Shigella IpaA mediates actin bundling through diffusible vinculin oligomers with activation imprint.

Upon activation, vinculin reinforces cytoskeletal anchorage during cell adhesion. Activating ligands classically disrupt intramolecular interactions between the vinculin head and tail domains that bind to actin filaments. Here, we show that Shigella IpaA triggers major allosteric changes in the head domain, leading to vinculin homo-oligomerization. Through the cooperative binding of its three vinculin-binding sites (VBSs), IpaA induces a striking reorientation of the D1 and D2 head subdomains associated with vinculin oligomerization. IpaA thus acts as a catalyst producing vinculin clusters that bundle actin at a distance from the activation site and trigger the formation of highly stable adhesions resisting the action of actin relaxing drugs. Unlike canonical activation, vinculin homo-oligomers induced by IpaA appear to keep a persistent imprint of the activated state in addition to their bundling activity, accounting for stable cell adhesion independent of force transduction and relevant to bacterial invasion.

Acute dermatitis in adult female patients receiving hypofractionated radiotherapy for breast cancer: experience from a low- and middle-income country.

Radiotherapy (RT) is an important component of treatment in the management of breast cancer patients. The radiation treatment paradigm has been shifted towards hypofractionated RT. This study aims to determine the severity of acute dermatitis in patients receiving hypofractionated RT for breast cancer at a tertiary care university hospital in Pakistan. Patients with biopsy-proven invasive breast carcinoma or DCIS who were referred for radical radiotherapy after discussion in the breast tumour board were retrospectively reviewed. Physical assessment of the patients for evaluation of the severity of radiation dermatitis will be carried out in the first week, last week and on the first follow-up after 1 month of completion of RT, according to the Radiation Therapy Oncology Group/European Organisation For Research And Treatment Of Cancer (RTOG/EORTC) criteria. We identified 92 female patients in 6 months at Aga Khan University Hospital, with a mean age of 53.1 years. Most of the treated patients had clinical stage 3 (64%) cancer, while others were stage 2 (42%), stage 1 (2%) and stage 0 (2%). The surgeries performed were mastectomy in 59 patients and breast-conserving surgery in 33 patients. Histology was Intra Ductal Carcinoma (IDC) (95%), DCIS (3%) and Invasive Lobular Carcinoma (ILC) (2%). Most of the patients received chemotherapy (96%). Radiotherapy dose was 4256 cGy in 16 fractions, followed by a boost of 10 Gy. The radiation techniques used were intensity-modulated radiotherapy (47.8%) and three-dimensional conformal radiotherapy (52.2%). Most of the patients experienced no toxicity (59%), while grade I toxicity was observed in 29% of the patients and grade II toxicity was observed in 11%. Only 1% of the patients experienced grade III skin toxicity. Hypofractionated radiation therapy is beneficial because of the shorter overall treatment time which reduces the socio-economic burden, not only for patients but also for radiotherapeutic institutions. However, extended follow-up is to be reported for long-term toxicity and other consequences.

OTX2 Non-Cell Autonomous Activity Regulates Inner Retinal Function.

OTX2 is a homeoprotein transcription factor expressed in photoreceptors and bipolar cells in the retina. OTX2, like many other homeoproteins, transfers between cells and exerts non-cell autonomous effects such as promoting the survival of retinal ganglion cells that do not express the protein. Here we used a genetic approach to target extracellular OTX2 in the retina by conditional expression of a secreted single-chain anti-OTX2 antibody. Compared with control mice, the expression of this antibody by parvalbumin-expressing neurons in the retina is followed by a reduction in visual acuity in 1-month-old mice with no alteration of the retinal structure or cell type number or aspect. The a-waves and b-waves measured by electroretinogram were also indistinguishable from those of control mice, suggesting no functional deficit of photoreceptors and bipolar cells. Mice expressing the OTX2-neutralizing antibody did show a significant doubling in the flicker amplitude and a reduction in oscillatory potential, consistent with a change in inner retinal function. Our results show that interfering in vivo with OTX2 non-cell autonomous activity in the postnatal retina leads to an alteration in inner retinal cell functions and causes a deficit in visual acuity.