A Queensland Health report points out that Māori and Pacific Island communities in Queensland are vulnerable due to social disadvantage and limited health service access. The researcher applies decolonisation and cultural safety models, emphasising the importance of understanding the historical, political, and socio-contextual determinants of these groups. Ethical considerations as applied in this research must be flexible and culturally safe, focusing on a reflective and respectful approach to data collection. The literature review is based on Charmaz's constructivist contextual framework, which underpins and later reveals that the socio-contextual determinants for Māori and Pacific Island communities in Queensland are multifaceted, with one direct factor being disengagement from child and family health services. To explore this, qualitative research used both decolonisation and cultural safety methodologies, with a focus on ethical considerations and the service user's experience, specifically examining how care is delivered, and not just the type of care provided. Embracing a decolonial perspective, the Talanoa method guided the data collection process. This involved interviewing 29 Māori and Pacific Island families in Townsville and Brisbane, as well as eight child health service providers in these areas. During data analysis, key interpretations were informed by conceptualisations of culturally safe health service delivery, supported by Charmaz's constructivist grounded theory, which aligns with the cultural safety methodology. The data analysis revealed key themes, including power dynamics, positionality, and identity versus cultural differences, the deficit discourse of trans-culturalism, and cultural disconnection in the portrayal of health service delivery to Queensland Māori and Pacific Island families. In this research context, trans-culturalism is associated with a deficit discourse. The application of the theoretical framework of cultural safety and decolonisation was two-fold; it reveals the importance of working in partnership and reveals significant power imbalances, causing a lack of engagement between service users and service providers. Furthermore, it reveals the unexamined privileges of service providers and the inherent marginalisation of service users. Of significance to the research problem statement, the 'lack of uptake of health service delivery', the grounded theoretical and traditional perspectives of cultural safety and decolonisation shift the focus from service users (Māori and Pacific Island communities) to explore the experiences of child health service providers in their interactions with Māori and Pacific Island families. The analysis uncovered misconceptions and a tendency to assume that healthcare delivery using a trans-cultural approach was culturally safe. Unearthing an understanding that challenges the deficit discourse of trans-culturalism to comprehend participants' positionality is essential for resolving and addressing the health issues faced by Queensland Māori and Pacific Island families accessing services. This recognition indicates an ongoing reliance on colonial imposition rather than promoting (a principle of cultural safety) self-determination in access to health service delivery for Queensland Māori and Pacific Island families.

Restoring disc matrix homeostasis: Dual-miRNA and human platelet lysate as a novel therapeutic strategy.

Recent advances in sex-specific reproductive microphysiological systems for the systematic evaluation of assisted reproductive technology.

Climate-resilient urban housing in sub-Saharan Africa: A decision support framework integrating cultural behavior modeling with multi-objective optimization

