A RAB35-p85/PI3K axis controls oscillatory apical protrusions required for efficient chemotactic migration

How cells move chemotactically remains a major unmet challenge in cell biology. Emerging evidences indicate that for interpreting noisy, shallow gradients of soluble cues a system must behave as an excitable process. Here, through an RNAi-based, high-content screening approach, we identify RAB35 as necessary for the formation of growth factors (GFs)-induced waves of Circular Dorsal Ruffles (CDRs), apically restricted actin-rich migratory protrusions. RAB35 is sufficient to induce recurrent and polarized CDRs that travel as propagating waves, thus behaving as an excitable system that can be biased to control cell steering. Consistently, RAB35 is essential for promoting directed chemotactic migration and chemoinvasion of various cells in response to gradients of motogenic GFs. Molecularly, RAB35 does so by directly regulating the activity of p85/PI3K polarity axis. We propose that RAB35 is a molecular determinant for the control of an excitable, oscillatory system that acts as steering wheel for GF-mediated chemotaxis and chemoinvasion

Effect of type I tympanoplasty on the resonant frequency of the middle ear: Comparison between chondrotympanoplasty and temporalis fascia grafting

Aims: To evaluate the effect of type I chondrotympanoplasty on the resonant frequency (RF) of the middle ear and compare it to the respective outcomes of type I tympanoplasty using temporalis fascia grafting (TFG). Hearing results and respective graft integration rates were also assessed. Materials and Methods: A retrospective comparative study was conducted of patients who had undergone type I tympanoplasty at a tertiary university hospital. Selection criteria included tympanic membrane perforation following chronic otitis media, trauma, or grommet insertion; an intact ossicular chain; a dry ear for at least 3 months; and normal middle ear mucosa. Patients with ossicular discontinuity, ossiculoplasty, cholesteatoma, previous ear surgery, syndromes affecting the middle ear, or younger than 16 years old were excluded. Results: Sixty-nine patients met the inclusion criteria; chondrotympanoplasty was performed in 39 and TFG in 30. Three patients showed incomplete tympanic membrane closure at follow-up. The graft integration rate was 97.4% in the chondrotympanoplasty group and 93.3% in the TFG group. An air-bone gap closure within 10 dB was achieved in 73.7% of the chondrotympanoplasty patients versus 67.9% of the TFG patients. Hearing gain of 21 to 30 dB in air conduction thresholds was obtained in 65.8% of the chondrotympanoplasty patients and 60.7% of their TFG counterparts. RF was 808 ± 458 Hz in the chondrotympanoplasty group and 628 ± 256 Hz in the TFG group. The RF remained within the normal range in 73.7% of chondrotympanoplasty patients versus 42.9% of TFG patients. Conclusions: Chondrotympanoplasty has hearing results comparable to those of TFG myringoplasty. The cartilage can be used without concerns regarding its impact on the middle ear mechanics as the sound-conducive properties of the tympanic membrane remain unchanged. © 2012 The Canadian Society of Otolaryngology-Head & Neck Surgery

Cell cycle-dependent force transmission in cancer cells

The generation of traction forces and their transmission to the extracellular environment supports the disseminative migration of cells from a primary tumor. In cancer cells, the periodic variation of nuclear stiffness during the cell cycle provides a functional link between efficient translocation and proliferation. However, the mechanical framework completing this picture remains unexplored. Here, the Fucci2 reporter was expressed in various human epithelial cancer cells to resolve their cell cycle phase transition. The corresponding tractions were captured by a recently developed reference-free confocal traction-force microscopy platform. The combined approach was conducive to the analysis of phase-dependent force variation at the level of individual integrin contacts. Detected forces were invariably higher in the G1 and early S phases than in the ensuing late S/G2, and locally colocalized with high levels of paxillin phosphorylation. Perturbation of paxillin phosphorylation at focal adhesions, obtained through the biochemical inhibition of focal adhesion kinase (FAK) or the transfection of nonphosphorylatable or phosphomimetic paxillin mutants, significantly diminished the force transmitted to the substrate. These data demonstrate a reproducible modulation of force transmission during the cell cycle progression of cancer cells, instrumental to their invasion of dense environments. In addition, they delineate a model in which paxillin phosphorylation supports the mechanical maturation of adhesions relaying forces to the substrate

COVID-19: ensuring our medical equipment can meet the challenge

To predict the spread of coronavirus disease globally and consequently prepare the hospital facilities with the required technology is a challenge. The availability of essential medical equipment to support patients affected by Covid-19 is globally limited. Areas covered: This perspective gives a technical view of the pandemic focusing on the main actions taken by regulatory agencies to cope with the shortage of devices. The risk/benefit assessment and the main infection control policies in the clinical practices are also looked at. Expert opinion: Regulatory agencies have amended their medical devices directives to address the pandemic, but each in a different way. In this exceptional situation scientist and technology experts in collaboration with medical specialists should work together to re-assess the risk analysis on medical equipment management and their use and re-use in this context with the aim to improve global health care Every effort must be made to provide the necessary devices at least with the minimum acceptable performances for Covid-19 patients while maintaining a high standard of safety for users. The aim of the present manuscript is to highlight the technical challenges in order to prevent, through targeted actions, operating standards from falling below the standards of care due to a lack of medical devices. Abbreviations: AKI: acute Kidney Injury; ARGMD: Australian Regulatory Guidelines for Medical Devices; Covid-19: Coronavirus disease; FDA: Food and Drug Administration; ECMO: Extracorporeal Membrane Oxygenation; EU: European Union; ICU: Intensive Care Unit; WHO: World Health Organization; MHRA: Medicines and Healthcare products Regulatory Agency; MDR: Medical Device Regulation; SARI: Severe Acute Respiratory Infection