Nuclear Factor I Family Members are Key Transcription Factors Regulating Gene Expression.

The Nuclear Factor I (NFI) family of transcription factors (TFs) plays key roles in cellular differentiation, proliferation, and homeostasis. As such, NFI family members engage in a large number of interactions with other proteins and chromatin. However, despite their well-established significance, the NFIs' interactomes, their dynamics, and their functions have not been comprehensively examined.

Using the Jurkat reporter T cell line for evaluating the functionality of novel chimeric antigen receptors.

T cells that are genetically modified with chimeric antigen receptor (CAR) hold promise for immunotherapy of cancer. Currently, there are intense efforts to improve the safety and efficacy of CAR T cell therapies against liquid and solid tumors. Earlier we designed a novel CAR backbone (FiCAR) where the spacer is derived from immunoglobulin (Ig) -like domains of the signal-regulatory protein alpha (SIRPα).

Novel modular chimeric antigen receptor spacer for T cells derived from signal regulatory protein alpha Ig-like domains.

T cells equipped with chimeric antigen receptors (CAR) have shown remarkable efficacy in targeting B lineage malignancies. Improvement of the CAR structure is needed, however, with a view to developing flexibly modifiable spacers that are inert in interactions with unwanted cells. Specifically, binding to cells carrying receptors for IgG's crystallizable fragment (FcR), that recognize IgG-derived domains in CARs is to be avoided.

CDNF Interacts with ER Chaperones and Requires UPR Sensors to Promote Neuronal Survival.

Cerebral dopamine neurotrophic factor (CDNF) is a neurotrophic factor that has beneficial effects on dopamine neurons in both in vitro and in vivo models of Parkinson's disease (PD). CDNF was recently tested in phase I-II clinical trials for the treatment of PD, but the mechanisms underlying its neuroprotective properties are still poorly understood, although studies have suggested its role in the regulation of endoplasmic reticulum (ER) homeostasis and the unfolded protein response (UPR). The aim of this study was to investigate the mechanism of action of CDNF through analyzing the involvement of UPR signaling in its anti-apoptotic function.

Human transcription factor protein interaction networks.

Transcription factors (TFs) interact with several other proteins in the process of transcriptional regulation. Here, we identify 6703 and 1536 protein-protein interactions for 109 different human TFs through proximity-dependent biotinylation (BioID) and affinity purification mass spectrometry (AP-MS), respectively. The BioID analysis identifies more high-confidence interactions, highlighting the transient and dynamic nature of many of the TF interactions.

The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-stress-regulated protein exhibiting cytoprotective properties through a poorly understood mechanism in various in vitro and in vivo models of neuronal and non-neuronal damage. Although initially characterized as a secreted neurotrophic factor for midbrain dopamine neurons, MANF has recently gained more interest for its intracellular role in regulating the ER homeostasis, including serving as a cofactor of the chaperone glucose-regulated protein 78 (GRP78). We aimed for a better understanding of the neuroprotective mechanisms of MANF.

Pharmacologically diverse antidepressants facilitate TRKB receptor activation by disrupting its interaction with the endocytic adaptor complex AP-2.

Several antidepressant drugs activate tropomyosin-related kinase B (TRKB) receptor, but it remains unclear whether these compounds employ a common mechanism for TRKB activation. Here, using MS, we found that a single intraperitoneal injection of fluoxetine disrupts the interaction of several proteins with TRKB in the hippocampus of mice. These proteins included members of adaptor protein complex-2 (AP-2) involved in vesicular endocytosis.

Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy.

Background: CCAAT enhancer-binding protein epsilon (C/EBPε) is a transcription factor involved in late myeloid lineage differentiation and cellular function. The only previously known disorder linked to C/EBPε is autosomal recessive neutrophil-specific granule deficiency leading to severely impaired neutrophil function and early mortality.

Objective: The aim of this study was to molecularly characterize the effects of C/EBPε transcription factor Arg219His mutation identified in a Finnish family with previously genetically uncharacterized autoinflammatory and immunodeficiency syndrome.

Systems pathology analysis identifies neurodegenerative nature of age-related vitreoretinal interface diseases.

Aging is a phenomenon that is associated with profound medical implications. Idiopathic epiretinal membrane (iEMR) and macular hole (MH) are the major vision-threatening vitreoretinal diseases affecting millions of aging people globally, making these conditions an important public health issue. iERM is characterized by fibrous tissue developing on the surface of the macula, which leads to biomechanical and biochemical macular damage.

Agonist-specific Protein Interactomes of Glucocorticoid and Androgen Receptor as Revealed by Proximity Mapping.

Glucocorticoid receptor (GR) and androgen receptor (AR) are steroid-inducible transcription factors (TFs). The GR and the AR are central regulators of various metabolic, homeostatic and differentiation processes and hence important therapeutic targets, especially in inflammation and prostate cancer, respectively. Hormone binding to these steroid receptors (SRs) leads to DNA binding and activation or repression of their target genes with the aid of interacting proteins, coregulators.

Systematic Analysis of Human Protein Phosphatase Interactions and Dynamics.

Coordinated activities of protein kinases and phosphatases ensure phosphorylation homeostasis, which, when perturbed, can instigate diseases, including cancer. Yet, in contrast to kinases, much less is known about protein phosphatase functions and their interactions and complexes. Here, we used quantitative affinity proteomics to assay protein-protein interactions for 54 phosphatases distributed across the three major protein phosphatase families, with additional analysis of their 12 co-factors.

Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes.

Background: The nuclear factor κ light-chain enhancer of activated B cells (NF-κB) signaling pathway is a key regulator of immune responses. Accordingly, mutations in several NF-κB pathway genes cause immunodeficiency.