Understanding the causes of autism in sub-Saharan Africa remains limited, contributing to stigma and delayed identification. This multi-site qualitative study examined community explanatory models of autism and related help-seeking practices in Northern Uganda. Data were generated through 25 semi-structured interviews and 4 focus group discussions (N = 64) across 1 urban and 2 rural districts in the Acholi sub-region. Participants included autistic young people, caregivers, health and education professionals, community, cultural and religious leaders, and government representatives. Data were analysed inductively. Four interrelated themes were identified: unknown causes, supernatural explanations, biopsychosocial attributions, and help-seeking pathways. Autism was frequently misunderstood and conflated with 'mental illness' or general learning difficulties. Supernatural accounts, such as witchcraft, curses, and divine punishment, were prevalent and often gendered, with mothers disproportionately blamed. Biopsychosocial explanations included contraceptive use, obstetric complications, genetic factors, and post-conflict trauma. These causal beliefs shaped different help-seeking trajectories, typically prioritising religious and traditional interventions before biomedical care. Stigmatising interpretations were linked to social exclusion, neglect, physical abuse, and, in extreme cases, infanticide. Findings highlight the entanglement of cultural, spiritual, and biomedical models in a post-conflict, low-resource context. Interventions addressing misconceptions and maternal blame may reduce stigma, support earlier identification, and prevent avoidable harms.Lay AbstractThis study looked at how people in Northern Uganda think about autism and what they believe causes it. Researchers spoke with 25 people through one-on-one interviews and 4 group discussions (with 8-10 people per group for a total of 39 people) in 3 districts of the Acholi region of Uganda, covering both urban and rural areas. The data were transcribed and interpreted to understand what seemed most important across all the participants from the interviews and focus groups. Four main themes were identified: (1) Unknown causes, (2) Supernatural causes, (3) Biopsychosocial causes, and (4) Help-seeking responses. Overall, the study found that autism is often poorly understood. Many participants linked it to supernatural explanations, such as witchcraft or punishment from God. Mothers were often blamed and seen as responsible for their child's condition. People also pointed to wider influences, including modern medical interventions and the long-term effects of war and displacement, as possible causes. These beliefs led to traditional, religious, and modern medical help-seeking responses. Where families followed traditional responses, this could have serious consequences, including harm or even death for the child. This study highlights the importance of working with communities in culturally respectful ways to better understand their perspectives. This can lead to earlier recognition, reduced stigmatisation, better education, and stronger support.

Effective cell adhesion under challenging mechanical situations is critical for a vital soft tissue sealing of the transmucosal parts of dental implants and thus essential for oral wound healing. To investigate this process in vitro, we developed a versatile flow chamber model that applies defined shear stress to assess the adhesion strength of relevant cell types. The system focuses mainly on primary human gingival fibroblasts, with preliminary experiments including also gingival keratinocytes. The chamber accommodates standard-sized titanium sample geometries used in projects dedicated to develop surface modifications preventing peri-implantitis. Actual shear stress was determined through computational fluid dynamics software, targeting a central 5×5mm region used for cell seeding. Shear stress ranged from 0.05Pa (0.4ml/min) to 0.49Pa (4ml/min). Key variables studied included shear stress magnitude and duration of the dynamic phase. We assessed two titanium surface topographies-polished and nanodiamond-coated-to explore the role of nano-roughness in resisting detachment. Results demonstrated that topography significantly influences cell retention, with highest differences observed under 0.36Pa shear stress for 1 to 2h of dynamic phase. Furthermore, we adapted the model to simulate wound healing, revealing that surface topography impacts repopulation dynamics. Of two compared arrangements for the co-culture of fibroblasts and keratocytes, either sequential seeding of keratinocytes on top of pre-seeded fibroblast or simultaneously in adjacent regions, we prefer the latter approach for this specific dynamic model. Overall, in all model modifications the nanorough surfaces supported a more stable attachment of both fibroblasts and keratinocytes, with greater shear sensitivity of the keratinocytes. This model offers a reproducible, physiologically relevant platform to evaluate adhesion strength and wound healing, with potential for future application in biomaterial screening and implant design.

Microvilli are conserved actin-based protrusions that expand surface area and absorptive capacity in epithelial tissues. In humans, the intestinal tract grows 300 trillion microvilli per day, yet the molecular mechanisms defining where and when microvilli grow remain unclear. Using a combination of live-cell confocal and super-resolution microscopy to investigate native intestinal tissues and epithelial cell culture models, we found that microvilli grow from Arp2/3-generated branched actin networks that form on the surface of clathrin-coated pits. These transient networks are stabilized by cortactin and localize to the apical plasma membrane minutes before reorganizing into the linear core actin bundles that support microvilli. Moreover, subpixel precision localization of coated pit and microvilli markers revealed that F-actin asymmetrically localizes to one side of a nascent clathrin-coated pit, and that microvilli grow from the side with the highest F-actin density. These findings support a model where the asymmetric accumulation of F-actin and growing barbed ends on the surface of a clathrin-coated pit offers a filament source to support microvilli formation.

