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The integrated stress response (ISR) is activated by diverse forms of cellular stress, including endoplasmic reticulum (ER) stress, and is associated with diseases. However, the molecular mechanism(s) whereby the ISR impacts on differentiation is incompletely understood. Here, we exploited a mouse model of Metaphyseal Chondrodysplasia type Schmid (MCDS) to provide insight into the impact of the ISR on cell fate. We show the protein kinase RNA-like ER kinase (PERK) pathway that mediates preferential synthesis of ATF4 and CHOP, dominates in causing dysplasia by reverting chondrocyte differentiation via ATF4-directed transactivation of Sox9. Chondrocyte survival is enabled, cell autonomously, by CHOP and dual CHOP-ATF4 transactivation of Fgf21. Treatment of mutant mice with a chemical inhibitor of PERK signaling prevents the differentiation defects and ameliorates chondrodysplasia. By preventing aberrant differentiation, titrated inhibition of the ISR emerges as a rationale therapeutic strategy for stress-induced skeletal disorders.

In protein folding and secretion disorders, activation of endoplasmic reticulum (ER) stress signaling (ERSS) protects cells, alleviating stress that would otherwise trigger apoptosis. Whether the stress-surviving cells resume normal function is not known. We studied the in vivo impact of ER stress in terminally differentiating hypertrophic chondrocytes (HCs) during endochondral bone formation. In transgenic mice expressing mutant collagen X as a consequence of a 13-base pair deletion in Col10a1 (13del), misfolded alpha1(X) chains accumulate in HCs and elicit ERSS. Histological and gene expression analyses showed that these chondrocytes survived ER stress, but terminal differentiation is interrupted, and endochondral bone formation is delayed, producing a chondrodysplasia phenotype. This altered differentiation involves cell-cycle re-entry, the re-expression of genes characteristic of a prehypertrophic-like state, and is cell-autonomous. Concomitantly, expression of Col10a1 and 13del mRNAs are reduced, and ER stress is alleviated. ERSS, abnormal chondrocyte differentiation, and altered growth plate architecture also occur in mice expressing mutant collagen II and aggrecan. Alteration of the differentiation program in chondrocytes expressing unfolded or misfolded proteins may be part of an adaptive response that facilitates survival and recovery from the ensuing ER stress. However, the altered differentiation disrupts the highly coordinated events of endochondral ossification culminating in chondrodysplasia.

The spatiotemporal proteome of the intervertebral disc (IVD) underpins its integrity and function. We present DIPPER, a deep and comprehensive IVD proteomic resource comprising 94 genome-wide profiles from 17 individuals. To begin with, protein modules defining key directional trends spanning the lateral and anteroposterior axes were derived from high-resolution spatial proteomes of intact young cadaveric lumbar IVDs. They revealed novel region-specific profiles of regulatory activities and displayed potential paths of deconstruction in the level- and location-matched aged cadaveric discs. Machine learning methods predicted a ‘hydration matrisome’ that connects extracellular matrix with MRI intensity. Importantly, the static proteome used as point-references can be integrated with dynamic proteome (SILAC/degradome) and transcriptome data from multiple clinical samples, enhancing robustness and clinical relevance. The data, findings, and methodology, available on a web interface ( http://www.sbms.hku.hk/dclab/DIPPER/ ), will be valuable references in the field of IVD biology and proteomic analytics. The backbone of vertebrate animals consists of a series of bones called vertebrae that are joined together by disc-like structures that allow the back to move and distribute forces to protect it during daily activities. It is common for these intervertebral discs to degenerate with age, resulting in back pain and severely reducing quality of life. The mechanical features of intervertebral discs are the result of their proteins. These include extracellular matrix proteins, which form the external scaffolding that binds cells together in a tissue, and signaling proteins, which allow cells to communicate. However, how the levels of different proteins in each region of the disc vary with time has not been fully examined. To establish how protein composition changes with age, Tam, Chen et al. quantified the protein levels and gene activity (which leads to protein production) of intervertebral discs from young and old deceased individuals. They found that the position of different mixtures of proteins in the intervertebral disc changes with age, and that young people have high levels of extracellular matrix proteins and signaling proteins. Levels of these proteins decreased as people got older, as did the amount of proteins produced. To determine which region of the intervertebral disc different proteins were in, Tam, Chen et al. also performed magnetic resonance imaging (MRI) of the samples to correlate image intensity (which represents water content) with the corresponding protein signature. The data obtained provides a high-quality map of how the location of different proteins changes with age, and is available online under the name DIPPER. This database is an informative resource for research into skeletal biology, and it will likely advance the understanding of intervertebral disc degeneration in humans and animals, potentially leading to the development of new treatment strategies for this condition.

