Publications by Year: 2026

Cells actively sense and transduce microenvironmental mechanical inputs into chemical signals via cytoskeletal rearrangements. During these mechanosensation and mechanotransduction processes, the role of the actin cytoskeleton is well-understood, whereas the role of the tubulin cytoskeleton remains largely elusive. Here, we report the dynamic changes in microtubules in response to microenvironmental stiffness during chondrocyte mitosis. Mechanical stiffness was found to be coupled with microtubule generation, directing microtubule dynamics in mitotic chondrocytes. Refilin B was found to be a key regulator of microtubule assembly in chondrocytes in response to mechanical stiffness. It was found to play its role in microtubule formation via the p-Smad3 signaling pathway. Additionally, integrin-linked kinase (ILK), triggered by mechanical stiffness, was found to play an indispensable role in the process of microtubule dynamics mediated by refilin B. Our data emphasizes stiffness-mediated dynamic changes in the microtubules of chondrocytes in a quiescent state (G0) and at anaphase, which improves our understanding of the mechanical regulation of microtubule assembly during the chondrocyte cell cycle and provides insights into microenvironment mechanics during tissue maintenance, wound healing, and disease occurrence.

Anatomy in Nazi Germany-in its work with bodies of the regime's victims-is arguably the most extreme example of state-sanctioned abuse of power over bodies of the dead in medicine. This history is highly relevant today because it contributed to the formulation of basic tenets of research ethics in the Nuremberg Code and allows for history-informed reasoning regarding anatomical body procurement and education. However, detailed information on anatomy institutes in Nazi Germany and its territories is often missing. This study offers first results of an investigation of activities at Breslau anatomy 1933 to 1945 (today Wrocław), including anatomists' politics and anatomical body procurement. In 1945, this anatomical institute ceased to exist when Breslau became Polish. Like their peers throughout Nazi Germany, Breslau anatomists coordinated the handover of bodies of the executed from prison with the authorities. Archival documentation reveals that Breslau anatomy received bodies of at least 30 executed prisoners. In addition, the body register of the city morgue was examined, disclosing the transfer of 442 unclaimed bodies to the anatomical institute from 1937 to 1944, more than half of them children. Also among them were 29 bodies of prisoners and Eastern European forced laborers. All these bodies were used in anatomy education, and the executed were preferred in research studies and dissertation theses, as documented in 16 publications. These findings confirm the close collaboration of Breslau anatomists with the Nazi regime, and their acceptance of the use of Nazi victims' bodies as an unquestioned professional opportunity.

BACKGROUND: Low bone mineral density (BMD) and increased fracture risk are common in individuals with cystic fibrosis (CF). The extent to which the CF transmembrane conductance regulator (CFTR) modulator elexacaftor-tezacaftor-ivacaftor (ETI) benefits BMD was a focus of the endocrine sub-study of PROMISE, a multicenter observational study of clinically prescribed ETI. We examined changes in whole-body (WB), lumbar spine (LS), total hip (TH), and femoral neck (FN) areal BMD (aBMD, g/cm2) in the 24-30 months (mos) following ETI initiation.

METHODS: Participants had CF, ≥1 F508del mutation, and were aged ≥12 years (y). Dual-energy X-ray absorptiometry (DXA) scans of the WB, LS, TH, and FN were collected before and following 12-18 mos and 24-30 mos of ETI therapy. Changes in aBMD Z-scores (aBMDZ) were examined with longitudinal mixed effects models.

RESULTS: Baseline aBMDZ was below-average at all skeletal sites in youth and adults (aBMDZ <0). Mixed model results for youth [n = 60 at baseline; average age 15y (range: 12-19.8); 48 % female] revealed decreases in WB (less head) (β-coefficient=-0.27; 95 %CI: -0.46, -0.09), LS (β=-0.26; 95 %CI: -0.42, -0.10), TH (β=-0.29; 95 %CI: -0.45, -0.13), and FN (β=-0.37; 95 %CI: -0.57, -0.17) aBMDZ between baseline and 12-18 mos. These changes persisted but did not worsen at 24-30 mos. Changes in adult [n = 73 at baseline; average age 28y (range: 20-58.8); 51 % female] aBMDZ were negative but modest compared to youth (no β-coefficient >-0.11).

