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Scapular morphological attributes show promise as prognostic indicators of retear following rotator cuff repair. Current evaluation techniques using single-slice magnetic-resonance imaging (MRI) are, however, prone to error, while more accurate computed tomography (CT)-based three-dimensional techniques, are limited by cost and radiation exposure. In this study we propose deep learning-based methods that enable automatic scapular morphological analysis from diagnostic MRI despite the anisotropic resolution and reduced field of view, compared to CT. A deep learning-based segmentation network was trained with paired CT derived scapula segmentations. An algorithm to fuse multi-plane segmentations was developed to generated high-resolution 3D models of the scapula on which morphological landmark- and axes were predicted using a second deep learning network for morphological analysis. Using the proposed methods, the critical shoulder angle, glenoid inclination and version were measured from MRI with accuracies of -1.3 ± 1.7 degrees, 1.3 ± 2.1 degree, and − 1.4 ± 3.4 degrees respectively, compared to CT. Inter-class correlation between MRI and CT derived metrics were substantial for the glenoid version and almost perfect for the other metrics. This study demonstrates how deep learning can overcome reduced resolution, bone border contrast and field of view, to enable 3D scapular morphology analysis on MRI.

Introduction: Osteoarthritis (OA) and rotator cuff tear (RCT) pathologies have distinct scapular morphologies that impact disease progression. Previous studies examined the correlation between scapular morphology and glenohumeral joint biomechanics through critical shoulder angle (CSA) variations. In abduction, higher CSAs, common in RCT patients, increase vertical shear force and rotator cuff activation, while lower CSAs, common in OA patients, are associated with higher compressive force. However, the impact of the complete patient-specific scapular morphology remains unexplored due to challenges in establishing personalized models. Methods: CT data of 48 OA patients and 55 RCT patients were collected. An automated pipeline customized the AnyBody™ model with patient-specific scapular morphology and glenohumeral joint geometry. Biomechanical simulations calculated glenohumeral joint forces and instability ratios (shear-to-compressive forces). Moment arms and torques of rotator cuff and deltoid muscles were analyzed for each patient-specific geometry. Results and discussion: This study confirms the increased instability ratio on the glenohumeral joint in RCT patients during abduction (mean maximum is 32.80% higher than that in OA), while OA patients exhibit a higher vertical instability ratio in flexion (mean maximum is 24.53% higher than that in RCT) due to the increased inferior vertical shear force. This study further shows lower total joint force in OA patients than that in RCT patients (mean maximum total force for the RCT group is 11.86% greater than that for the OA group), attributed to mechanically advantageous muscle moment arms. The findings highlight the significant impact of the glenohumeral joint center positioning on muscle moment arms and the total force generated. We propose that the RCT pathomechanism is related to force magnitude, while the OA pathomechanism is associated with the shear-to-compressive loading ratio. Overall, this research contributes to the understanding of the impact of the complete 3D scapular morphology of the individual on shoulder biomechanics.

The organization and biophysical properties of the cytoplasm influence all cellular reactions, including molecular interactions and the mobility of biomolecules. It has become clear that the cytoplasm does not behave like a simple fluid but instead is a densely crowded and highly organized environment. Yet, the detailed properties of the cytoplasm, the molecular mechanisms that control them and how they influence the biochemistry of cells remain poorly understood. Here, we investigate the diffusive properties of the cytoplasm in silico and in vivo, employing mRNPs (messenger ribonucleoprotein) and GEM (genetically encoded multimeric) particles as rheological probes in proliferating cells. We demonstrate that cytoplasmic diffusivity increases upon polysome disassembly due to translation inhibition or upon a reduction in mRNA levels. Reducing ribosome concentration by up to 20-25% without a change in polysome levels has no effect in vivo. In addition, we show that upon polysome disassembly, mRNA condensation into P-bodies does not affect cytosolic diffusion in budding yeast. Altogether, our results show that mRNAs and their organization into polysomes control the biophysical properties of the eukaryotic cytoplasm. Polysomes control the biophysical properties of cytoplasm. mRNP and GEM mobility is enhanced upon translation inhibition that leads to polysome disassembly Perturbation of mRNA levels leads to an increase in cytosolic diffusion.

