Domain Family Research Articles

Work-family interference and life satisfaction: the role of life goals

ABSTRACT The interface between work and family domains has received considerable scholarly attention in recent decades due to its substantial impact on outcomes related to work, family, health, and well-being. However, individuals experience this impact differently, with some demonstrating resilience while others are more vulnerable to negative effects. In this study, we investigate the role of individuals’ life goals and gender in the work-family interface, using the framework of the work-home resources model and selfregulation theory. Using Structural Equation Modeling with data from Waves 8 and 10 of the German Family Panel (pairfam), we found that life goals significantly moderate these effects: individuals prioritizing agentic goals feel the detrimental impact of work-to-family interference (WtFI) on life satisfaction more intensely than those who prioritize communal goals and those whose goals are balanced. In contrast, the effect of family-to-work interference (FtWI) on life satisfaction was significant only for individuals prioritizing communal goals, with no significant moderation effect observed across the other life goal groups. We observed no significant gender difference in the impact of either WtFI or FtWI on life satisfaction. We also discuss potential theoretical and practical implications in light of our findings.

Abstract 4116949: Specialized Pericyte Subtypes in the Pulmonary Capillary

Introduction: Lung pericytes (PCs) are mural cells in close contact with endothelial cells (ECs) in the microvasculature. A significant challenge in investigating PC biology is largely due to the absence of a unique cell marker, making it difficult to distinguish them from other mural cell populations. The identification of such a marker would allow investigators to describe the role of PCs in various diseases including pulmonary arterial hypertension. Hypothesis: We hypothesize that HIG1 hypoxia-inducible domain family member 1B ( Higd1b ) is exclusively expressed in lung PCs, which contributes to hypoxia (Hx)-induced vascular remodeling. Methods: We utilized single-cell RNA sequence (scRNA-seq) databases, spatial transcriptomics, and RNAscope from human and murine lungs to identify a PC-specific cell marker and compare the gene expression between PC subtypes. We utilized Cre-LoxP and CRISPR technology to construct a novel tamoxifen-inducible Higd1b-CreERT2 knock-in mouse model and performed lineage-tracing studies to describe the role of PC subtypes in Hx-induced pulmonary hypertension (PH). Results: ScRNA-seq analysis from the lungs of humans and mice identified Higd1b as a specific gene marker for PCs whose expression is absent in other mural cell populations. Validation with a reporter mouse line Higd1b-CreERT2::R26-tdT confirmed Higd1b-Cre+ cells specifically label PCs and no other mural cells ( Fig 1A ). Lineage tracing in the Hx-induced murine model of PH demonstrated the accumulation of PCs in the muscularized distal arterioles ( Fig 1B ). Through scRNA-seq and immunofluorescence validation, we identified two HIGD1B + PC subtypes that exist in the pulmonary capillary: Type 1 PCs, which are quiescent in the capillaries, and Type 2 PCs exhibit multipotent cell-like properties and accumulate in the arterioles after exposure to Hx. Furthermore, we found Type 2 PCs transited into SMC-like cells via the upregulation of Vimentin, contributing to vascular remodeling in Hx-induced PH. Conclusion: We identified Higd1b as a unique marker for PCs and generated a novel Higd1b-CreERT2 mouse that specifically labels PCs in the lungs. The discovery of PC-subtype specialization advances our understanding of lung pericyte biology and PC’s contribution to capillary remodeling under pathological conditions.

