Notes

Lithium keeps peritoneal membrane layer honesty by curbing mesothelial cell αB-crystallin.
Here, we show that treatment of the mutant mice with drugs targeting epigenetic enzymes improves muscle strength, RyR1 protein content, and muscle ultrastructure. This study provides proof of concept for the pharmacological treatment of patients with congenital myopathies linked to recessive RYR1 mutations.Type III Secretion Systems (T3SS) deliver subunits from the bacterial cytosol to nascent cell surface flagella. Early flagellar subunits that form the rod and hook substructures are unchaperoned and contain their own export signals. A gate recognition motif (GRM) docks them at the FlhBc component of the FlhAB-FliPQR export gate, but the gate must then be opened and subunits must be unfolded to pass through the flagellar channel. This induced us to seek further signals on the subunits. Here, we identify a second signal at the extreme N-terminus of flagellar rod and hook subunits and determine that key to the signal is its hydrophobicity. We show that the two export signal elements are recognised separately and sequentially, as the N-terminal signal is recognised by the flagellar export machinery only after subunits have docked at FlhBC via the GRM. The position of the N-terminal hydrophobic signal in the subunit sequence relative to the GRM appeared to be important, as a FlgD deletion variant (FlgDshort), in which the distance between the N-terminal signal and the GRM was shortened, 'stalled' at the export machinery and was not exported. The attenuation of motility caused by FlgDshort was suppressed by mutations that destabilised the closed conformation of the FlhAB-FliPQR export gate, suggesting that the hydrophobic N-terminal signal might trigger opening of the flagellar export gate.Equilibrium fluctuations and triggered conformational changes often underlie the functional cycles of membrane proteins. For example, transporters mediate the passage of molecules across cell membranes by alternating between inward- and outward-facing states, while receptors undergo intracellular structural rearrangements that initiate signaling cascades. Although the conformational plasticity of these proteins has historically posed a challenge for traditional de novo protein structure prediction pipelines, the recent success of AlphaFold2 (AF2) in CASP14 culminated in the modeling of a transporter in multiple conformations to high accuracy. Given that AF2 was designed to predict static structures of proteins, it remains unclear if this result represents an underexplored capability to accurately predict multiple conformations and/or structural heterogeneity. Here, we present an approach to drive AF2 to sample alternative conformations of topologically diverse transporters and G-protein-coupled receptors that are absent from the AF2 training set. Whereas models of most proteins generated using the default AF2 pipeline are conformationally homogeneous and nearly identical to one another, reducing the depth of the input multiple sequence alignments by stochastic subsampling led to the generation of accurate models in multiple conformations. In our benchmark, these conformations spanned the range between two experimental structures of interest, with models at the extremes of these conformational distributions observed to be among the most accurate (average template modeling score of 0.94). These results suggest a straightforward approach to identifying native-like alternative states, while also highlighting the need for the next generation of deep learning algorithms to be designed to predict ensembles of biophysically relevant states.During development, cells aggregate at tissue boundaries to form normal tissue architecture of organs. However, how cells are segregated into tissue precursors remains largely unknown. Cornea development is a perfect example of this process whereby neural crest cells aggregate in the periocular region prior to their migration and differentiation into corneal cells. Our recent RNA-seq analysis identified upregulation of nephronectin (Npnt) transcripts during early stages of corneal development where its function has not been investigated. We found that Npnt mRNA and protein are expressed by various ocular tissues, including the migratory periocular neural crest (pNC), which also express the integrin alpha 8 (Itgα8) receptor. Knockdown of either Npnt or Itgα8 attenuated cornea development, whereas overexpression of Npnt resulted in cornea thickening. Moreover, overexpression of Npnt variants lacking RGD-binding sites did not affect corneal thickness. Neither the knockdown nor augmentation of Npnt caused significant changes in cell proliferation, suggesting that Npnt directs pNC migration into the cornea. In vitro analyses showed that Npnt promotes pNC migration from explanted periocular mesenchyme, which requires Itgα8, focal adhesion kinase, and Rho kinase. Combined, these data suggest that Npnt augments cell migration into the presumptive cornea extracellular matrix by functioning as a substrate for Itgα8-positive pNC cells.Eprinomectin and praziquantel, nematodicide and cestodicide compounds, are both combined with the insecticide and acaricide compounds fipronil and (S)-methoprene in Frontline® Protect/Broadline®, or esafoxolaner in NexGard® Combo. These topical feline endectoparasiticide products were tested for efficacy against fleas and intestinal helminths in a field trial in Brazil. Flea- and/or helminth-infested domestic cats were treated twice at a monthly interval following label instructions 160 cats with Frontline® Protect/Broadline® and 165 cats with NexGard® Combo. The flea and intestinal helminth infestations were evaluated using comb counts and copromicroscopy, respectively before first treatment for baseline value, then 9 and 30 days after each treatment for fleas, and 9 days after each treatment for helminths. Multiparasitism was very frequent at baseline, as amongst the 325 included cats, 295, 280, 86 and 93 cats were at least infested with Ctenocephalides fleas, Ancylostoma, Toxocara and Dipylidium caninum, respectively. Efficacies were calculated by comparing the geometric means at baseline and at post-treatment timepoints for each parasite genus/species. Inclusive of both products and of all evaluation timepoints, the Ctenocephalides, Ancylostoma, Toxocara and D. caninum efficacies were at least 98.3%, 99.8%, 99.8% and 96.3%, respectively. No adverse reactions were observed, except for a few instances of mild, transient, and self-resolving hypersalivation occurring on the day of treatment in both groups. This field trial demonstrated high-level efficacy of Frontline® Protect/Broadline® and NexGard® Combo against major parasites of cats in Brazil.Diaphragm myositis is a rare manifestation of idiopathic inflammatory myopathies, barely portrayed in literature despite its potential severity. We describe a 57-year-old Caucasian male with anti-MDA5 positive dermatomyositis, that had a 4-month history of progressive dyspnoea requiring oxygen-therapy, scarcely responsive to prednisolone. Chest high resolution computed tomography (HRCT) showed mild interstitial lung disease (ILD), whereas pulmonary function tests evidenced severe restrictive syndrome with high lung ultrasound score. Diaphragm ultrasound revealed a marked diaphragm dysmotility, confirmed by electromyography (EMG). The patient was treated with intravenous immunoglobulins and mofetil mycophenolate with progressive improvement of dyspnoea, lung volumes and ILD at CT scan. Ultrasound examination also revealed marked improvement of the diaphragmatic disfunction and a reduction of lung ultrasound score. The use of ultrasound may provide a valuable tool in the diagnosis of diaphragm myositis, which may play a major role in the respiratory impairment of these patients. A combined lung and diaphragm examination allowed bedside monitoring of the improvements in both lung aeration and diaphragm contractility.Capillary leak syndrome (CLS) is a rare condition characterised by increased capillary permeability, with subsequent hypoalbuminemia and hypotension, leading to an increased risk of shock and death. AUZ454 inhibitor We present the case of a patient with anti-transcriptional intermediary factor 1γ dermatomyositis that developed CLS one week after starting treatment with rituximab and prophylactic co-trimoxazole. The patient was admitted to the Intensive Care Unit (ICU), recovered after treatment with intravenous immunoglobulin, albumin, and Ringer lactate, but died a month after the discharge due to a poorly differentiated hepatocarcinoma diagnosed in the ICU.
Relapsing polychondritis (RP) evolves with variable and intermittent involvement of cartilage and proteoglycan-rich structures. Ocular manifestations are present in up to two-thirds of RP patients. Necrotising scleritis (NS) and peripheral ulcerative keratitis (PUK) may be inaugural and may lead to eye perforation and vision loss. We aimed to review NS and PUK in RP, in order to characterise them, to identify successful treatment options and unmet needs.