CONCLUSIONS: Youth aBMDZ was lower at multiple skeletal sites 12-18 mos after ETI initiation, and these changes persisted at 24-30 mos. Adult aBMDZ generally remained unchanged.

BACKGROUND AND OBJECTIVES: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of seizure-related deaths in people with epilepsy. Despite evidence that SUDEP counseling does not cause stress, improves treatment adherence, and empowers people with epilepsy and their caregivers, it remains underdiscussed. This study aimed to explore the in-depth perspectives of parents who have lost a child to SUDEP, focusing on their experiences, grief, and coping strategies, while factoring in their demographics, the clinical features of their deceased children, and their previous awareness of SUDEP, all aspects that have not been systematically investigated before.

METHODS: This qualitative phenomenological study involved in-depth semistructured interviews with 51 parents of 43 children who died of SUDEP. Transcripts were analyzed using immersion/crystallization qualitative methodology with Dedoose software, using an iterative consensus-building process. Thematic analysis revealed common perspectives, grief narratives, coping strategies, and perceived needs among parents after their child's SUDEP.

RESULTS: Of the 51 participating parents (mean age 54.1 ± 9.4 years, 71% female), 27 reported being unaware of SUDEP before it occurred, whereas 24 reported previous awareness of it. These groups shared similar demographics and clinical characteristics. However, "unaware" parents expressed more intense trauma and prolonged maladaptive grief, characterized by guilt, extreme anger, and medical distrust. By contrast, "aware" parents described mitigated trauma, with less guilt- and anger-ridden grief, and reduced reliance on specialized support groups. Previous SUDEP awareness provided emotional preparation, buffering the devastating reality and fostering agency and acceptance. Another theme highlighted the struggles parents faced immediately after SUDEP, particularly with law enforcement and treating physicians. Unanimously, parents emphasized the paramount importance of counseling about the known relationship between epilepsy and SUDEP.

DISCUSSION: Previous awareness of SUDEP (or lack thereof) has complex and far-reaching effects on the subsequent parental perceived trauma, grief, and coping processes. Furthermore, emergency responders, official personnel, and treating physicians may mishandle the aftermath of SUDEP. This study's findings strongly advocate for a paradigm shift in SUDEP-related practices across multiple disciplines, including legislation. Emphasis should be placed on increasing proactive SUDEP counseling to mitigate the traumatic effect and subsequent grieving process when SUDEP occurs.

OBJECTIVE: Cerebral cavernous malformations (CCMs) are groups of blood vessels that develop abnormally in both the brain and/or spinal cord. Currently, MRI and/or CT are the primary methods for assessing CCMs. Plasma-based biomarkers could serve as a complement to standard imaging techniques by providing a quantitative and molecular-based technique to detect disease at lower cost. Therefore, the authors evaluated cell division cycle 42 binding protein beta (CDC42BPB) as a potential novel plasma biomarker for CCMs.

METHODS: Plasma samples were obtained from patients with pathological analysis-confirmed CCM (n = 10, age 1-16 years) and compared to controls (n = 24, age 1-19 years). The protein levels were measured using the Olink Proximity Extension Assay. Findings were confirmed with ELISA. CDC42BPB expression was further analyzed with Western blot and immunohistochemistry analysis in patient-derived primary cells and CCM tissues, respectively.

RESULTS: CCM patients exhibited significantly higher CDC42BPB plasma levels compared to controls (approximately 6-fold greater expression, p = 0.004). Furthermore, the high CDC42BPB plasma expression was concordant with the protein levels in CCM tissues and patient-derived primary cells.

CONCLUSIONS: The authors present data supporting the measurement of CDC42BPB plasma level as a putative biomarker for CCMs. These findings have implications relevant to improving diagnosis, follow-up, and molecular pathophysiological analysis.

BACKGROUND: Cognitive deficits are cardinal features of schizophrenia-spectrum disorders (SSD) and bipolar disorder (BD). However, their heterogeneous and overlapping characteristics require a dimensional approach to better understand the neurobiological basis of cognition in the psychosis spectrum. To date, only a few studies have examined the neuroanatomical features of cognitive subgroups in transdiagnostic samples, and white matter microstructural characteristics of these subgroups have not been elucidated. This study aimed to investigate white matter and cortical thickness alterations in cognitive subgroups in the schizophrenia-bipolar spectrum.