Proteomics analysis of extracellular vesicles for biomarkers of autism spectrum disorder

BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by symptoms that include social interaction deficits, language difficulties and restricted, repetitive behavior. Early intervention through medication and behavioral therapy can eliminate some ASD-related symptoms and significantly improve the life-quality of the affected individuals. Currently, the diagnosis of ASD is highly limited.MethodsTo investigate the feasibility of early diagnosis of ASD, we tested extracellular vesicles (EVs) proteins obtained from ASD cases. First, plasma EVs were isolated from healthy controls (HCs) and ASD individuals and were analyzed using proximity extension assay (PEA) technology to quantify 1,196 protein expression level. Second, machine learning analysis and bioinformatic approaches were applied to explore how a combination of EV proteins could serve as biomarkers for ASD diagnosis.ResultsNo significant differences in the EV morphology and EV size distribution between HCs and ASD were observed, but the EV number was slightly lower in ASD plasma. We identified the top five downregulated proteins in plasma EVs isolated from ASD individuals: WW domain-containing protein 2 (WWP2), Heat shock protein 27 (HSP27), C-type lectin domain family 1 member B (CLEC1B), Cluster of differentiation 40 (CD40), and folate receptor alpha (FRalpha). Machine learning analysis and correlation analysis support the idea that these five EV proteins can be potential biomarkers for ASD.ConclusionWe identified the top five downregulated proteins in ASD EVs and examined that a combination of EV proteins could serve as biomarkers for ASD diagnosis.

ZSCAN16 expedites hepatocellular carcinoma progression via activating TBC1D31

ObjectiveHepatocellular carcinoma (HCC) is fatal and poses great challenges to early diagnosis and effective treatment. This paper sought to expound the function of Zinc finger and SCAN domain-containing protein 16 (ZSCAN16) and TBC1 domain family member 31 (TBC1D31) in HCC progression.MethodsZSCAN16 and TBC1D31 levels were detected by RT-qPCR, Western blot, and immunohistochemistry. The transcriptional regulation of TBC1D31 by ZSCAN16 was demonstrated by ChIP-qPCR and dual-luciferase assay. Colony formation assay, migration and invasion assays, TUNEL staining, CCK-8 assay, flow cytometry, and western blot analysis were adopted to evaluate the biological activity of HCC cells. The role of the ZSCAN16/TBC1D31 axis in HCC was demonstrated by lentiviral gene intervention combined with functional rescue experiments. Hep3B cells were used to establish a nude mouse xenograft tumor model to study the role of the ZSCAN16/TBC1D31 axis in vivo.ResultsZSCAN16 and TBC1D31 were highly expressed in HCC. Downregulation of ZSCAN16 repressed the proliferation, migration, and invasion of HCC cells while promoting apoptosis, as well as curbing tumor growth in vivo. Mechanistic studies showed that ZSCAN16 mediated the transcriptional activation of TBC1D31, which in turn led to tumor development. TBC1D31 overexpression reversed the inhibitory effect of ZSCAN16 knockdown on the malignant behavior and tumor growth of HCC cells and accelerated tumor development.ConclusionZSCAN16 mediates transcriptional activation of TBC1D31 and promotes HCC progression.

Long non‑coding RNA SNHG1 promotes autophagy in vascular smooth muscle cells induced by facilitating CLEC7A.

Long non‑coding RNAs serve a crucial role in autophagy of vascular smooth muscle cells (VSMCs). The present study aimed to investigate the effect of small nucleolar RNA host gene 1 (SNHG1) on autophagy in VSMCs and the associated underlying mechanisms. Rapamycin was used to induce autophagy in VSMCs and the effects of SNHG1 on the proliferation and migration of VSMCs and the change in phenotype were tested following overexpression and silencing of SNHG1. The target gene of SNHG1 was predicted and validated. SNHG1‑regulated autophagy of VSMCs via C‑type lectin domain family 7 member A (CLEC7A) was determined by combined silencing of SNHG1 and overexpression of CLEC7A. Rapamycin‑induced autophagy in VSMCs changed the cell phenotype from contractile to synthetic, with decreased expression of α‑smooth muscle actin and smooth muscle protein 22a and increased expression of osteopontin. Overexpression of SNHG1 caused the same change in phenotype while the opposite change was observed following SNHG1 silencing. Overexpression of SNHG1 promoted the proliferation and migration of VSMCs. CLEC7A was identified as a target gene of SNHG1 and a direct binding relationship between them was confirmed by RNA immunoprecipitation and RNA pull‑down assays. Overexpression of SNHG1 increased the expression of CLEC7A. The expression of both SNHG1 and CLEC7A was increased during autophagy of VSMCs. Overexpression of SNHG1 promoted autophagy of VSMCs and silencing of CLEC7A reduced this effect of SNHG1. In conclusion, SNHG1 and CLEC7A were increased in VSMCs following autophagy. SNHG1 promotes the conversion of VSMCs from a contractile phenotype to a synthetic phenotype by facilitating CLEC7A expression.

