory-verbal hallucinations (AVH). These three groups were then tested on both an olfactory and an auditory-verbal source-monitoring task. We found evidence of a modality-specific impairment. The OH group was less accurate in determining whether an odor had been imagined or smelled relative to NC and AVH groups. In contrast, the AVH group was least accurate in determining the source of a word, relative to the OH and NC groups. These findings provide the first evidence of a source-monitoring impairment in schizophrenic participants with OHs and suggest that this impairment is modality specific., ((PsycINFO Database Record (c) 2012 APA, all rights reserved).)

Olfactory hallucinations (OHs) are present in a significant minority of people with schizophrenia, yet these symptoms are under-researched and poorly understood. This study aimed to identify the neuropsychological impairments that associate with OHs in schizophrenia. Patients with schizophrenia or schizoaffective disorder were classified into an OH group and a group with auditory-verbal hallucinations (AVHs) and no lifetime history of OHs. Patients were age- and gender-matched to a healthy control group. All participants were assessed using: a test of odor identification; decision-making and socio-emotional tests of orbitofrontal cortex (OFC) and amygdala function; and a battery of standardized executive tests. Patients, as a whole, performed more poorly than controls on the tests of odor identification, emotion processing and executive function, consistent with previous research. Only two tests of OFC functioning: the Object Alternation Task, taken from Oscar-Berman and Zola-Morgan's (1980a, 1980b) Comparative Neuropsychological Tasks, and a test of "faux pas" understanding discriminated between the OH and AVH patients. Findings provide the first preliminary support for OH-specific neuropsychological impairments associated with OFC dysfunction in schizophrenia. (JINS, 2012, 18, 1-10).

The 18q deletion syndrome (18q-) is a chromosomal disorder involving deletion of the distal segment of chromosome 18. Typifying features include poor cerebral myelination, reduced intellectual functioning and developmental delay. The present study reports the case of an 8-year-old girl diagnosed with 18q-, whose genetic analysis revealed a break at q21.3. Comprehensive neuropsychological testing indicated impaired functioning across most cognitive domains. However, verbal abilities were intact. Given the preservation of verbal skills on a background of relatively global impairment, CB's genetic and cognitive profile has implications for delineation of neuropsychological features associated with specific breakpoints in 18q-.

Introduction: Selective attention to threat-related information has been associated with clinical delusions in schizophrenia and nonclinical delusional ideation in healthy individuals. However, it is unclear whether biased attention for threat reflects early engagement effects on selective attention, or later difficulties in disengaging attention from perceived threat. The present study examined which of these processes operate in nonclinical delusion-prone individuals., Methods: A total of 100 psychologically healthy participants completed the Peters et al. (1999) Delusions Inventory (PDI). Twenty-two scoring in the upper quartile (high-PDI group) and 22 scoring in the lower quartile (low-PDI group) completed a modified dot-probe task. Participants detected dot-probes appearing 200, 500, or 1250 ms after an angry-neutral face pair or a happy-neutral face pair., Results: High-PDI individuals responded faster to dot-probes presented in the same location as angry compared to happy faces at the short 200 ms stimulus onset asynchrony (SOA), but only when the emotional faces were presented to the left visual field. At the two longer SOAs (500 ms, 1250 ms), the high-PDI group were also faster to respond to dot-probes presented in the same location as angry compared to happy faces and slower to respond to dot-probes presented in different spatial locations to angry (vs. happy) faces. The latter effects were seen whether emotional faces were presented to the left or the right visual field., Conclusions: Results support the operation of emotion-selective engagement and defective disengagement for threat-related facial expressions (i.e., anger) in delusion-prone individuals.