Mice have been increasingly used as preclinical model to elucidate mechanisms and test therapeutics for treating intervertebral disc degeneration (IDD). Several intervertebral disc (IVD) histological scoring systems have been proposed, but none exists that reliably quantitate mouse disc pathologies. Here, we report a new robust quantitative mouse IVD histopathological scoring system developed by building consensus from the spine community analyses of previous scoring systems and features noted on different mouse models of IDD. The new scoring system analyzes 14 key histopathological features from nucleus pulposus (NP), annulus fibrosus (AF), endplate (EP), and AF/NP/EP interface regions. Each feature is categorized and scored; hence, the weight for quantifying the disc histopathology is equally distributed and not driven by only a few features. We tested the new histopathological scoring criteria using images of lumbar and coccygeal discs from different IDD models of both sexes, including genetic, needle‐punctured, static compressive models, and natural aging mice spanning neonatal to old age stages. Moreover, disc sections from common histological preparation techniques and stains including H&E, SafraninO/Fast green, and FAST were analyzed to enable better cross‐study comparisons. Fleiss's multi‐rater agreement test shows significant agreement by both experienced and novice multiple raters for all 14 features on several mouse models and sections prepared using various histological techniques. The sensitivity and specificity of the new scoring system was validated using artificial intelligence and supervised and unsupervised machine learning algorithms, including artificial neural networks, k‐means clustering, and principal component analysis. Finally, we applied the new scoring system on established disc degeneration models and demonstrated high sensitivity and specificity of histopathological scoring changes. Overall, the new histopathological scoring system offers the ability to quantify histological changes in mouse models of disc degeneration and regeneration with high sensitivity and specificity. We have developed a new Mouse intErveRtebral disC histopathologY (MERCY) system using a step‐wise approach that included building consensus in the spine community, testing reliability using various mouse disc degeneration models for agreement by multiple raters, validating for high sensitivity and specificity using AI and machine learning algorithms, and applied on established models of murine disc degeneration. Hence, this new system can be broadly applied to quantify mouse IVD histopathology in disc degeneration and regeneration models.

Abstract The spatiotemporal proteome of the intervertebral disc (IVD) underpins its integrity and function. We present DIPPER, a deep and comprehensive IVD proteomic resource comprising 94 genomewide profiles from 17 individuals. To begin with, protein modules defining key directional trends spanning the lateral and anteroposterior axes were derived from high-resolution spatial proteomes of intact young cadaveric lumbar IVDs. They revealed novel region-specific profiles of regulatory activities, and displayed potential paths of deconstruction in the level- and location-matched aged cadaveric discs. Machine learning methods predicted a “hydration matrisome” that connects extracellular matrix with MRI intensity. Importantly, the static proteome used as point-references can be integrated with dynamic proteome (SILAC/degradome) and transcriptome data from multiple clinical samples, enhancing robustness and clinical relevance. The data, findings and methodology, available on a web interface, will be valuable references in the field of IVD biology and proteomic analytics. Competing Interest Statement The authors have declared no competing interest. Footnotes * KSEC is a senior editor at eLife. All other authors declare that they do not have any conflict of interests * Title has been changed to: DIPPER: a spatiotemporal proteomics atlas of human intervertebral discs for exploring ageing and degeneration dynamics