Multiple Machine Learning Identifies Key Gene PHLDA1 Suppressing NAFLD Progression.

Non-alcoholic fatty liver disease (NAFLD) poses a serious global health threat, with its progression mechanisms not yet fully understood. While several molecular markers for NAFLD have been developed in recent years, a lack of robust evidence hampers their clinical application. Therefore, identifying novel and potent biomarkers would directly aid in the prediction, prevention, and personalized treatment of NAFLD. We downloaded NAFLD-related datasets from the Gene Expression Omnibus (GEO). Differential expression analysis and functional analysis were initially conducted. Subsequently, Weighted Gene Co-expression Network Analysis (WGCNA) and multiple machine learning strategies were employed to screen and identify key genes, and the diagnostic value was assessed using Receiver Operating Characteristic (ROC) analysis. We then explored the relationship between genes and immune cells using transcriptome data and single-cell RNA sequencing (scRNA-seq) data. Finally, we validated our findings in cell and mouse NAFLD models. We obtained 23 overlapping differentially expressed genes (DEGs) across three NAFLD datasets. Enrichment analysis revealed that DEGs were associated with Apoptosis, Parathyroid hormone synthesis, secretion and action, Colorectal cancer, p53 signaling pathway, and Biosynthesis of unsaturated fatty acids. After employing machine learning strategies, we identified one gene, pleckstrin homology like domain family A member 1 (PHLDA1), downregulated in NAFLD and showing high diagnostic accuracy. CIBERSORT analysis revealed significant associations of PHLDA1 with various immune cells. Single-cell data analysis demonstrated downregulation of PHLDA1 in NAFLD, with PHLDA1 exhibiting a significant negative correlation with macrophages. Furthermore, we found PHLDA1 to be downregulated in an in vitro hepatic steatosis cell model, and overexpression of PHLDA1 significantly reduced lipid accumulation, as well as the expression of key molecules involved in hepatic lipogenesis and fatty acid uptake, such as FASN, SCD-1, and CD36. Additionally, gene set enrichment analysis (GSEA) pathway enrichment analysis suggested that PHLDA1 may influence NAFLD progression through pathways such as Cytokine Cytokine Receptor Interaction, Ecm Receptor Interaction, Parkinson's Disease, and Ribosome pathways. Our conclusions were further validated in a mouse model of NAFLD. Our study reveals that PHLDA1 inhibits the progression of NAFLD, as overexpression of PHLDA1 significantly reduces lipid accumulation in cells and markedly decreases the expression of key molecules involved in liver lipogenesis and fatty acid uptake. Therefore, PHLDA1 may emerge as a novel potential target for future prediction, diagnosis, and targeted prevention of NAFLD.

Silencing METTL3 Increases HSP70 Expression and Alleviates Fibrosis in Keratocytes.

