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Natural killer (NK) cells play a vital role in innate immunity and show great promise in cancer immunotherapy. Traditional sources of NK cells, such as the peripheral blood, are limited by availability and donor variability. In addition, in vitro expansion can lead to functional exhaustion and gene editing challenges. This study aimed to harness induced pluripotent stem cell (iPSC) technology to provide a consistent and scalable source of NK cells, overcoming the limitations of traditional sources and enhancing the potential for cancer immunotherapy applications. We developed human placental–derived iPSC lines using reprogramming techniques. Subsequently, an optimized two‐step differentiation protocol was introduced to generate high‐purity NK cells. Initially, iPSCs were differentiated into hematopoietic‐like stem cells using spin‐free embryoid bodies (EBs). Subsequently, the EBs were transferred to ultra‐low attachment plates to induce NK cell differentiation. iPSC‐derived NK (iNK) cells expressed common NK cell markers (NKp46, NKp30, NKp44, CD16 and eomesodermin) at both RNA and protein levels. iNK cells demonstrated significant resilience to cryopreservation and exhibited enhanced cytotoxicity. The incorporation of a chimeric antigen receptor (CAR) construct further augmented their cytotoxic potential. This study exemplifies the feasibility of generating iNK cells with high purity and enhanced functional capabilities, their improved resilience to cryopreservation and the potential to have augmented cytotoxicity through CAR expression. Our findings offer a promising pathway for the development of potential cellular immunotherapies, highlighting the critical role of iPSC technology in overcoming challenges associated with traditional NK cell sources. [ABSTRACT FROM AUTHOR]

Individuals with schizophrenia face significant challenges in daily functioning, and although social cognition predicts how well patients respond to these challenges, associated physiological mechanisms remain unspecified. The present study draws from polyvagal theory and tested the hypothesis that respiratory sinus arrhythmia (RSA), an established indicator of the capacity to self-regulate and adapt to environmental demands, combines with social cognition to predict functional outcome. Using data from 41 schizophrenia patients and 36 healthy comparison subjects, we replicated group differences in RSA and social cognition and also demonstrated that RSA and social cognition interact to predict how effectively patients manage work and independent living activities. Specifically, RSA did not enhance functional outcomes when social cognition was already strong, but higher levels of RSA enabled effective role functioning when social-cognitive performance was impaired. Jointly, RSA and social cognition accounted for 40% of the variance in outcome success, compared with 21% when evaluating social cognition alone. As polyvagal theory suggests, physiological flexibility and self-regulatory capacity may compensate for poorer social-cognitive skills among schizophrenia patients.

Emotional and motivational dysfunction is fundamental to schizophrenia, and yet, the nature and scope of associated deficits are not well understood. This study assessed the integrity of emotional responding from the perspective of its underlying motivational systems during different phases of schizophrenia. Evaluative, somatic, and autonomic responses were measured during viewing of pictures categorized by emotional content, including threat, mutilation, contamination, illness, pollution, mild erotica, families, food, and nature. Participants were 13 patients at ultra high risk or prodromal for psychosis, 40 first-episode schizophrenia patients, 37 chronic schizophrenia patients, and 74 healthy comparison subjects. Irrespective of phase of illness, schizophrenia patients showed a robust and normal pattern of response across multiple systems, with differential engagement of the defensive and appetitive systems as a function of the motivational significance assigned to specific emotional contexts. Although the integrity of core motivational states also appeared to be intact in prodromal patients, a less consistent pattern of response was observed. As continuing efforts are made to identify emotional and motivational abnormalities in schizophrenia, identified deficits will likely be independent of a fundamental dysfunction in basic emotion and motivation response systems and involve integration with higher order processes. Keywords: schizophrenia, emotion, motivation, attention, startle reflex DOI: 10.1037/a0018475

The extensive array of bHLH transcription factors and their combinations as dimers underpin the diversity of molecular function required for cell type specification during embryogenesis. The bHLH factor TWIST1 plays pleiotropic roles during development. However, which combinations of TWIST1 dimers are involved and what impact each dimer imposes on the gene regulation network controlled by TWIST1 remain elusive. In this work, proteomic profiling of human-TWIST1 expressing cell lines and transcriptome analysis of mouse cranial mesenchyme have revealed that TWIST1 homodimer and heterodimers with TCF3, TCF4, and TCF12 E-proteins are the predominant dimer combinations. Disease-causing mutations in TWIST1 can impact on dimer formation or shift the balance of different types of TWIST1- dimers in the cell, which may underpin the defective differentiation of the craniofacial mesenchyme. Functional analyses of the loss and gain of TWIST1-E-protein dimer activity have revealed previously unappreciated roles in guiding lineage differentiation of embryonic stem cells: TWIST1-E-protein heterodimers activate the differentiation of mesoderm and neural crest cells, which is accompanied by the epithelial-to-mesenchymal transition. At the same time, TWIST1 homodimers maintain the stem cells in a progenitor state and block entry to the endoderm lineage. [ABSTRACT FROM AUTHOR]