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Mechanical stimuli drive many physiological processes, including touch and pain sensation, hearing, and blood pressure regulation. Mechanically activated (MA) cation channel activities have been recorded in many cells, but the responsible molecules have not been identified. We characterized a rapidly adapting MA current in a mouse neuroblastoma cell line. Expression profiling and RNA interference knockdown of candidate genes identified Piezo1 (Fam38A) to be required for MA currents in these cells. Piezo1 and related Piezo2 (Fam38B) are vertebrate multipass transmembrane proteins with homologs in invertebrates, plants, and protozoa. Overexpression of mouse Piezo1 or Piezo2 induced two kinetically distinct MA currents. Piezos are expressed in several tissues, and knockdown of Piezo2 in dorsal root ganglia neurons specifically reduced rapidly adapting MA currents. We propose that Piezos are components of MA cation channels.

Background Stroke is the leading cause of acquired motor deficiencies in adults. Restoring prehension abilities is challenging for individuals who have not recovered active hand opening capacities after their rehabilitation. Self-triggered functional electrical stimulation applied to finger extensor muscles to restore grasping abilities in daily life is called grasp neuroprosthesis (GNP) and remains poorly accessible to the post-stroke population. Thus, we developed a GNP prototype with self-triggering control modalities adapted to the characteristics of the post-stroke population and assessed its impact on abilities. Methods Through two clinical research protocols, 22 stroke participants used the GNP and its control modalities (EMG activity of a pre-defined muscle, IMU motion detection, foot switches and voice commands) for 3 to 5 sessions over a week. The NeuroPrehens software interpreted user commands through input signals from electromyographic, inertial, foot switches or microphone sensors to trigger an external electrical stimulator using two bipolar channels with surface electrodes. Users tested a panel of 9 control modalities, subjectively evaluated in ease-of-use and reliability with scores out of 10 and selected a preferred one before training with the GNP to perform functional unimanual standardized prehension tasks in a seated position. The responsiveness and functional impact of the GNP were assessed through a posteriori analysis of video recordings of these tasks across the two blinded evaluation multi-crossover N-of-1 randomized controlled trials. Results Non-paretic foot triggering, whether from EMG or IMU, received the highest scores in both ease-of-use (median scores out of 10: EMG 10, IMU 9) and reliability (EMG 9, IMU 9) and were found viable and appreciated by users, like voice control and head lateral inclination modalities. The assessment of the system’s general responsiveness combined with the control modalities latencies revealed median (95% confidence interval) durations between user intent and FES triggering of 333 ms (211 to 561), 217 ms (167 to 355) and 467 ms (147 to 728) for the IMU, EMG and voice control types of modalities, respectively. The functional improvement with the use of the GNP was significant in the two prehension tasks evaluated, with a median (95% confidence interval) improvement of 3 (− 1 to 5) points out of 5. Conclusions The GNP prototype and its control modalities were well suited to the post-stroke population in terms of self-triggering, responsiveness and restoration of functional grasping abilities. A wearable version of this device is being developed to improve prehension abilities at home. Trial Registration: Both studies are registered on clinicaltrials.gov: NCT03946488, registered May 10, 2019 and NCT04804384, registered March 18, 2021.