To explore the potential role of N6-methyladenosine (m6A) and its regulatory factors in corneal fibrosis response using both in vivo and in vitro models. This study utilized the C57BL/6 mouse corneal alkali burn as an in vivo model and stimulated keratocytes with transforming growth factor beta 1 (TGF-β1) in vitro. Small interfering RNA (siRNA) was employed to downregulate the expression of YTH domain family member 2 (YTHDF2), methyltransferase-like 3 (METTL3), and fat mass and obesity-associated protein (FTO) in keratocytes. The expression of relevant genes was quantified by real-time quantitative reverse-transcription PCR (qRT-PCR), western blotting, and immunohistochemistry. After an alkali burn, m6A modification in corneas increased, with the most notable increase observed on the fourth day after the injury. The levels of METTL3 and FTO initially decreased and then increased. After 21 days following an alkali burn, the corneal fibrosis was most significant. The levels of METTL3 and FTO were elevated. There were higher levels in m6A modification and the expression of METTL3 and FTO in keratocytes stimulated by TGF-β1. In corneas after alkali burns and in keratocytes stimulated by TGF-β1, the expression of heat shock protein 70 (HSP70) was negatively correlated with fibrotic response markers. Silencing METTL3 and YTHDF2 in keratocytes increased HSP70 expression and reduced the expression of fibrosis-related indicators in keratocytes stimulated by TGF-β1. However, silencing FTO did not significantly affect the expression of HSP70 and fibrosis. These findings indicate that METTL3 is involved in the modulation of corneal fibrosis through the regulation of HSP70 expression in a manner that is dependent on YTHDF2.

Massively Parallel Screening of Toll/Interleukin-1 Receptor (TIR)-Derived Peptides Reveals Multiple Toll-Like Receptors (TLRs)-Targeting Immunomodulatory Peptides.

Toll-like receptors (TLRs) are critical regulators of the immune system, and altered TLR responses lead to a variety of inflammatory diseases. Interference of intracellular TLR signaling, which is mediated by multiple Toll/interleukin-1 receptor (TIR) domains on all TLRs and TLR adapters, is an effective therapeutic strategy against immune dysregulation. Peptides that inhibit TIR-TIR interactions by fragmenting interface residues have potential as therapeutic decoys. However, a systematic method for discovering TIR-targeting moieties has been elusive, limiting exploration of the vast, unsequenced space of the TIR domain family. A comprehensive parallel screening method is developed to uncover novel TIR-binding peptides derived from previously unexplored surfaces on a wide range of TIR domains. A large peptide library is constructed, named TIR surfacesome, by tiling surface sequences of the large TIR domain family and screening against MALTIR and MyD88TIR, TIRs of two major TLR adaptor proteins, resulting in the discovery of hundreds of TIR-binding peptides. The selected peptides inhibited TLR signaling and demonstrated anti-inflammatory effects in macrophages, and therapeutic potential in mouse inflammatory models. This approach may facilitate the development of TLR-targeted therapeutics.

Bromodomain and extraterminal domain (BET) promote autophagy in buffalo sertoli cells

Sertoli cells (SCs) play a pivotal role in spermatogenesis, with autophagy modulation being an evolutionarily conserved mechanism for maintaining cellular homeostasis and protecting spermatogenic cells against apoptosis. The bromodomain and extraterminal domain (BET) family are transcriptional regulators of autophagy. This study investigated the relationship between BET inhibition and autophagy in buffalo SCs. Our findings reveal that BET inhibition suppresses cell proliferation and alters the biological characteristics of SCs. RNA-seq analysis demonstrated significant downregulation of autophagy-related genes upon BET inhibition. Moreover, our bioinformatics analysis suggested the involvement of the PI3K-AKT signaling pathway in autophagy regulation within buffalo SCs. Immunofluorescence and Transmission electron microscopy observations indicated that BET inhibition results in autophagosome accumulation and impedes autophagosome-lysosome degradation, thereby compromising autophagy activity and flux. In summary, this study sheds light on the indispensable role of BET proteins in autophagy and paves the way for further investigations into the mechanisms governing BET protein-mediated autophagy regulation and its implications for male reproduction.