Objective: We sought to identify the cause of disease in 3 unrelated Finnish kindreds with variable symptoms of immunodeficiency and autoinflammation.

Pituitary-gonadal Relationship in the Catfish Clarias batrachus (L): A Study Correlating Gonadotrophin-II and Sex Steroid Dynamics.

A heterologous radioimmunoassay was developed for measuring gonadotrophin-II (GTH-II) in the catfish Clarias batrachus. Serum and/or pituitary levels of GTH-II showed significant annual/seasonal variations in male and female catfish, which could be correlated with both gonadosomatic index and/or serum testosterone level. GTH-II was not detected in resting phase, increased during gonadal recrudescence to peak values in late prespawning /spawning phases, and declined to low values in postspawning phase.

Metabolism of tibolone and its metabolites in uterine and vaginal tissue of rat and human origin.

In postmenopausal women, tibolone shows clear tissue differences in its stimulatory effects on the vagina and uterus. In rats, however, it has stimulatory effects on both tissues, with a different, more estrogenic, effect on the uterus than in humans. This may be due to differences in local metabolism.

Hypocorticism and interrenal hyperplasia are not directly related to masculinization in XX mas(-1)/mas(-1) carp, Cyprinus carpio.

This study reports on a homozygous XX male strain of common carp (E5), which fail to mount a normal cortisol stress response. Earlier classical genetic analysis had indicated that masculinization of E5 fish was caused by a putative recessive mutation (mas(-1)/mas(-1)). Hypocorticism in E5 fish was studied to investigate if it was related to masculinization.

Nuclear magnetic resonance for the assessment of the effects of alcohol septal ablation in hypertrophic cardiomyopathy.

Alcohol ablation of the interventricular septum is a well-established method of treatment in hypertrophic obstructive cardiomyopathy (HOCM). The extent of ablation-induced iatrogenic infarction is usually assessed by the use of echocardiography. The role of nuclear magnetic resonance (NMR) in this setting has not yet been well established.

Stress adaptation, cortisol and pubertal development in the male common carp, Cyprinus carpio.

This paper reviews a series of recent studies on the effect of adaptation to chronic stress on pubertal development in the common carp. In pre-pubertal male common carp adaptation to temperature stress caused a retardation of testicular development. Stress-induced delay of the first wave of spermatogenesis could be prevented by treatment with a cortisol antagonist, indicating that the stress effect is mediated by cortisol.

Sex steroids and their involvement in the cortisol-induced inhibition of pubertal development in male common carp, Cyprinus carpio L.

The onset and regulation of puberty is determined by functional development of the brain-pituitary-gonad (BPG) axis. Sex steroids produced in the gonads play an important role in the onset of puberty. Stress interferes with reproduction and the functioning of the BPG axis, and cortisol has frequently been indicated as a major factor mediating the suppressive effect of stress on reproduction.

Gonadotropin-releasing hormone does not directly stimulate luteinizing hormone biosynthesis in male African catfish.

Besides gonadotropin release, GnRH stimulates gonadotropin subunit gene transcription and translation in gonadotrophs. In the African catfish, Clarias gariepinus, chicken GnRH-II (cGnRH-II: [His5,Trp7,Tyr8]-GnRH) and catfish GnRH (cfGnRH: [His5,Asn8]-GnRH) are two endogenous forms of GnRH. Studying their effects on LH subunit steady-state mRNA levels, LH de novo synthesis, and LH release in primary pituitary cell cultures of adult males, we found that cGnRH-II hardly influenced the steady-state levels of LH subunit mRNAs or LH de novo synthesis, although it stimulated LH release.

Evolutionary development of three gonadotropin-releasing hormone (GnRH) systems in vertebrates.

Gonadotropin-releasing hormone (GnRH) is the neuropeptide that links the brain to the reproductive system. Most vertebrate species express two forms of GnRH, which differ in amino acid sequence, localization, distribution, and embryological origin. The GnRH system in the ventral forebrain produces a species-specific GnRH form and projects toward the gonadotropic cell in the pituitary.

Corticosteroids affect the testicular androgen production in male common carp (Cyprinus carpio L.).

Our previous experiments to study the effect of stress adaptation on pubertal development in carp showed that repeated temperature stress and prolonged feeding with cortisol-containing food pellets, which mimics the endocrine stress effects, retarded the first waves of spermatogenesis and decreased 11-ketotestosterone (11KT) plasma levels. The objective of the present study was to investigate whether the decrease in plasma 11KT is caused by a direct effect of cortisol on the steroid-producing capacity of the testis or by an indirect effect, such as a decrease in plasma LH. Pubertal and adolescent isogenic male common carp (Cyprinus carpio L.

Testosterone inhibits 11-ketotestosterone-induced spermatogenesis in African catfish (Clarias gariepinus).

Male fish produce 11-ketotestosterone as a potent androgen in addition to testosterone. Previous experiments with juvenile African catfish (Clarias gariepinus) showed that 11-ketotestosterone, but not testosterone, stimulated spermatogenesis, whereas testosterone, but not 11-ketotestosterone, accelerated pituitary gonadotroph development. Here, we investigated the effects of combined treatment with these two types of androgens on pituitary gonadotroph and testis development.

Metabolism of norethisterone and norethisterone derivatives in rat uterus, vagina, and aorta.

The 19-nor-progestogen norethisterone is used as a progestogen component in contraceptives and in continuous- and sequential combined hormone replacement therapy (HRT) in postmenopausal women. Metabolism of norethisterone in HRT target tissues may play a role in its biological response. The aim of this study was to investigate which steroid-metabolizing enzymes are present in rat uterus, vagina, and aorta, three HRT target tissues.