Interface Gain-of-Function Mutations in TLR7 Cause Systemic and Neuro-inflammatory Disease

TLR7 recognizes pathogen-derived single-stranded RNA (ssRNA), a function integral to the innate immune response to viral infection. Notably, TLR7 can also recognize self-derived ssRNA, with gain-of-function mutations in human TLR7 recently identified to cause both early-onset systemic lupus erythematosus (SLE) and neuromyelitis optica. Here, we describe two novel mutations in TLR7, F507S and L528I. While the L528I substitution arose de novo, the F507S mutation was present in three individuals from the same family, including a severely affected male, notably given that the TLR7 gene is situated on the X chromosome and that all other cases so far described have been female. The observation of mutations at residues 507 and 528 of TLR7 indicates the importance of the TLR7 dimerization interface in maintaining immune homeostasis, where we predict that altered homo-dimerization enhances TLR7 signaling. Finally, while mutations in TLR7 can result in SLE-like disease, our data suggest a broader phenotypic spectrum associated with TLR7 gain-of-function, including significant neurological involvement

Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Experimental and quantitative investigation of a free round jet

Flow visualization, basic image processing and statistical treatment are used to investigate the flow characteristics of an axisymmetric free air jet having an initially uniform velocity profile. Vortical structures and their development in the transition zone of the jet are visualized for a range of Reynolds numbers from 1300 to 1700. It is shown the onset and growth of these structures which propagate downstream of the nozzle exit at approximately 0.65 of the velocity of the mean flow. The duration of this development mechanism, before reaching the zone of turbulence, is estimated at 7.6 × 10-3. Near-field and intermediate-field region lengths, separation distance between two neighboring vortical structures, apparition frequency and jet Strouhal number are measured as functions of the Reynolds number. In particular, it is shown that the Strouhal number, which is estimated at 0.64 in our case, is independent of Reynolds numbers

Effect of Froude Number on the Turbulent Wall Jet in Coflow Stream

Sixth Conference on Design and Modeling of Mechanical Systems (CMSM 2015), Hammamet, TUNISIA, MAR 23-25, 2015International audienceThe influence of the coflow velocity ratio on the behavior of a non isothermal turbulent wall jet has been determined numerically. The numerical resolution of the governing equations is carried out using a finite difference method. Turbulence modeling is performed by a modified low-Reynolds number k-epsilon model. In this work, we are interested in the study of the effect of the coflow stream on the behavior of the dynamic and thermal properties of the wall jet subjected to a constant temperature. A comparison with a simple wall jet is carried out. Further, we will examine the influence of the Froude number on the wall jet emerging in a coflow stream

First evidence of the protective role of melatonin in counteracting cadmium toxicity in the rat ovary via the mTOR pathway.

Herein, the first evidence of the ability of melatonin (MLT) to counteract cadmium (Cd) toxic effects on the rat ovary is reported. Cd treatment, enhancing oxidative stress, provoked clear morphological, histological and biomolecular alterations, i.e. in the estrous cycle duration, in the ovarian and serum E2 concentration other than in the steroidogenic and folliculogenic genes expression. Results demonstrated that the use of MLT, in combination with Cd, avoided the changes, strongly suggesting that it is an efficient antioxidant for preventing oxidative stress in the rat ovary. Moreover, to explore the underlying mechanism involved, at molecular level, in the effects of Cd-MLT interaction, the study focused on the mTOR and ERK1/2 pathways. Interestingly, data showed that Cd influenced the phosphorylation status of mTOR, of its downstream effectors and of ERK1/2, inducing autophagy and apoptosis, while cotreatment with MLT nullified these changes. This work highlights the beneficial role exerted by MLT in preventing Cd-induced toxicity in the rat ovary, encouraging further studies to confirm its action on human ovarian health with the aim to use this indolamine to ameliorate oocyte quality in women with fertility disorders