The deficient CLEC5A ameliorates the behavioral and pathological deficits via the microglial Aβ clearance in Alzheimer’s disease mouse model

BackgroundAlzheimer’s disease (AD) is a neurodegenerative disease that causes cognitive dysfunction in older adults. One of the AD pathological factors, β-Amyloid (Aβ), triggers inflammatory responses and phagocytosis of microglia. C-type lectin domain family 5 member A (CLEC5A) induces over-reactive inflammatory responses in several virus infections. Yet, the role of CLEC5A in AD progression remains unknown. This study aimed to elucidate the contribution of CLEC5A to Aβ-induced microglial activation and behavioral deficits.MethodsThe AD mouse model was crossed with Clec5a knockout mice for subsequent behavioral and pathological tests. The memory deficit was revealed by the Morris water maze, while the nociception abnormalities were examined by the von Frey filament and hotplate test. The Aβ deposition and microglia recruitment were identified by ELISA and immunohistochemistry. The inflammatory signals were identified by ELISA and western blotting. In the Clec5a knockdown microglial cell model and Clec5a knockout primary microglia, the microglial phagocytosis was revealed using the fluorescent-labeled Aβ.ResultsThe AD mice with Clec5a knockout improved Aβ-induced memory deficit and abnormal nociception. These mice have reduced Aβ deposition and increased microglia coverage surrounding the amyloid plaque, suggesting the involvement of CLEC5A in AD progression and Aβ clearance. Moreover, the phagocytosis was also increased in the Aβ-stressed Clec5a knockdown microglial cell lines and Clec5a knockout primary microglia.ConclusionThe Clec5a knockout ameliorates AD-like deficits by modulating microglial Aβ clearance. This study implies that targeting microglial Clec5a could offer a promising approach to mitigate AD progression.

The relationships between resilience and child health behaviors in a national dataset.

Resilience mechanisms at the individual, family, and environmental levels may improve health outcomes despite potentially harmful stress exposure partly through the practice of positive health behaviors. We performed a secondary analysis of 2016-2021 National Survey of Children's Health data to assess the relationships between three resilience domains - child, family, neighborhood - and six health behaviors using multiple regression models adjusted for the other resilience domain(s) and potential confounders. Analysis revealed significant associations between each resilience domain and multiple health behaviors in a total weighted analytic sample of 70,156,540 children. For each outcome, the odds of better health behaviors were highest with high resilience in all possible domains. For example, among children ages 0-5 years, the adjusted odds of having "good quality" vs. "poor quality" sleep for those with "high" resilience in all domains were 2.21 times higher (95% CI 1.78, 2.63) than for those with "low" resilience in all domains. This line of research may help to inform the design of resilience and health behavior promotion interventions by targeting multiple socio-ecological domains of influence to improve health and development outcomes in children exposed to experiences or sources of potential stress. This study assessed the associations between three socio-ecological resilience domains (child, family, and neighborhood) and six child and family health behaviors in a national dataset. Resilience exists within multiple socio-ecological levels and supports healthy functioning despite experiencing stress. Studies in adults and limited pediatric sub-populations show associations between resilience and health behaviors, which in turn influence numerous health outcomes. Resilience at three levels of socio-ecological levels was found to be associated with the performance of multiple child and family health behaviors in a nationally representative general pediatric population. These findings have important implications for child and family health promotion efforts.

A High-Throughput Screen for Antiproliferative Peptides in Mammalian Cells Identifies Key Transcription Factor Families.

