Ethnic density and first episode psychosis in the British Pakistani population: findings from the East Lancashire Early Intervention Service.

BACKGROUND: Elevated risk of psychosis for ethnic minority groups has generally been shown to be mitigated by high ethnic density. However, past survey studies examining UK Pakistani populations have shown an absence of protective ethnic density effects, which is not observed in other South Asian groups. AIMS: To assess the ethnic density effect at a local neighbourhood level, in the UK Pakistani population in East Lancashire. METHOD: Data was collected by the East Lancashire Early Intervention Service, identifying all cases of first episode psychosis (FEP) within their catchment area between 2012 and 2020. Multilevel Poisson regression analyses were used to compare incidence rates between Pakistani and White majority groups, while controlling for age, gender and area-level deprivation. The ethnic density effect was also examined by comparing incidence rates across high and low density areas. RESULTS: A total of 455 cases of FEP (364 White, 91 Pakistani) were identified. The Pakistani group had a higher incidence of FEP compared to the White majority population. A clear effect of ethnic density on rates of FEP was shown, with those in low density areas having higher incidence rates compared to the White majority, whereas incidence rates in high density areas did not significantly differ. Within the Pakistani group, a dose-response effect was also observed, with risk of FEP increasing incrementally as ethnic density decreased. CONCLUSIONS: Higher ethnic density related to lower risk of FEP within the Pakistani population in East Lancashire, highlighting the impact of local social context on psychosis incidence.

Initial Experience and Clinical Assessment of the Karl Storz FLEX-XC1 Single-Use Flexible Ureteroscope.

INTRODUCTION: The Karl Storz FLEX-XC1 is a novel single-use flexible ureteroscope that uses the same videographics platform as its reusable digital counterpart. We evaluated the technical performance of the FLEX-XC1 in its initial clinical use. METHODS: We reviewed a series of consecutive ureteroscopy procedures performed by 2 endourologists using the FLEX-XC1 for indications for which we typically use a single-use device: total stone burden > 15 mm or > 10 mm in the lower pole, anticipated case duration > 60 minutes, bilateral procedure, or upper tract urothelial cancer procedures. We assessed device tip deflection, intraoperative mechanical failure, and clinical outcomes for each case. Surgeons rated visual clarity, image quality, and maneuverability on a 1 to 5 Likert scale. RESULTS: Of 29 procedures using FLEX-XC1, 27 (93%) were successfully completed. Preoperative upward deflection was < 270° in 6 (21%) cases, and downward deflection was < 270° in 9 (31%) cases. Three types of intraoperative malfunctions occurred: rotational twisting of deflectable tip (4 cases, 13%), device not advancing through distal ureter (1 case, 3%), and working channel not accommodating a 365-µm laser (1 case, 3%). Visual clarity, image quality, and maneuverability were rated as 5 "very good" or 4 "good" in 100%, 100%, and 97% of cases, respectively. No device-specific or general 30-day complications were observed. CONCLUSIONS: The FLEX-XC1 showed comparable image quality and maneuverability to reusable digital devices. We observed incomplete deflection in up to 31% of cases and mechanical failure in 2 cases. The FLEX-XC1 may be advantageous in prolonged cases where maintaining visual clarity is paramount.

Developmental Outcomes for Children With Unoperated Metopic or Sagittal Craniosynostosis: Findings at 3 and 7 Years From the Craniofacial Collaboration UK.

The Craniofacial Collaboration UK (CC-UK) is a shared initiative with the aim of addressing key limitations in the existing literature and examining the development of homogenous samples of children with craniosynostosis. This article preliminarily describes developmental, behavioral, and cognitive outcomes for children with either metopic synostosis (MS) or sagittal synostosis (SS), who were unoperated and managed conservatively under the CC-UK protocol. A total of 112 patients were included, and assessments conducted at 3 and/or 7 years of age are presented. The majority of unoperated patients were assessed as having mild clinical severity. Findings are broadly consistent with previous work, indicating that the majority of unoperated patients perform within the average ranges across assessments. For unoperated MS patients, higher than expected rates of developmental concerns were seen at 3 years, particularly relating to gross and fine motor skills, and personal social skills. Slightly elevated rates of behavioral concerns relating to hyperactivity and prosocial behavior were also consistently shown. Few developmental issues were found for SS patients at 3 years. Some minor concerns with peer relationships and prosocial behavior at 3 years, and emotional problems at 7 years were shown, but these were inconsistent over time. Cognitive ability in both groups at 7 years seems to be close to average. Overall findings are positive, and future work should build on these findings by recruiting larger samples and examining longer-term outcomes in adolescence and adulthood, to better understand the developmental trajectory of patients with unoperated craniosynostosis.