Mitochondrial fusion orchestrated by hepatitis E virus couples pro-viral autophagy and innate immune evasion for efficient replication.

The evolution of in vitro culture systems for the study of hepatitis E virus infection.

Artificial ovary systems for fertility preservation: Current advances, bioengineering strategies, and translational perspectives.

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by cognitive decline and memory loss. Current treatments offer limited efficacy, necessitating the development of innovative multitarget therapeutic strategies. Here, we present N3,N5-bis(2-(5-methoxy-1H-indol-3-yl)ethyl)-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxamide (HCM-01), a novel compound developed to target multiple neurodegenerative pathways implicated in AD. In vitro assays included MTT-based cell viability analyses performed in two complementary experimental settings: primary neuronal cultures and astrocyte-based in vitro cell culture models exposed to glutamate. In primary hippocampal neuronal cultures, glutamate exposure induced a statistically significant reduction in cell viability compared with vehicle-treated controls, consistent with glutamate-induced excitotoxicity. Under these conditions, HCM-01 treatment resulted in a statistically significant improvement in neuronal viability, showing a greater protective effect compared with donepezil and memantine. In contrast, in astrocyte-based in vitro cultures, the applied glutamate concentration did not induce overt cytotoxicity, in line with the intrinsic neuroprotective and glutamate-buffering role of astrocytes. Accordingly, astrocytic experiments were designed to assess functional modulation of glutamate-handling mechanisms rather than cell survival. Western blot analysis in C8-D1A astrocytic cells demonstrated increased expression of excitatory amino acid transporter 2 (EAAT2) following HCM-01 treatment compared with control and reference drug-treated groups, suggesting modulation of astrocyte-mediated glutamate homeostasis. In parallel, redox analyses revealed that HCM-01 improved oxidative/antioxidative balance, as evidenced by increased total antioxidant capacity (TAC) and reduced total oxidant status (TOS), supporting an indirect antioxidant contribution to its functional effects. In vivo behavioral assessment of HCM-01 in a streptozotocin (STZ)-induced Alzheimer's model in female Sprague-Dawley rats demonstrated that administration of HCM-01 at doses of 50 mg/kg orally (oral, P.O. and intraperitoneal, I.P.) and 100 mg/kg (P.O.), significantly improved cognitive and memory functions in the passive avoidance (PA), Morris water maze (MWM), and locomotor activity tests. Moreover, histopathological and immunohistochemical analyses of different hippocampal regions revealed reduced neuronal damage, attenuation of tau pathology, antiamyloidogenic effect, and restoration of cholinergic function. Complementary in silico studies, including molecular docking, molecular dynamics simulations (MDS), and free energy calculations, suggested potential interactions of HCM-01 with the allosteric site of EAAT2. Taken together, these findings suggest that HCM-01 exerts neuroprotective effects against glutamate-induced excitotoxicity in primary hippocampal neurons while additionally modulating glutamatergic homeostasis and redox balance through functional mechanisms in astrocyte-based models, supporting its relevance as a multitarget preclinical candidate for early stage AD mechanisms.

Axon initial segment (AIS) dysfunction disrupts neuronal compartmentalization, which leads to pathological processes like Tau missorting in Alzheimer's disease (AD). However, the molecular mechanisms that destabilize the AIS scaffold are incompletely understood. Our group has previously shown that the Abl1 non-receptor tyrosine kinase is aberrantly activated in AD mouse models and promotes dendritic spine collapse, Tau hyperphosphorylation, and neuronal apoptosis. Given the important role of Abl1 in AD and its emerging significance in Tau pathology, we examined how it contributes to AIS collapse. We find that activation of Abl1 by amyloid-β fibrils promotes AIS disruption, as determined by the loss of clustered AnkG in the proximal axon, and that this can be prevented by pharmacological inhibition of Abl kinases. Cytosolic extraction experiments show that active Abl1 associates to the AIS scaffold, and this association increases in response to amyloid-β fibril treatment. Furthermore, using expansion microscopy, we show that Abl1 localizes to the AIS in dissociated hippocampal cultures and in mouse brain slices. We find a decrease in AIS actin patches, key for maintenance of neuronal compartmentalization, following Abl kinase activation. Finally, we show that Abl1 activation promotes missorting of somatodendritic Rab11 into the axon and the axonal protein Tau into the somatodendritic compartment, indicating a bidirectional failure in AIS barrier function. Taken together, our results show that Abl1 plays an important role in AIS destabilization and that its activation compromises protein compartmentalization in a primary neuron culture model of AD.