Context:Growth hormone (GH) is prescribed for an increasing range of indications, but there has been concern that it might raise cancer risk. Published data are limited.Objective:To examine cancer risks in relation to GH treatment.Design:Cohort study.Setting:Population-based.Patients:Cohort of 23,984 patients treated with recombinant human GH (r-hGH) in eight European countries since this treatment was first used in 1984. Cancer expectations from country-specific national population statistics.Main Outcome Measures:Cancer incidence and cancer mortality.Results:Incidence and mortality risks in the cohort were raised for several cancer sites, largely consequent on second primary malignancies in patients given r-hGH after cancer treatment. There was no clear raised risk in patients with growth failure without other major disease. Only for bone and bladder cancers was incidence significantly raised in GH-treated patients without previous cancer. Cancer risk was unrelated to duration or cumulative dose of r-hGH treatment, but for patients treated after previous cancer, cancer mortality risk increased significantly with increasing daily r-hGH dose (P trend < 0.001). Hodgkin lymphoma (HL) incidence increased significantly with longer follow-up (P trend = 0.001 for patients overall and 0.002 for patients without previous cancer).Conclusions:Our results do not generally support a carcinogenic effect of r-hGH, but the unexplained trend in cancer mortality risk in relation to GH dose in patients with previous cancer, and the indication of possible effects on bone cancer, bladder cancer, and HL risks, need further investigation.A total of 23,984 patients treated with recombinant growth hormone in eight countries since 1984 were followed. Cancer incidence overall did not relate to growth hormone, but certain cancers showed raised risks.

Mechanosensation is perhaps the last sensory modality not understood at the molecular level. Ion channels that sense mechanical force are postulated to play critical roles in a variety of biological processes including sensing touch/pain (somatosensation), sound (hearing), and shear stress (cardiovascular physiology); however, the identity of these ion channels has remained elusive. We previously identified Piezo1 and Piezo2 as mechanically activated cation channels that are expressed in many mechanosensitive cell types. Here, we show that Piezo1 is expressed in endothelial cells of developing blood vessels in mice. Piezo1-deficient embryos die at midgestation with defects in vascular remodeling, a process critically influenced by blood flow. We demonstrate that Piezo1 is activated by shear stress, the major type of mechanical force experienced by endothelial cells in response to blood flow. Furthermore, loss of Piezo1 in endothelial cells leads to deficits in stress fiber and cellular orientation in response to shear stress, linking Piezo1 mechanotransduction to regulation of cell morphology. These findings highlight an essential role of mammalian Piezo1 in vascular development during embryonic development.

To clarify the relationships between marginal zone lymphomas (MZLs) and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas (WM/LPLs), immunoglobulin heavy chain variable gene ( IGHV ) features were analyzed and the occurrence of MYD88 L265P mutations was identified in a series of 123 patients: 53 MZLs from the spleen (SMZLs), 11 from lymph nodes (NMZLs), 28 mucosa-associated lymphatic tissue (MALT) lymphomas and 31 WM/LPLs. SMZLs were characterized by overrepresentation of IGHV1–2 gene rearrangements with a canonical motif, without selection pressure and with long CDR3 segments. NMZLs had increased frequencies of IGHV3 genes. The IGHV gene was unmutated in most cases, often with long CDR3 segments. MALT lymphomas were usually associated with a mutated IGHV gene, but with the absence of selection pressure. WM/LPLs were associated with an IGHV3–23 overrepresentation and high IGHV mutation rate, with features of selection pressure and short CDR3 segments. MYD88 L265P mutations were almost restricted exclusively to WM/LPL patients. Taken all diagnoses together, all patients with MYD88 L265P mutations had an immunoglobulin M peak and almost all patients except one had bone marrow infiltration. These results demonstrate that the history of antigen exposure of the four entities studied was different and MYD88 L265P was specifically associated with WM/LPLs. WM/LPL may thus be functionally associated with constitutive nuclear factor-κB activation.