Apicosome: Newly identified cell-type-specific organelle in mouse cochlear and vestibular hair cells.

Cochlear and vestibular hair cells are highly specialized sensory receptors for hearing and balance. Here, we report a serendipitous identification of a hair-cell-specific organelle in neonatal mouse inner ear, which we name "apicosome." The apicosome is ∼500 nm in diameter and shows itinerant nature and transient appearance during development in cochlear hair cells. In contrast to cochlear hair cells, the apicosome persists in vestibular hair cells even in adult. The timing of apicosome translocation and disappearance in cochlear hair cells during development is correlated with kinocilium development and maintenance. The apicosome is not seen in supporting cells despite the fact that nascent supporting cells have microvilli and a primary cilium. Interestingly, transdifferentiated hair cells from supporting cells also contain apicosome, suggesting that it is unique to hair cells. Thus, our study identifies a previously undescribed organelle in hair cells and lays the foundation for further characterization of this specialized structure.

Autoinhibitory mechanism controls binding of centrosomin motif 1 to γ-tubulin ring complex.

The γ-tubulin ring complex (γTuRC) is the principal nucleator of cellular microtubules, and the microtubule-nucleating activity of the complex is stimulated by binding to the γTuRC-mediated nucleation activator (γTuNA) motif. The γTuNA is part of the centrosomin motif 1 (CM1), which is widely found in γTuRC stimulators, including CDK5RAP2. Here, we show that a conserved segment within CM1 binds to the γTuNA and blocks its association with γTuRCs; therefore, we refer to this segment as the γTuNA inhibitor (γTuNA-In). Mutational disruption of the interaction between the γTuNA and the γTuNA-In results in a loss of autoinhibition, which consequently augments microtubule nucleation on centrosomes and the Golgi complex, the two major microtubule-organizing centers. This also causes centrosome repositioning, leads to defects in Golgi assembly and organization, and affects cell polarization. Remarkably, phosphorylation of the γTuNA-In, probably by Nek2, counteracts the autoinhibition by disrupting the γTuNA‒γTuNA-In interaction. Together, our data reveal an on-site mechanism for controlling γTuNA function.

THY1 (CD90) Maintains the Adherens Junctions in Nasopharyngeal Carcinoma via Inhibition of SRC Activation.

We had previously shown that THY1 (CD90) is a tumor suppressor in nasopharyngeal carcinoma (NPC) and that its down-regulation and loss of expression are associated with tumor metastasis, yet the mechanism leading to such effects remains unknown. In this study we show that tumor invasion could be suppressed by THY1 via adherens junction formation in a few NPC cell lines, and knockdown of THY1 would disrupt this cell-cell adhesion phenotype. Mechanistically, the activity of the SRC family kinase (SFK) member, SRC, and canonical Wnt signaling were dramatically reduced when THY1 was constitutively expressed. Previous studies by others have found that high levels of SRC activity in NPCs are associated with EMT and a poor prognosis. We hypothesized that THY1 can suppress tumor invasion in NPC via inhibition of SRC. By gene silencing of SRC, we found that the in vitro NPC cell invasion was significantly reduced and adherens junctions were restored. Through proteomic analysis, we identified that platelet-derived growth factor receptor ß (PDGF-Rß) and protein tyrosine phosphatase nonreceptor type 22 (PTPN22) are novel and potential binding partners of THY1, which were subsequently verified by co-immunoprecipitation (co-IP) analysis. The ligand of PDGF-Rß (PDGF-BB) could highly induce SRC activation and NPC cell invasion, which could be almost completely suppressed by THY1 expression. On the other hand, the PTPN22 siRNA could enhance both the SRC activities and the cell invasion and could also disrupt the adherens junctions in the THY1-expressing NPC cells; the original THY1-induced phenotypes were reverted when the PTPN22 expression was reduced. Together, our results identified that PTPN22 is essential for THY1 to suppress cell invasion and SRC activity, maintain tight adherens junctions, and prevent NPC metastasis. These results suggested that PDGF-Rß and SRC can be used as drug targets for suppressing NPC metastasis. Indeed, our in vivo assay using the SRC inhibitor KX2-391, clearly showed that inhibition of SRC signaling can prevent the metastasis of NPC, indicating that targeting SRC can be a promising approach to control the NPC progression.