CYLD cutaneous syndrome (CCS) skin tumours develop from puberty onwards, can number in the hundreds and progressively grow over time. Patients with CCS lack medical therapies and require repeated surgery to control tumour burden. CYLD loss of heterozygosity drives tumour growth, and CCS tumours have previously been shown to demonstrate increased canonical nuclear factor kappa B (NF-κB) and Wnt signalling. To investigate NF-κB signalling in CCS tumours and CCS tumour keratinocytes, with the aim of identifying druggable targets. We used complementary bulk transcriptomics and proteomics in patient-derived CCS tumour cell fractions, as well as single-cell RNA sequencing of CCS tumour cells to investigate aberrant NF-κB signalling. We developed a patient-derived CCS tumour spheroid culture model to determine the utility of targeting aberrant NF-κB cell signalling. We demonstrate evidence of non-canonical NF-κB signalling in CCS tumour keratinocytes, with increased p100 to p52 processing and RelB protein expression compared with normal skin. We identify IκB kinase alpha (IKKα) as a candidate target in the noncanonical NF-κB signalling pathway. A novel, highly selective IKKα inhibitor (SU1644) used in patient-derived CCS tumour spheroid cultures demonstrated that IKKα inhibition reduced tumour spheroid viability. These data provide the preclinical rationale for the assessment of topical IKKα inhibitors as a novel preventive treatment for CCS.

Endometriosis (EMs) is a prevalent gynecological disorder characterized by the ectopic growth of functional endometrial tissue, and its fibrotic pathology represents a primary contributor to chronic pain and infertility in affected patients. Hypoxia, a hallmark of the endometriotic microenvironment, is a well-established driver of fibrogenesis. However, the precise molecular mechanisms translating hypoxic signaling into pro-fibrotic responses remain elusive. The mechanosensitive ion channel Piezo1 is recognized as a contributor to fibrosis in various diseases; whereas its specific role in endometriosis is poorly understood. We demonstrate that hypoxia-inducible factor 1-alpha (HIF-1α) and Piezo1 are co-upregulated alongside fibrosis in EMs patient lesions. Functionally, both hypoxia and Piezo1 agonism promote fibrogenesis in HESCs. Mechanistically, hypoxia acts through Piezo1 to induce Ca²⁺-dependent mitochondrial damage and mitochondrial DNA (mtDNA) leakage, which in turn activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling and subsequently drives fibrosis. Therefore, we identifying the axis as a promising therapeutic target for future intervention. This study combines clinical tissue analysis with in vitro cellular experiments. Normal endometrial tissue, eutopic and ectopic endometrial samples from patients with endometriosis were collected. Immunohistochemistry (IHC), immunofluorescence (IF), western blotting, and quantitative reverse transcription PCR (qRT-PCR) were used to analyse the expression levels of HIF-1α, Piezo1, cGAS, STING, and the fibrosis markers α-smooth muscle actin (α-SMA) and type I collagen (Collagen I). In vitro experiments, we utilized HESCs to establish a hypoxic culture model. IF, western blotting, and qRT-PCR were employed to assess the expression of HIF-1α, Piezo1, and fibrosis-related markers across experimental conditions. Combined flow cytometric analysis and EdU assays, 24h was selected as the optimal intervention duration for subsequent experiments. To clarify the role of Piezo1, its activity was modulated via lentiviral knockdown or agonist (Yoda1) activation. Cytosolic and mitochondrial Ca²⁺ fluxes were tracked with fluorescent probes; mitochondrial morphology and function were evaluated by immunofluorescence and JC-1 staining. Cytosolic mtDNA leakage was quantified by immunofluorescence and qRT-PCR. We report that Piezo1 and HIF-1α are co-upregulated in ectopic endometrial lesions, correlating with fibrotic severity. The expression of HIF-1α and Piezo1 was time-dependently induced by hypoxia in HESCs. Mechanistically linking hypoxia to fibrosis, we found that hypoxia-induced Piezo1 upregulation drives mitochondrial damage and mtDNA release into the cytosol, which activates the cGAS-STING pathway and ultimately upregulates the fibrosis markers α-SMA and collagen I. Consequently, genetic or pharmacological inhibition of Piezo1, as well as blockade of cGAS with RU.521 or STING with C-176, effectively suppressed cGAS-STING pathway activation and attenuated fibrosis in HESCs. Piezo1 exerts a crucial regulatory function in the process of hypoxia-driven fibrogenesis in endometriosis. This study reveals the central role of the hypoxia/Piezo1/mtDNA/cGAS-STING signaling axis in EMs fibrosis and provides a novel therapeutic strategy for targeting this pathway to delay EMs progression.