The delivery of medical agents to a specific diseased tissue or cell is critical for diagnosing and treating patients. Nanomaterials are promising vehicles to transport agents that include drugs, contrast agents, immunotherapies and gene editors. They can be engineered to have different physical and chemical properties that influence their interactions with their biological environments and delivery destinations. In this Review Article, we discuss nanoparticle delivery systems and how the biology of disease should inform their design. We propose developing a framework for building optimal delivery systems that uses nanoparticle–biological interaction data and computational analyses to guide future nanomaterial designs and delivery strategies.This Review proposes a framework for designing delivery systems to target diseased tissues based on the biology of the target, the journey and computational algorithms.

Background: Amino acid tracer positron emission tomography–magnetic resonance imaging (PET-MRI) was shown to be superior to MRI alone for evaluating central nervous system (CNS) tumours in adults. This study aimed to investigate the utility of amino acid PET-MRI in children with CNS tumours. Methods: We reviewed the amino acid PET-MRI findings of children with suspected or confirmed CNS neoplasms managed in a territory-wide referral centre in Hong Kong from 2022 to 2025. Maximal standardized uptake values (SUVmax) were captured, and tumour-to-background SUVmax ratios (TBRmax) were measured with reference to adjacent or contralateral normal brain structures. Comparisons were made among patients with clinical high-grade and low-grade/non-neoplastic lesions. Results: Thirty-seven patients were included, with 63 PET-MRIs performed. PET-MRI was performed as part of initial diagnostics in 41% of the cases, for response assessment in 48%, and evaluation of residual/relapsed disease in 11%. High-grade lesions had a significantly higher SUVmax and TBRmax compared to low-grade/non-malignant lesions (median SUVmax 3.7 vs. 1.6, p = 0.00006; median TBRmax 2.06 vs. 0.91, p = 0.00002). Optimal SUVmax and TBRmax cut-offs by ROC analysis were 2.38 and 1.62, respectively. Similar performance was reproduced by focusing on the subset of patients with suspected CNS germ cell tumours (CNS-GCT). The impact of amino acid PET availability is considerable, as clinical management was modified in 65% of patients. Conclusions: Our study demonstrates the performance and clinical utility of amino acid PET-MRI in the management of children with CNS pathologies. Amino acid PET-MRI contributes to the diagnosis, monitoring, and treatment guidance of these patients, providing crucial information for decision-making.

BackgroundOral corticosteroid remains the first-line treatment of IgG4-related ophthalmic disease, but steroid-dependence is common and serious. Factors associated with steroid dependence and relapse have to be further explored.Study populationA city-wide, biopsy-proven, Chinese cohort.MethodsRetrospective, masked review of medical records, orbital images and histopathology reports.ResultsThere were 101 patients with at least 24-month follow-up. Up to 82% (82/101) received oral corticosteroid as first-line treatments, and 7 of them received also concomitant steroid-sparing agents (SSA)/biological agents as primary treatment. There was 61% (50/82) of patients required long-term corticosteroid (alone=23, with SSA=27) after 1.9±0.7 (range 1–5) relapses. When compared with the 21% (17/82) of patients who tapered corticosteroid successfully for 24 months, steroid dependence was associated with elevated baseline serum IgG4 level (94% vs 65%, p<0.01) and Mikulicz syndrome (46% vs 18%, p<0.05). Up to 13% (11/82) of patients tolerated residual disease after tapering off corticosteroid. There was 17% (17/101) of patients did not require any medications after biopsies. They were more likely to have debulking surgeries (71% vs 40%, p<0.05), discrete orbital lesions (65% vs 26%, p<0.05), normal baseline serum IgG4 level (24% vs 6%, p<0.05) and no Mikulicz syndrome (94% vs 61%, p<0.05).ConclusionIn this cohort, 60% of patients required long-term maintenance oral corticosteroid. Elevated pretreatment serum IgG4 level and Mikulicz syndrome were associated with steroid dependence. Debulking surgery is an alternative for a subgroup of patients with discrete orbital lesions, normal baseline IgG4 level and no Mikulicz syndrome.