Understanding the identity of lived experience researchers and providers: a conceptual framework and systematic narrative review.

BACKGROUND: Identity is how we understand ourselves and others through the roles or social groups we occupy. This review focuses on lived experience researchers and providers and the impact of these roles on identity. Lived experience researchers and providers use their lived experience of mental or physical disability either as experts by experience, researchers, peer workers, or mental health professionals with lived experience. They must navigate both professional and personal aspects to their roles which can be complex. Performing roles simultaneously embodying professional and lived experiences contribute towards a lack of clarity to identity. This is not adequately explained by the theoretical evidence base for identity. MAIN BODY: This systematic review and narrative synthesis aimed to provide a conceptual framework to understand how identity of lived experience researchers and providers is conceptualised. A search strategy was entered into EBSCO to access Academic search complete, CINAHL, MEDLINE, PsycINFO, Psych Articles, and Connected papers. Out of the 2049 yielded papers, thirteen qualitative papers were eligible and synthesised, resulting in a conceptual framework. Five themes explained identity positions: Professional, Service user, Integrated, Unintegrated and Liminal. The EMERGES framework, an original conception of this review, found themes of: Enablers and Empowerment, Motivation, Empathy of the self and others, Recovery model and medical model, Growth and transformation, Exclusion and Survivor roots contributed to lived experience researcher and provider identities. CONCLUSIONS: The EMERGES framework offers a novel way to understand the identities of lived experience researchers and providers, helping support effective team working in mental health, education, and research settings.

Patients now commonly help to teach healthcare professionals from their own perspective of what it is like to experience health difficulties and healthcare services. Consequently, the needs of patients are being better recognised by healthcare providers. Patients are also involved in research. These types of patient involvement lead to improved research and care. Patients included in this type of work are frequently referred to as patient providers, service user researchers, peer workers, experts by experience or lived experience researchers and providers. This might mean they are no longer viewed as people who use services but as people who provide a service. This review helps us understand how those in these roles are affected and how they understand themselves. We found they were sometimes described as either patients or professionals. Sometimes they were described as both patient and professional at the same time. Other times they were described as somewhere between a patient or professional. There were other important ideas that affected how they viewed themselves because of these experiences. These included feelings of empowerment and motivation from doing this important teaching and clinical work. The roles gave them a better understanding of their own experiences. These roles led to a personal growth and sense of achievement. The experiences of exclusion, and of being a patient affected how patient providers think of themselves. This understanding can lead to patient providers being better understood and leads to better teaching and training of healthcare professionals.

CDK5RAP2 is a Wnt target gene and promotes stemness and progression of oral squamous cell carcinoma.

In oral squamous cell carcinoma (OSCC), a highly aggressive and frequently lethal malignancy, the role and action mechanism of the microtubule regulatory protein CDK5RAP2 have not been fully understood. Here, we show that CDK5RAP2 is highly expressed in OSCC and its expression correlates with clinical stage and lymph node metastasis of the disease. The expression of CDK5RAP2 is regulated by the Wnt signaling pathway. Depletion of CDK5RAP2 inhibits the tumorigenesis and migration of OSCC cells and alters the OSCC cancer stem (-like) cell (CSC) signature. Notably, suppression of CDK5RAP2 expression disrupts spindle orientation during mitosis. Collectively, these results identify CDK5RAP2 as a potential CSC marker and reveal a mechanism that controls the CSC population in OSCC.

Detection and Analysis of Microtubule Nucleator γ-Tubulin Ring Complex.