A systematic review of the currently available evidence in PubMed, EMBASE and Scopus was performed according to PRISMA, including observational studies, single case reports and case series of NS/PUK in RP. Study design, number of patients, age, gender, treatment and outcome, were extracted. Two RP patients also provided their opinion.

Five case reports and two case series were eligible for inclusion. We identified 10 RP patients with eye-threatening complications (NS and/or PUK), 9 adults (2 males, 7 females, aged 35-72, median age 57.6 years) and one pthe prognosis of these serious complications of RP.
To evaluate effects of whole-body cryotherapy (WBC) in rheumatoid arthritis (RA).

Patients with active RA undergoing a 16-day multimodal rheumatologic complex treatment were randomly assigned to either WBC (6 applications in 14 days at -130°C for 3 min) or no treatment. The primary outcome was the difference between groups in pain on a numerical rating scale after intervention. Secondary outcomes assessed effects on i) disease activity, ii) functional capacity, iii) cytokine levels, and iv) use of analgesics.

A total of 56 RA patients completed the trial (intervention group [IG] 31 patients, control group [CG] 25 patients). The mean change (± standard error) in pain after intervention was -2 in the IG (95% confidence interval [CI] -2.75 to -1.31, p<0.001) and -0.88 (95% CI -1.43 to -0.33, p=0.003) in the CG, with a baseline-adjusted between-group difference of -1.31 ± 0.4 (95% CI -2.1 to -0.53; p=0.002). Pain at the 12-week follow-up visit remained significantly below baseline values in the IG. Disease activity and functional capacity showed statistically and clinically meaningful improvement after intervention but were not significant at the 12-week follow up. TNF and IL-6 levels changed significantly in the IG. Eighteen of 31 (58%) patients of the IG reduced or discontinued analgesics at the 12-week follow-up. No WBC-related side effects were reported.

WBC in RA reduces pain and disease activity significantly and in a clinically meaningful manner, resulting in a reduction of analgesics. These effects are potentially based on a change in cytokine levels.
WBC in RA reduces pain and disease activity significantly and in a clinically meaningful manner, resulting in a reduction of analgesics. These effects are potentially based on a change in cytokine levels.
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