Background HIV-associated neurocognitive disorder (HAND) remains prevalent in the era of combination antiretroviral therapy (cART). The prevalence of HAND in Hong Kong is not known. Methods Between 2013 and 2015, 98 treatment-naïve HIV-1-infected individuals were referred to and screened by the AIDS Clinical Service, Queen Elizabeth Hospital with (1) the International HIV Dementia Scale (IHDS), a screening tool that targets moderate to severe HAND, (2) the Montreal Cognitive Assessment (MoCA), a frequently used cognitive screening test and (3) the Patient Health Questionnare-9 (PHQ-9), a 9-item questionnaire that evaluates depression symptoms. Within the study period, 57 of them completed the second set of IHDS and MoCA at 6 months after baseline assessment. Results Most participants were male (94%), with a median age of 31 years. At baseline, 38 (39%) and 25 (26%) of them scored below the IHDS (≤10) and MoCA (25/26) cut-offs respectively. Poor IHDS performers also scored lower on MoCA ( p  = 0.039) but the correlation between IHDS and MoCA performance was weak (r = 0.29, p  = 0.004). Up to a third of poor IHDS performers (13/38) showed moderate depression (PHQ-9 > 9). In the multivariable analysis, a lower education level ( p  = 0.088), a history of prior psychiatric illness ( p  = 0.091) and the presence of moderate depression ( p  = 0.079) tended to be significantly associated with poor IHDS performance. At follow-up, 54 out of 57 were on cART, of which 46 (85%) had achieved viral suppression. Their blood CD4+ T-lymphocytes and IHDS scores were higher at follow-up compared to baseline values (both p  < 0.001) but their MoCA performance was similar at both assessments. Of note, 17 participants in this subgroup scored below the IHDS cut-off at both assessments. Conclusions Poor IHDS performance, and likely cognitive impairment, was frequently observed in treatment-naïve HIV-infected individuals in our locality. A considerable proportion continued to score below the IHDS cut-off at 6 months after cART. Depression was frequently observed in this vulnerable population and was associated with poor IHDS performance.

This systematic review and meta-analysis investigated whether self-compassion-related therapies, including compassion-focussed therapy, mindfulness-based cognitive therapy and acceptance and commitment therapy, are effective in promoting self-compassion and reducing psychopathology in clinical and subclinical populations. A total of 22 randomised controlled trials met inclusion criteria, with data from up to 1172 individuals included in each quantitative analysis. Effect sizes were the standardised difference in change scores between intervention and control groups. Results indicated that self-compassion-related therapies produced greater improvements in all three outcomes examined: self-compassion ( g  = 0.52, 95% CIs [0.32, 0.71]), anxiety ( g  = 0.46, 95% CIs [0.25, 0.66]) and depressive symptoms ( g  = 0.40, 95% CIs [0.23, 0.57]). However, when analysis was restricted to studies that compared self-compassion-related therapies to active control conditions, change scores were not significantly different between the intervention and control groups for any of the outcomes. Patient status (clinical vs. subclinical) and type of therapy (explicitly compassion-based vs. other compassion-related therapies, e.g. mindfulness) were not moderators of outcome. There was some evidence that self-compassion-related therapies brought about greater improvements in the negative than the positive subscales of the Self-Compassion Scale, although a statistical comparison was not possible. The methodological quality of studies was generally good, although risk of performance bias due to a lack of blinding of participants and therapists was a concern. A narrative synthesis found that changes in self-compassion and psychopathology were correlated in several studies, but this relationship was observed in both intervention and control groups. Overall, this review presents evidence that third-wave therapies bring about improvements in self-compassion and psychopathology, although not over and beyond other interventions.