Proper spindle orientation is essential for organogenesis and tissue homeostasis. Cortical tethering complexes, such as the Gαi-LGN-NuMA complex, anchor astral microtubules to guide spindle orientation. However, how astral microtubule stability is coupled to mitosis-dependent regulatory mechanisms remains unclear. Here, we identified suppressor APC domain-containing 2 (SAPCD2) as a cell cycle-regulated factor that functionally links astral microtubule stability to spindle orientation control, utilizing non-polarized HeLa and HaCaT cell culture models. Live-cell imaging revealed that siRNA-mediated depletion of SAPCD2 induces spindle misorientation, leading to mitotic delay and aberrant cell division. Mechanistically, SAPCD2 acts as a previously uncharacterized microtubule-associated protein that promotes microtubule stability, whereas CDK1-mediated phosphorylation at S157, together with phosphorylation at S276, generates a mitosis-specific phosphorylated isoform that destabilizes astral microtubules. Importantly, disruption of SAPCD2 phosphorylation at both S157 and S276 fails to rescue the spindle misorientation caused by SAPCD2 depletion. These findings deepen our understanding of how mitosis-dependent dynamic phosphorylation of microtubule-associated proteins orchestrates astral microtubule behavior to ensure accurate spindle orientation.

Respiratory viruses, such as influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remain major global health threats, and the emergence of drug-resistant variants underscores the urgent need for host-targeted antiviral strategies. Prohibitins (PHBs), mitochondrial scaffold proteins involved in diverse cellular processes, are host factors exploited by multiple viruses. Here, we investigated the antiviral potential of two PHB-binding triazine melanogenin derivatives, Mel56 and Mel6, against IAV and SARS-CoV-2. Mel56, but not Mel6, exhibited potent anti-IAV activity. In particular, Mel56 increased cell survival, suppressed viral nucleoprotein expression, and reduced viral gene transcription in IAV-infected Madin-Darby canine kidney (MDCK) cells and A549 human lung carcinoma cells. PHB2 knockdown enhanced the inhibitory effect of Mel56, supporting the involvement of PHBs in its antiviral mechanism. Transcriptomic profiling revealed that Mel56 downregulates virus-induced immune response genes while upregulating antioxidant response-related genes, including nuclear factor erythroid 2-related factor 2 (NRF2) target genes. NRF2 activation by Mel56 was confirmed using a reporter assay. Consistent with these findings, Mel56 impaired mitochondrial ATP synthesis and electron transport in isolated rat liver mitochondria and attenuated mitochondrial membrane potential and promoted mitochondrial reactive oxygen species production in live MDCK cells. Importantly, Mel56 exhibited potent anti-SARS-CoV-2 activity in human induced pluripotent stem cell-derived lung organoids. Mel56 did not upregulate NRF2 target genes in SARS-CoV-2-infected organoids. These findings identify Mel56 as a PHB-binding compound with broad-spectrum antiviral activity and support the development of PHB-targeting ligands as a novel host-directed therapeutic strategy against respiratory viral infections.IMPORTANCEThis study identifies Mel56 as a novel host-directed antiviral compound that targets prohibitins and suppresses both influenza A virus and severe acute respiratory syndrome coronavirus 2. Mel56 exhibits broad-spectrum antiviral activity in conventional cell culture models as well as in physiologically relevant human lung organoids. Mechanistically, Mel56 