Transcription factors (TFs) are a promising therapeutic target for a multitude of diseases. TFs perform their cellular roles by participating in multiple specific protein-protein interactions. For example, homo- or heterodimerization of some TFs controls DNA binding, while interactions between TFs and components of basal transcriptional machinery or chromatin modifiers can also be critical. While, in theory, small molecules could be used to disrupt specific protein-protein interfaces required for TF function, in practice, it is difficult to identify small molecules with the necessary specificity and efficacy, likely due to the extensive protein-protein interfaces that often underlie TF function. However, in contrast to small molecules, peptides have the potential to provide both the specificity and efficacy required to disrupt such interfaces. Here, we identified ∼15 peptides that inhibit the proliferation of leukemia cells using a high-throughput pooled screen of a library of 80-mer protein regions (peptides) derived from human nuclear-localized proteins. The antiproliferative peptides were enriched for regions known to be involved in specific TF dimerization, including the basic leucine zipper (bZIP) domain family. One of these bZIP domains, JDP2;bZIP_1, from the TF JDP2, was the top antiproliferative peptide, reducing the proliferation of K562 cells by 2-fold. JDP2;bZIP_1 inhibited AP-1 transcriptional activity and phenocopied JDP2 overexpression, suggesting that the peptide affected proliferation through a native JDP2 mechanism. Unexpectedly, given the strong conservation of the bZIP domain, residues outside of the annotated dimerization domain were critical for the peptide's antiproliferative potency. The peptide-mediated antiproliferative effect initiated erythrocyte differentiation in K562 cells and increased G0/G1 cells across multiple cell line models. We also found that many of the antiproliferative peptides identified in this study, including JDP2;bZIP_1, did not require a nuclear localization signal to function, a potential benefit for delivering these peptides in therapeutic applications.

Intergenerational transmission and multilingual dynamics: exploring language policies in Chaoshan families through a contextual lens

ABSTRACT Amidst the rapid processes of industrialization and globalization, the interplay between minority and majority languages has garnered increasing attention, highlighting concerns surrounding linguistic diversity and the efficacious enactment of language policies. This study delves into the intricacies of language planning within the familial domain, specifically scrutinizing Chaoshan families in the Chaoshan region as pivotal arenas for nurturing the enduring vitality of Teochew. Employing a methodological approach integrating family visits, interaction recordings, and interviews, this study probes the dynamics of family language policies and individuals’ perceptions vis-à-vis the nexus between linguistic practices and identity formation, with particular emphasis on intergenerational transmission. The results highlight that although Teochew continues to be actively used in family conversations and is closely linked to local identity formation, it is gradually losing ground among younger generations. This decline in passing down the dialect from one generation to the next is noticeable and poses a challenge to its long-term continuity. These insights indicate potential challenges to the sustained perpetuation of Teochew, warranting concerted societal and individual endeavors to safeguard its status as a cherished linguistic asset. The study underscores the importance of societal and individual efforts in preserving Teochew as a valuable linguistic resource.

Dark Microglia Are Abundant in Normal Postnatal Development, where they Remodel Synapses via Phagocytosis and Trogocytosis, and Are Dependent on TREM2.

This study examined dark microglia-a state linked to central nervous system pathology and neurodegeneration-during postnatal development in the mouse ventral hippocampus, finding that dark microglia interact with blood vessels and synapses and perform trogocytosis of pre-synaptic axon terminals. Furthermore, we found that dark microglia in development notably expressed C-type lectin domain family 7 member A (CLEC7a), lipoprotein lipase (LPL) and triggering receptor expressed on myeloid cells 2 (TREM2) and required TREM2, differently from other microglia, suggesting a link between their role in remodeling during development and central nervous system pathology. Together, these results point towards a previously under-appreciated role for dark microglia in synaptic pruning and plasticity during normal postnatal development.

The importance of recognition: predictors and outcomes of carer recognition among working carers of ageing relatives

ABSTRACT Many people manage the dual roles of employment and providing unpaid care for an older relative. Although this is increasingly common, carers frequently observe that their caring role is undervalued. This lack of recognition and the adverse consequences that flow from it are of increasing interest to policymakers, advocacy bodies, and employers who have advanced legislative, policy, and workplace accreditation initiatives to enhance recognition of caring. However, the design and impact of these initiatives are constrained by the scarcity of research on carer recognition, its predictors, and its outcomes. Drawing on data from the Australian National Carer Survey, we utilise path analysis to test a conceptual model outlining how life experiences shape carer recognition and subsequent personal outcomes. Our findings provide support for the mediating role of carer recognition linking care-related disruptions in multiple domains (aged care services, employment, family) with carer outcomes (social connectedness, personal well-being, psychological distress, personal time alongside caring). Employees who experienced less disruption in aged care services, employment, and family domains reported higher carer recognition and better outcomes than employees with more disruptive experiences in each domain. The findings suggest new points of intervention to enhance carer perceptions of recognition, and in turn, carer outcomes.