METHODS: Globally Impaired (n = 31) and Near-Normal (n = 28) cognitive subgroups, comprising individuals diagnosed with schizophrenia (SZ), schizoaffective disorder (SAD) or BD, and healthy controls (HCs, n = 29), underwent 3T T1-weighted structural magnetic resonance imaging and diffusion tensor imaging scanning. Fractional anisotropy and cortical thickness measures were compared between the cognitive subgroups and healthy controls.

RESULTS: Abnormalities in white matter microstructure were only observed in patients with global cognitive impairment compared to HCs. The Near-Normal subgroup did not differ from HCs in white matter integrity. A bilateral reduction in cortical thickness was observed in both the Globally Impaired and Near-Normal subgroups when compared to HCs. Cortical thickness measures did not differentiate between the cognitive subgroups.

CONCLUSIONS: While reductions in cortical thickness in frontal and temporal regions appear to be a common feature of SZ and BD, abnormalities in white matter microstructure are associated with global cognitive impairment in the schizophrenia-bipolar spectrum. These original findings may be important in identifying more biologically valid clinical syndromes within the schizophrenia-bipolar spectrum.

BACKGROUND: Abdominal aortic calcification (AAC) is a subclinical measure of atherosclerotic cardiovascular disease (ASCVD). AAC can be captured on lateral spine images obtained from bone density machines during routine osteoporosis screening. Identifying individuals with AAC provides a new opportunity to prevent disease progression.

OBJECTIVES: The aim of the study was to externally validate a machine learning-derived AAC 24-point algorithm (ML-AAC24) with incident ASCVD.

METHODS: Middle-aged individuals from the UK Biobank Imaging Study with lateral spine images, obtained via dual-energy x-ray absorptiometry, were included. ML-AAC24 scores were grouped as low (<2), moderate (2 to <6), and high (≥6). Linked health records were used to identify ASCVD-associated events, including hospitalizations and death.

RESULTS: Among 53,611 participants (52% female; mean age 65 years), 78.2% had low, 16.4% had moderate, and 5.4% had high ML-AAC24. After excluding people with prevalent ASCVD or missing data, 1,163 (2.3%) of 50,923 people had an incident ASCVD event over a median follow-up of 4.1 [3.0-5.5] years. In age- and sex-adjusted analysis, compared to those with low ML-AAC24, those with moderate (HR: 1.80 [95% CI: 1.57-2.08]) and high ML-AAC24 (HR: 2.87 [95% CI: 2.39-3.44]) had a higher HR for incident ASCVD. Results remained comparable after adjustment for established ASCVD risk factors. Consistent patterns were observed when considering incident coronary artery disease, myocardial infarction, and stroke.

CONCLUSIONS: Assessing ML-AAC24 on lateral spine images offers a new and promising screening method to identify people with higher risk of incident ASVD events.

BACKGROUND: MECOM encodes a developmental and haematopoietic transcription factor associated with a rare early-onset syndrome including bone marrow failure, skeletal and other congenital anomalies. Heterozygous de novo variants are the primary cause. We previously identified MECOM as a candidate gene for paediatric pulmonary arterial hypertension (PAH) using trio exome sequencing.

METHODS: To test the role of MECOM in paediatric PAH and further define the clinical phenotype of MECOM-associated syndrome, we queried GeneMatcher and screened rare disease databases for individuals with predicted deleterious MECOM variants. We analysed the clinical spectrum of patients, performed protein modelling of genetic variants and assessed cardiopulmonary expression.

RESULTS: We identified 15 individuals with MECOM variants, including 11 unrelated probands and 8 de novo variants. 11 individuals had severe or mild thrombocytopenia, 9 had skeletal issues, 8 had cardiac anomalies, 6 had PAH and 10 had additional conditions. Three were diagnosed in utero and died in the neonatal period. All missense variants map to the zinc finger 6 or zinc finger 8/9 region, a known hotspot for MECOM-associated syndrome. Protein modelling predicted that both regions are DNA-binding, and that the variants may interfere with binding to a VEGFR2/KDR enhancer. Data from LungMAP showed that MECOM is primarily expressed in pulmonary arterial endothelial cells.

CONCLUSION: Rare MECOM variants are associated with early-onset syndromic PAH. PAH monitoring should be considered for all individuals with rare MECOM variants. We speculate that the pathogenetic mechanism for PAH and cardiac defects may be impaired VEGFR2/KDR signalling.