Nuclear mRNA export via nuclear pore complexes is an essential step in eukaryotic gene expression. Although factors involved in mRNA transport have been characterized, a comprehensive mechanistic understanding of this process and its regulation is lacking. Here, we use single-RNA imaging in yeast to show that cells use mRNA retention to control mRNA export during stress. We demonstrate that upon glucose withdrawal the essential RNA-binding factor Nab2 forms RNA-dependent condensate-like structures in the nucleus. This coincides with a reduced abundance of the DEAD-box ATPase Dbp5 at the nuclear pore. Depleting Dbp5, and consequently blocking mRNA export, is necessary and sufficient to trigger Nab2 condensation. The state of Nab2 condensation influences the extent of nuclear mRNA accumulation and can be recapitulated in vitro, where Nab2 forms RNA-dependent liquid droplets. We hypothesize that cells use condensation to regulate mRNA export and to control gene expression during stress. The nuclear poly(A)-binding protein Nab2 forms RNA-containing condensate-like structures upon glucose starvation and upon acute cellular depletion of the DEAD-box ATPase Dbp5 The Nab2 multimerization interface but not the intrinsically disordered regions (IDRs) are essential for condensation in vitro and in vivo Glucose stress leads to poly(A) RNA retention in the nucleus, which is affected by the state of the Nab2 condensate

Unidirectional transport of mRNA from the nucleus to the cytoplasm via nuclear pore complexes is an essential step in the gene expression of all eukaryotes. Although factors involved in mRNA transport have been characterized, a comprehensive mechanistic understanding of this critical process and its regulation is lacking. Here, we use real-time single RNA imaging to demonstrate that acute depletion of the budding yeast DEAD-box ATPase Dbp5 causes rapid nuclear accumulation of mRNAs in vivo and dramatic changes in nuclear dynamics of RNA export factors. In particular, the essential export factor Nab2 ceases to shuttle between the nucleus and cytoplasm and forms an RNA-dependent condensate throughout the nucleus. Phase-separation can be recapitulated in vitro, with Nab2 forming RNA-dependent liquid droplets, which depend on the presence of Dbp5. Intriguingly, in glucose stress, condensation of Nab2 blocks bulk mRNA export while selectively allowing the passage of stress-induced mRNAs from the nucleus to the cytoplasm to elicit a timely cellular stress response. This is accompanied by a lowered abundance of the DEAD-box ATPase Dbp5 at the cytoplasmic sites of nuclear pore complexes, which leads to the formation of the Nab2 condensates. Our results suggest that cells use selective mRNA retention in nuclear Nab2 condensates to re-wire mRNA export and to regulate gene expression during stress. Competing Interest Statement The authors have declared no competing interest.

We hypothesized that the double hit conferred by sex and diagnosis increases the risk for internalizing disorders in adolescent females with autism spectrum disorder (ASD). In a sample of 32 adolescents with ASD and 32 controls, we examined the effects of sex, diagnostic factors, and developmental stages on depression and anxiety. A 3-way interaction revealed that females with ASD exhibited greater depressive symptoms than males with ASD and female controls particularly during early adolescence; therefore, females with ASD might have a unique combination of genetic, hormonal, and psychosocial vulnerabilities that heighten their risk for depression during early adolescence. Additionally, the ASD group reported high levels of separation anxiety and panic in late adolescence, possibly indicating atypical development of independence.

A complete understanding of RNA biology requires methods for tracking transcripts in vivo. Common strategies rely on fluorogenic probes that are limited in sensitivity, dynamic range, and depth of interrogation, owing to their need for excitation light and tissue autofluorescence. To overcome these challenges, we report a bioluminescent platform for serial imaging of RNAs. The RNA tags are engineered to recruit light-emitting luciferase fragments (termed RNA lanterns) upon transcription. Robust photon production is observed for RNA targets both in cells and in live animals. Importantly, only a single copy of the tag is necessary for sensitive detection, in sharp contrast to fluorescent platforms requiring multiple repeats. Overall, this work provides a foundational platform for visualizing RNA dynamics from the micro to the macro scale. Studying RNA dynamics in vivo often relies on fluorogenic approaches, but these can be hampered by factors such as limited sensitivity and sample autofluorescence. Here, the authors describe an ultrasensitive platform for RNA imaging, which features RNA tags that recruit light-emitting luciferase fragments.