Golgi-derived microtubules constitute an asymmetrical microtubule network that drives polarized transport of vesicles to support cell polarization and directional migration. Golgi-based microtubule nucleation requires the γ-tubulin ring complex (γTuRC), the principal microtubule nucleator in animal cells. In this chapter, we present methods for detecting γTuRC components and associated proteins on the Golgi, examining Golgi-based microtubule nucleation, and measuring the microtubule-nucleating activity of isolated γTuRCs. These approaches have been demonstrated to be effective for assessing the microtubule-organizing function of the Golgi complex.

Protocol to measure inter-centrosome distance in adherent cells using epifluorescence microscopy.

We present here a protocol to assay the centrosome separation events at late-G2 phase of the cell cycle by immunofluorescence microscopy. We describe the steps required for imaging and measurement of inter-centrosome distance. Here, we use GAS2L1 as an example, but the protocol can be used to test any protein for a role in centrosome separation and cohesion. The steps below are specific for hTERT RPE-1 cell lines, but other adherent cell lines (e.g., U2OS, MRC-5) are also amenable for this protocol. For complete details on the use and execution of this protocol, please refer to Au et al. (2017) and Au et al. (2020).

Comparison of Different Pulse Modulation Modes for Holmium:Yttrium-Aluminum-Garnet Laser Lithotripsy Ablation in a Benchtop Model.

Introduction: Manipulation of Holmium:Yttrium-Aluminum-Garnet laser parameters such as pulse energy (PE), frequency, and duration can impact laser lithotripsy ablation efficiency. In 2017, Lumenis introduced Moses™ Technology, which uses pulse modulation to enhance the delivery of energy from fiber to stone as well as to minimize stone retropulsion. Since the introduction of Moses Technology, other companies have brought additional pulse modulation concepts to market. The purpose of this in vitro study is to compare the pulse characteristics and stone ablation efficiency of Lumenis Moses Technology with Quanta's Vapor Tunnel™. Materials and Methods: Submerged BegoStone phantoms were systematically ablated using either the Lumenis Moses Pulse 120H or the Quanta Litho 100 clinical laser system. Two PEs (0.4 and 1 J), three fiber-stone standoff distances (SDs) (0.5, 1, 2 mm), and all available pulse duration and modulation modes for each laser were tested in combination. Fiber speed was adjusted to scan across the stone surface at either 1 or 10 pulses/mm to form single pulse craters or an ablation trough, respectively. Volumes of single craters and 1 mm trough segments were imaged and quantified using optical coherence tomography. Results: Ablation volumes decreased with decreasing PE and increasing SD. Statistically significant variability was seen between pulse types (PT) at every tested parameter set. Among pulse modulation modes, Moses Distance (MD) was superior at 0.5 mm in all testing and at 2 mm in trough testing. Vapor Tunnel (VT) was superior in 2 mm single crater testing. All modulated pulses performed similarly at 1 mm. Conclusions: In this benchtop model of laser lithotripsy, stone ablation was significantly impacted by PT. MD demonstrated superior or noninferior stone ablation at most tested parameters. VT maintained its efficacy the best as SD increased. Future work should focus on the mechanistic differences of these modes relative to other traditional laser pulse modes.

Proteolysis of γ-tubulin small complex proteins is mediated by the ubiquitin-proteasome system.

Microtubule nucleation is mainly mediated by the γ-tubulin ring complex (γTuRC), whose core components are γ-tubulin and γ-tubulin complex proteins GCP2-6. A substantial fraction of γ-tubulin also exists with GCP2 and GCP3 in a tetramer called the γ-tubulin small complex (γTuSC). To date, the mechanisms underlying the turnover of γ-tubulin and GCPs have remained unclear. Here, we show that γ-tubulin, GCP2, and GCP3 are proteolyzed by the ubiquitin-proteasome system, and we identify cullin 1, cullin 4A, and cullin 4B as the E3 ligases that mediate the ubiquitination and, consequently, the degradation of γ-tubulin. Notably, we found that γTuSC disassembly promotes the degradation of γ-tubulin, GCP2, and GCP3, which indicates a role for γTuSCs in the stabilization of its components.