Cancer stem cells (CSCs) play an important role during metastasis, but the dynamic behavior and induction mechanisms of CSCs are not well understood. Here, we employ high-resolution intravital microscopy using a CSC biosensor to directly observe CSCs in live mice with mammary tumors. CSCs display the slow-migratory, invadopod-rich phenotype that is the hallmark of disseminating tumor cells. CSCs are enriched near macrophages, particularly near macrophage-containing intravasation sites called Tumor Microenvironment of Metastasis (TMEM) doorways. Substantial enrichment of CSCs occurs on association with TMEM doorways, contributing to the finding that CSCs represent >60% of circulating tumor cells. Mechanistically, stemness is induced in non-stem cancer cells upon their direct contact with macrophages via Notch-Jagged signaling. In breast cancers from patients, the density of TMEM doorways correlates with the proportion of cancer cells expressing stem cell markers, indicating that in human breast cancer TMEM doorways are not only cancer cell intravasation portals but also CSC programming sites. Intravital imaging reveals macrophage-driven de novo induction of cancer stem cells in vivo, and their dramatic enrichment on dissemination through TMEM doorways. These findings provide a mechanism for the validated ability of TMEM doorway density to be prognostic for distant recurrence of metastatic tumors in breast cancer patients.

The actions of corticotropin-releasing hormone (Crh), a mediator of endocrine 1 and behavioural responses to stress 2 , and the related hormone urocortin 3 (Ucn) are coordinated by two receptors, Crhr1 (encoded by Crhr ) and Crhr2 (refs 4 , 5 ). These receptors may exhibit distinct functions due to unique tissue distribution 6 and pharmacology 4 , 5 . Crhr -null mice have defined central functions for Crhr1 in anxiety and neuroendocrine stress responses 7 , 8 . Here we generate Crhr2 −/− mice and show that Crhr2 supplies regulatory features to the hypothalamic-pituitary-adrenal axis (HPA) stress response. Although initiation of the stress response appears to be normal, Crhr2 −/− mice show early termination of adrenocorticotropic hormone (Acth) release, suggesting that Crhr2 is involved in maintaining HPA drive. Crhr2 also appears to modify the recovery phase of the HPA response, as corticosterone levels remain elevated 90 minutes after stress in Crhr2 −/− mice. In addition, stress-coping behaviours associated with dearousal are reduced in Crhr2 –/– mice. We also demonstrate that Crhr2 is essential for sustained feeding suppression (hypophagia) induced by Ucn. Feeding is initially suppressed in Crhr2 −/− mice following Ucn, but Crhr2 −/− mice recover more rapidly and completely than do wild-type mice. In addition to central nervous system effects, we found that, in contrast to wild-type mice, Crhr2 −/− mice fail to show the enhanced cardiac performance or reduced blood pressure associated with systemic Ucn, suggesting that Crhr2 mediates these peripheral haemodynamic effects. Moreover, Crhr2 −/− mice have elevated basal blood pressure, demonstrating that Crhr2 participates in cardiovascular homeostasis. Our results identify specific responses in the brain and periphery that involve Crhr2.

Objectives Syndromic diarrhoea/tricho-hepato-enteric syndrome (SD/THE) is a rare congenital syndrome. The main features are intractable diarrhoea of infancy, hair abnormalities, facial dysmorphism, intrauterine growth restriction and immune system abnormalities. It has been linked to abnormalities in two components of the putative human ski complex: SKIV2L and TTC37. The long-term outcome of this syndrome is still unknown. We aim to describe the long-term outcome, in the French cohort of patients born since 1992. Design Review of the clinical and biological features of the 15 patients with SD/THE, followed in France and born between 1992 and 2010. Results All patients presented typical SD/THE syndrome features, of intractable diarrhoea in infancy requiring parenteral nutrition, a facial dysmorphism with hair abnormalities, and immunological disorders. Half of them also had liver and skin abnormalities. Five children died, among which 3 died due to infections. Probabilities of survival according to the Kaplan-Meier method were 93.3%, 86.7%, 74.3 and 61.9%, respectively at 1 year, 5 years, 10 years and 15 years of age. 3/15 were weaned from parenteral nutrition (PN) with likelihood of weaning being 10% at 5 years and 40% at 10 years. At birth 80% were small for gestational age and the short stature persisted in 60%. Haemophagocytic syndrome was noted in 60% and mild mental retardation was present in 60%. Conclusions SD/THE is a rare disease with high morbidity and mortality. Management should be focused on nutrition and immunological defects.