EYA protein complex is required for Wntless retrograde trafficking from endosomes to Golgi.

Retrograde transport of WLS (Wntless) from endosomes to trans-Golgi network (TGN) is required for efficient Wnt secretion during development. However, the molecular players connecting endosomes to TGN during WLS trafficking are limited. Here, we identified a role for Eyes Absent (EYA) proteins during retrograde trafficking of WLS to TGN in human cell lines. By using worm, fly, and zebrafish models, we found that the EYA-secretory carrier-associated membrane protein 3 (SCAMP3) axis is evolved in vertebrates. EYAs form a complex and interact with retromer on early endosomes. Retromer-bound EYA complex recruits SCAMP3 to endosomes, which is necessary for the fusion of WLS-containing endosomes to TGN. Loss of EYA complex or SCAMP3 leads to defective transport of WLS to TGN and failed Wnt secretion. EYA mutations found in patients with hearing loss form a dysfunctional EYA-retromer complex that fails to activate Wnt signaling. These findings identify the EYA complex as a component of retrograde trafficking of WLS from the endosome to TGN.

Inorganic Biomaterials Shape the Transcriptome Profile to Induce Endochondral Differentiation.

Minerals play a vital role, working synergistically with enzymes and other cofactors to regulate physiological functions including tissue healing and regeneration. The bioactive characteristics of mineral-based nanomaterials can be harnessed to facilitate in situ tissue regeneration by attracting endogenous progenitor and stem cells and subsequently directing tissue-specific differentiation. Here, cellular responses of human mesenchymal stem/stromal cells to traditional bioactive mineral-based nanomaterials, such as hydroxyapatite, whitlockite, silicon-dioxide, and the emerging synthetic 2D nanosilicates are investigated. Transcriptome sequencing is utilized to probe the cellular response and determine the significantly affected signaling pathways due to exposure to these inorganic nanomaterials. Transcriptome profiles of stem cells treated with nanosilicates reveals a stabilized skeletal progenitor state suggestive of endochondral differentiation. This observation is bolstered by enhanced deposition of matrix mineralization in nanosilicate treated stem cells compared to control or other treatments. Specifically, use of 2D nanosilicates directs osteogenic differentiation of stem cells via activation of bone morphogenetic proteins and hypoxia-inducible factor 1-alpha signaling pathway. This study provides  insight into impact of nanomaterials on cellular gene expression profile and predicts downstream effects of nanomaterial induction of endochondral differentiation.

Stiffness assisted cell-matrix remodeling trigger 3D mechanotransduction regulatory programs.

Engineered matrices provide a valuable platform to understand the impact of biophysical factors on cellular behavior such as migration, proliferation, differentiation, and tissue remodeling, through mechanotransduction. While recent studies have identified some mechanisms of 3D mechanotransduction, there is still a critical knowledge gap in comprehending the interplay between 3D confinement, ECM properties, and cellular behavior. Specifically, the role of matrix stiffness in directing cellular fate in 3D microenvironment, independent of viscoelasticity, microstructure, and ligand density remains poorly understood. To address this gap, we designed a nanoparticle crosslinker to reinforce collagen-based hydrogels without altering their chemical composition, microstructure, viscoelasticity, and density of cell-adhesion ligand and utilized it to understand cellular dynamics. This crosslinking mechanism utilizes nanoparticles as crosslink epicenter, resulting in 10-fold increase in mechanical stiffness, without other changes. Human mesenchymal stem cells (hMSCs) encapsulated in 3D responded to mechanical stiffness by displaying circular morphology on soft hydrogels (5 kPa) and elongated morphology on stiff hydrogels (30 kPa). Stiff hydrogels facilitated the production and remodeling of nascent extracellular matrix (ECM) and activated mechanotransduction cascade. These changes were driven through intracellular PI3AKT signaling, regulation of epigenetic modifiers and activation of YAP/TAZ signaling. Overall, our study introduces a unique biomaterials platform to understand cell-ECM mechanotransduction in 3D for regenerative medicine as well as disease modelling.

Is basal cisternostomy in traumatic brain injury a need of hour or white elephant - A randomized trial to answer.

Background: Basal cisternostomy (BC) recently emerged as an adjuvant/alternative procedure to decompressive craniectomy (DC) in traumatic brain injuries (TBIs) with its potential to effectively reduce both intracranial pressure (ICP) and brain edema. However, its role in TBI is not yet established in the true sense and with clarity. The objective of the present study was to evaluate the effect of adjuvant BC on ICP, mortality, and clinicoradiological outcome. Methods: A single-center randomized control trial was conducted. Fifty patients were assigned to each DC-group and DC+BC-group. Randomization was done using the sealed envelope method. Both groups were followed in the postoperative period to compare the impact of surgery on ICP, radiological changes, and clinical outcome (mortality, days on ventilator/in intensive care unit (ICU), and Glasgow outcome scale-extended (GOS-E) at 12 weeks). Results: Both groups were comparable in terms of preoperative clinicoradiological characteristics. On postoperative days 1, 2, and 3, mean ICP was significantly low in the DC+BC-group (P < 0.0001). The decline in ICP in the DC+BC-group was significant in both moderate and severe TBI patients. In comparison, DC+BC-group has a shorter duration of mechanical ventilation/ICU stay and significantly better GOS-E score at 12 weeks (P < 0.0001*). The mortality rate was less in the DC+BC-group (48%) as compared to the DC-group (64%). Among radiological features, mean midline shift and mean outward brain herniation were significantly less in the DC+BC group. Bone-flap replacement was possible in ten patients of DC+BC-group at the time of primary surgery. Conclusion: Results of our study indicated that BC is beneficial in reducing both ICP and brain edema, which translates into favorable clinicoradiological outcomes.