The Role of Cavitation in Energy Delivery and Stone Damage During Laser Lithotripsy.

Purpose: Although cavitation during laser lithotripsy (LL) contributes to the Moses effect, the impact of cavitation on stone damage is less clear. Using different laser settings, we investigate the role of cavitation bubbles in energy delivery and stone damage. Materials and Methods: The role of cavitation in laser energy delivery was characterized by using photodetector measurements synced with high-speed imaging for laser pulses of varying durations. BegoStone samples were treated with the laser fiber oriented perpendicularly in contact with the stone in water or in air to assess the impact of cavitation on crater formation. Crater volume and geometry were quantified by using optical coherence tomography. Further, the role of cavitation in stone damage was elucidated by treatment in water with the fiber oriented parallel to the stone surface and by photoelastic imaging. Results: Longer pulse durations resulted in higher energy delivery but smaller craters. Stones treated in water resulted in greater volume, wider yet shallower craters compared with those treated in air. Stones treated with the parallel fiber showed crater formation after 15 pulses, confirmed by high-speed imaging of the bubble collapse with the resultant stress field captured by photoelastic imaging. Conclusions: Despite improved energy delivery, the longer pulse mode produced smaller crater volume, suggesting additional processes secondary to photothermal ablation are involved in stone damage. Our critical observations of the difference in stone damage treated in water vs in air, combined with the crater formation by parallel fiber, suggest that cavitation is a contributor to stone damage during LL.

Benchtop Assessment of a New Single-Use Flexible Ureteroscope.

Introduction: Single-use flexible ureteroscopes are an increasingly popular alternative to reusable ureteroscopes. In this study, we performed a benchtop examination of the physical and optical properties of the new Dornier Axis™ (Webling, Germany) single-use ureteroscope. Methods: Ten new, never-used Dornier Axis ureteroscopes were assessed for optical performance, maximal tip deflection, and irrigation flow rate with an empty working channel and with insertion of 200 and 365 µm laser fibers, and a 1.9F nitinol basket. All ureteroscopes were then fully deflected 100 times in each direction, and maximal deflection angles were re-measured with and without instruments in the working channel. All measurements were performed in duplicate. In vitro optical testing for resolution, image distortion, and depth of field was performed and compared vs the LithoVue™ (Boston Scientific, Marlborough, MA) single-use ureteroscope. Statistical analyses using paired Wilcoxon rank-sum tests and Kruskal-Wallis multiple-group comparison tests were performed in R. Results: Median maximal deflection angles exceeded 300° in both directions before and after 100 full deflection cycles for all groups except the 365 µm laser fiber group. After 100 deflection cycles, there was no change in the majority of working instruments, except a decrease in upward flexion with an empty channel and 200 µm Moses™ laser fiber, and downward flexion with 200 µm Flexiva™ laser fiber (all <10°). After excluding the 365 µm fiber, there was no difference in multi-group comparison for upward and downward flexion pre- and post-cycling. Median flow rate through an empty channel was 48.0 mL/min, and it decreased significantly with all used instruments (p < 0.001). Compared with the LithoVue, the Axis demonstrated superior resolution at all tested distances and less distortion. Conclusions: The new Dornier Axis single-use ureteroscope demonstrates excellent tip deflection, which remains unchanged after 100 manual flexions in each direction. The Axis also demonstrates superior optical performance compared with the LithoVue in benchtop testing.

Nek2-mediated GAS2L1 phosphorylation and centrosome-linker disassembly induce centrosome disjunction.

Centrosome disjunction occurs in late G2 to facilitate bipolar spindle formation and is mediated by the NIMA-related kinase Nek2. Here, we show that GAS2L1, a microtubule- and F-actin-binding protein required for centrosome disjunction, undergoes Nek2-mediated phosphorylation at Ser352 in G2/M. The phosphorylation is essential for centrosome disjunction in late G2 and for proper spindle assembly and faithful chromosome segregation in mitosis. GAS2L1 contains a calponin-homology (CH) domain and a GAS2-related (GAR) domain, which bind to F-actin and microtubules, respectively. Notably, the CH and GAR domains bind to each other to inhibit the functions of both domains, and Ser352 phosphorylation disrupts the interaction between the two domains and relieves the autoinhibition. We dissected the roles of the GAS2L1 phosphorylation and of centrosome-linker disassembly, which is another Nek2-mediated event, and found that these events together trigger centrosome disjunction. Therefore, our findings demonstrate the concerted Nek2 actions that split the centrosomes in late G2.