Roles of the Dbl family of RhoGEFs in mechanotransduction - a review.

Rho guanine nucleotide exchange factors (RhoGEFs) comprise a wide range of proteins with a common domain responsible for the activation of the Rho family of small GTPases and various domains in other regions. The evolutionary divergence of RhoGEFs enables actin cytoskeletal reorganization, leading to complex cellular responses in higher organisms. In this review, we address the involvement of RhoGEFs in the mechanical stress response of mammalian cells. The cellular mechanical stress response is essential for the proper and orderly regulation of cell populations, including the maintenance of homeostasis, tissue morphogenesis, and adaptation to the mechanical environment. In particular, this review focuses on the recent findings regarding the Dbl family of RhoGEFs involved in mechanical stress responses at the cell-cell and cell-substrate adhesion sites, and their molecular mechanisms underlying actin cytoskeleton remodeling and signal transduction.

Navigating the Gap Between Correlational and Intervention Studies of Fatherhood and Children’s Development: A Family Systems Ecological Perspective

SYNOPSIS Objective. In fatherhood research, a large gap has emerged between correlation-based studies and the design of interventions to increase the quantity and quality of fathers’ involvement in their families. The correlational research suggests that all family members could benefit from fatherhood intervention designs that attempt to reduce risks and strengthen protective conditions in multiple family domains—an approach consistent with family systems theories and ecological theories of child development. But most fatherhood interventions have been designed solely for fathers and focus primarily on parenting. Even in rare instances in which both parents are included in a father-focused parenting intervention, the curriculum rarely attends to the quality of relationship between the co-parents, despite the fact that this relationship is a prime correlate and predictor of father involvement and father-child relationship quality. Design. This narrative review describes the current gap between multidimensional correlational studies of fathers and families and the restricted designs of most father involvement interventions. We describe a family systems ecological intervention approach to bringing the correlational and intervention streams of fatherhood research closer together. Results. Evidence from empirical studies of correlations between risk/protective factors and outcomes supports a family systems ecological model of five domains relevant for inclusion in fatherhood intervention curricula and measurement protocols. Evaluations of interventions based on these five domains show that when both parents participate, the interventions have greater impact than interventions directed only to fathers. Fathering is not simply behavior that occurs between a father and his child. In addition to the quality of his direct interaction with his child, fathering is a dynamic product of his well-being, the quality of the relationship between the co-parents, the transmission of behavioral patterns across generations, and the balance between outside-the-family stressors and the supports available to cope with them. Conclusions. This family systems ecological approach has implications for theory testing, future intervention research, and policy decisions about fatherhood services.

TBC1D15-regulated mitochondria–lysosome membrane contact exerts neuroprotective effects by alleviating mitochondrial calcium overload in seizure