Background Reactivation of the telomerase reverse transcriptase gene TERT is a central feature for unlimited proliferation of the majority of cancers. However, the underlying regulatory processes are only partly understood. Results We assembled regulator binding information from serveral sources to construct a generic human and mouse gene regulatory network. Advancing our “Mixed Integer linear Programming based Regulatory Interaction Predictor” (MIPRIP) approach, we identified the most common and cancer-type specific regulators of TERT across 19 different human cancers. The results were validated by using the well-known TERT regulation by the ETS1 transcription factor in a subset of melanomas with mutations in the TERT promoter. Our improved MIPRIP2 R-package and the associated generic regulatory networks are freely available at https://github.com/KoenigLabNM/MIPRIP . Conclusion MIPRIP 2.0 identified common as well as tumor type specific regulators of TERT . The software can be easily applied to transcriptome datasets to predict gene regulation for any gene and disease/condition under investigation.

The chromatin‐organizing factor CCCTC‐binding factor (CTCF) is involved in transcriptional regulation, DNA‐loop formation, and telomere maintenance. To evaluate the clinical impact of CTCF in prostate cancer, we analyzed CTCF expression by immunohistochemistry on a tissue microarray containing 17 747 prostate cancers. Normal prostate tissue showed negative to low CTCF expression, while in prostate cancers, CTCF expression was seen in 7726 of our 12 555 (61.5%) tumors and was considered low in 44.6% and high in 17% of cancers. Particularly, high CTCF expression was significantly associated with the presence of the transmembrane protease, serine 2:ETS‐related gene fusion: Only 10% of ERG‐negative cancers, but 30% of ERG‐positive cancers had high‐level CTCF expression (P < 0.0001). CTCF expression was significantly associated with advanced pathological tumor stage, high Gleason grade (P < 0.0001 each), nodal metastasis (P = 0.0122), and early biochemical recurrence (P < 0.0001). Multivariable modeling revealed that the prognostic impact of CTCF was independent from established presurgical parameters such as clinical stage and Gleason grade of the biopsy. Comparison with key molecular alterations showed strong associations with the expression of the Ki‐67 proliferation marker and presence of phosphatase and tensin homolog deletions (P < 0.0001 each). The results of our study identify CTCF expression as a candidate biomarker for prognosis assessment in prostate cancer. The transcriptional repressor CCCTC‐binding factor, which is involved in modeling the chromatin face in the nucleus of a cell, was analyzed for its expression in prostate cancer. We report here that its upregulation was associated with a shorter prostate‐specific antigen recurrence‐free survival after prostatectomy in a large cohort of prostate cancer patients.

OBJECTIVE: There is growing evidence that osteocalcin, an osteoblast-derived protein locally acting on bone formation, can increase insulin secretion as well as insulin sensitivity and thus prevent the development of obesity and diabetes in experimental animals. In humans, osteocalcin has been reported to be decreased in patients with type 2 diabetes. Because gestational diabetes mellitus (GDM) can serve as a model of pre-type 2 diabetes, the aim of this study was to investigate osteocalcin in GDM. RESEARCH DESIGN AND METHODS: Osteocalcin measurement and an oral glucose tolerance test were performed in 78 pregnant women (26 women had GDM and 52 women had normal glucose tolerance [NGT] during pregnancy; women were matched for age and BMI) and in 34 women postpartum. RESULTS: During pregnancy osteocalcin was significantly higher in the women with GDM than in the women with NGT (15.6 ± 6.4 vs. 12.6 ± 4.0 ng/ml; P < 0.015), whereas no difference was observed between the two groups at 12 weeks postpartum (36.2 ± 10.2 vs. 36.2 ± 13.0 ng/ml), when osteocalcin was found to be increased compared with the level in the pregnant state in all women (+145 ± 102% in GDM vs. +187 ± 119% in NGT; P < 0.0001). Moreover, osteocalcin showed a significant correlation with basal and total insulin secretion in the whole study group (R = 0.3, P < 0.01). CONCLUSIONS: In GDM osteocalcin was higher and thus less restrained than in women with NGT during pregnancy and furthermore correlated with insulin secretion parameters. Therefore, it could be hypothesized that osteocalcin can enhance insulin secretion in insulin-resistant states; alternatively an effect of hyperinsulinemia on osteocalcin secretion cannot be excluded.