Sexual minority status and symptoms of psychosis: The role of bullying, discrimination, social support, and drug use - Findings from the Adult Psychiatric Morbidity Survey 2007.

OBJECTIVE: Sexual minorities have an increased risk of psychosis, potentially explained by experiences of social adversity. Sexual minorities may also have a specific risk of paranoid symptoms. The current study aimed to determine whether sexual minorities have increased risk of psychosis, whether they have a specific increased risk of paranoia when compared to auditory verbal hallucinations (AVHs), and whether social adversity such as bullying, recent discrimination, lack of social support, and drug use can explain this risk. METHODS: The study used data from the Adult Psychiatric Morbidity Survey 2007 (n = 7,403), exploring both sexual identity and past sexual behaviour. Associations between sexual minority status and probable psychosis, paranoia, and AVH were analysed using logistic regression. Mediation analysis was also conducted using the Karlson-Holm-Breen method, with bullying, recent discrimination, social support, and drug use as mediators assessing pathways between sexual minority status and paranoia/AVH. Socio-demographic confounders were included in analyses. RESULTS: Sexual minority status did not significantly predict probable psychosis. Findings generally indicated a specific association between sexual minority status and paranoia when contrasted with AVH. However, sexual behaviour remained significantly associated with AVH in logistic regression models. Bullying, lack of social support, and drug use partially mediated the association between sexual minority status and paranoia. CONCLUSIONS: Sexual minority status appears to have a specific association with paranoia symptoms, which may be partially explained by experiences of social adversity. However, the cross-sectional nature of the study limits direct inference about causality of such symptoms. PRACTITIONER POINTS: Sexual minority groups may be more likely to experience symptoms of paranoia. It may be important to consider experiences of social adversity such as bullying, lack of social support, and also history of drug use in the context of paranoia within these groups.

Cytolinker Gas2L1 regulates axon morphology through microtubule-modulated actin stabilization.

Crosstalk between the actin and microtubule cytoskeletons underlies cellular morphogenesis. Interactions between actin filaments and microtubules are particularly important for establishing the complex polarized morphology of neurons. Here, we characterized the neuronal function of growth arrest-specific 2-like 1 (Gas2L1), a protein that can directly bind to actin, microtubules and microtubule plus-end-tracking end binding proteins. We found that Gas2L1 promotes axon branching, but restricts axon elongation in cultured rat hippocampal neurons. Using pull-down experiments and in vitro reconstitution assays, in which purified Gas2L1 was combined with actin and dynamic microtubules, we demonstrated that Gas2L1 is autoinhibited. This autoinhibition is relieved by simultaneous binding to actin filaments and microtubules. In neurons, Gas2L1 primarily localizes to the actin cytoskeleton and functions as an actin stabilizer. The microtubule-binding tail region of Gas2L1 directs its actin-stabilizing activity towards the axon. We propose that Gas2L1 acts as an actin regulator, the function of which is spatially modulated by microtubules.

The catalytic subunit of DNA polymerase δ is a nucleocytoplasmic shuttling protein.

The DNA polymerase δ catalytic subunit (PolD1) is a highly conserved protein with established functions in both the nucleus and the cytoplasm: whereas PolD1 participates in the replication and repair of nuclear DNA, it plays a role in the control of cytoplasmic microtubule growth by directly acting on microtubule-nucleator γ-tubulin ring complexes. Here, we show that PolD1 shuttles between the nucleus and the cytoplasm. PolD1 harbors two nuclear localization signals that mediate the active transport of PolD1 to the nucleus; conversely, PolD1 is exported from the nucleus by the exportin CRM1-dependent mechanism, a major nuclear-export pathway that mediates the export of various cargos. These findings suggest that the nucleocytoplasmic distribution of PolD1 is influenced by both the nuclear import and export activities of the protein.