Mitochondrial calcium overload plays an important role in the neurological insults in seizure. The Rab7 GTPase-activating protein, Tre-2/Bub2/Cdc16 domain family member 15 (TBC1D15), is involved in the regulation of mitochondrial calcium dynamics by mediating mitochondria–lysosome membrane contact. However, whether TBC1D15-regulated mitochondria–lysosome membrane contact and mitochondrial calcium participate in neuronal injury in seizure is unclear. We aimed to investigate the effect of TBC1D15-regulated mitochondria–lysosome membrane contact on epileptiform discharge-induced neuronal damage and further explore the underlying mechanism. Lentiviral vectors (Lv) infection and stereotaxic adeno-associated virus (AAV) injection were used to regulate TBC1D15 expression before establishing in vitro epileptiform discharge and in vivo status epilepticus (SE) models. TBC1D15’s effect on inter-organellar interactions, mitochondrial calcium levels and neuronal injury in seizure was evaluated. The results showed that abnormalities in mitochondria–lysosome membrane contact, mitochondrial calcium overload, mitochondrial dysfunction, increased levels of reactive oxygen species, and prominent neuronal damage were partly relieved by TBC1D15 overexpression, whereas TBC1D15 knockdown markedly deteriorated these phenomena. Further examination revealed that epileptiform discharge-induced mitochondrial calcium overload in primary hippocampal neurons was closely associated with abnormal mitochondria–lysosome membrane contact. This study highlights the crucial role played by TBC1D15-regulated mitochondria–lysosome membrane contact in epileptiform discharge-induced neuronal injury by alleviating mitochondrial calcium overload.

Distinguished varieties in a family of domains associated with spectral interpolation and operator theory

We find characterization for the distinguished varieties in the symmetrized polydisc $\mathbb G_n \; (n\geq 2)$ and thus generalize the work [\textit{J. Funct. Anal.}, 266 (2014), 5779 -- 5800] on $\mathbb G_2$ by the author and Shalit. We show that a distinguished variety $\Lambda$ in $\mathbb G_n$ is a part of an algebraic curve, which is a set-theoretic complete intersection, and that $\Lambda$ can be represented by the Taylor joint spectrum of $n-1$ commuting scalar matrices satisfying certain conditions. An $n$-tuple of commuting Hilbert space operators $(S_1, \dots ,S_{n-1},P)$ for which $\Gamma_n=\overline{\mathbb G_n}$ is a spectral set is called a $\Gamma_n$-contraction. To every $\Gamma_n$-contraction $(S_1, \dots ,S_{n-1},P)$ there is a unique operator tuple $(F_1, \dots , F_{n-1})$, called the $\mathcal F_O$-tuple of $(S_1, \dots ,S_{n-1},P)$, satisfying \[ S_i-S_{n-i}^*P=D_PF_iD_P \,,\quad i=1, \dots ,n-1. \] We produce concrete functional model for the pure isometric-operator tuples associated with $\Gamma_n$ and by an application of that model we establish that the $\Gamma_n$-contractions $(S_1, \dots ,S_{n-1},P)$ and $(S_1^*, \dots , S_{n-1}^*,P^*)$ admit normal $\partial \overline{ \Lambda}_{\Sigma}-$dilations for a unique distinguished variety $\Lambda_{\Sigma}$ in $\mathbb G_n$, when $\Lambda_{\Sigma}$ is determined by the $\mathcal F_O$-tuple of $(S_1, \dots ,S_{n-1}, P)$. Further, we show that the dilation of $(S_1^*, \dots ,S_{n-1}^*,P^*)$ is minimal and acts on the minimal unitary dilation space of $P^*$. Also, we show interplay between the distinguished varieties in $\mathbb G_2$ and $\mathbb G_{3}$.

Discovery of reversible and covalent TEAD 1 selective inhibitors MSC-1254 and MSC-5046 based on one scaffold

The Transcriptional Enhanced Associated Domain (TEAD) family of transcription factors are key components of the Hippo signalling family which play a crucial role in the regulation of cell proliferation, differentiation and apoptosis. The identification of inhibitors of the TEAD transcription factors are an attractive strategy for the development of novel anticancer therapies. A HTS campaign identified hit 1, which was optimised using structure-based drug design, to deliver potent TEAD1 selective inhibitors with both a reversible and covalent mode of inhibition. The preference for TEAD1 could be rationalised by steric differences observed in the lower pocket of the palmitoylation-site between subtypes, with TEAD1 having the largest available volume to accommodate substitution in this region