upregulates antioxidant response-related genes, activates nuclear factor erythroid 2-related factor 2, impairs mitochondrial function, and enhances mitochondrial reactive oxygen species production. Notably, its effects differ depending on the cellular context, underscoring the complexity of host signaling pathways during viral infection. These findings highlight prohibitins as promising therapeutic targets and provide proof of concept for the development of host-directed strategies to combat respiratory viruses and mitigate the emergence of drug resistance.

Automated stem cell-derived organoid platforms for disease modeling.

End-to-End Automation of Organ-on-a-Chip Culture and Drug Testing: Enhancing Scalability and Expandability.

Mycoplasma pneumoniae, a bacterial pathogen that causes chronic respiratory infections, grows as biofilm towers in both axenic culture and submerged tissue culture model systems. In these towers, virulence factor production is reduced. The clinical relevance of these towers is unclear because biofilms have not been examined in air-liquid interface (ALI) models of M. pneumoniae infection. We used differentiated HBEC3-KT human bronchial epithelial cells at an ALI to understand how M. pneumoniae grows on and interacts with airway cells in a more physiologically relevant setting than submerged systems, and to characterize the global transcriptional response of host cells in this context. We used scanning electron microscopy to examine the growth of M. pneumoniae on HBEC3-KT cells over time, employing a modified protocol to preserve mucus. This protocol revealed abundant biofilm towers associated with both ciliary tips and the mucus layer. RNA-seq analysis of HBEC3-KT cells at days 1 and 7 after infection indicated an early tempered cytokine response, followed later by induction of type III interferon, which is unexpected not only because that response is more typical of viruses, but also because M. pneumoniae is not known to enter host cells at an ALI. We assessed barrier function using transepithelial electrical resistance and culture of medium from the basal side of the host cells, revealing that disruption occurred, but only after prolonged infection. These results collectively suggest that M. pneumoniae limits damage to host cells when growing as biofilm towers by provoking only a selective inflammatory response, promoting chronic infection.

This data paper presents a dataset, of 12,361 observations compiled from the Happiness Meanders project, which explores cultural variations in individual and family well-being, ideal and actual happiness, emotional experiences and expressions, and cultural models of selfhood across 48 countries. Participants were recruited through academic networks. Data were collected using standardised scales, including the Satisfaction with Life Scale, the Interdependent Happiness Scale, the Cultural Models of Selfhood Scale, and the Emotional Experience and Expression inspired by Affect Valuation Index. The dataset underwent thorough technical validation, including checks for variable consistency, handling missing data, and identifying potential response biases. A filter for data quality was applied, with potentially unreliable data flagged for exclusion. This dataset offers a valuable resource for examining cultural influences on emotional dynamics (frequence of experience and expression), individual and family oriented evaluations of happiness, ideal and actual evaluation of happiness, cultural models of selfhood, and can support further research in cross-cultural psychology and related social sciences.