The dynamics of the β-propeller domain in Kelch protein KLHL40 changes upon nemaline myopathy-associated mutation

Evolutionarily widespread, functionally and structurally diverse and still largely unexplored, Kelch proteins, characterized by the presence of a conserved C-terminal β-propeller, are implicated in a number of diverse fundamental biological functions, including cytoskeletal arrangement, regulation of cell morphology and organization, and protein degradation. Mutations in the genes encoding for Kelch superfamily members are being discovered as the cause of several neuromuscular diseases and cancer. The E528K mutation in Kelch protein KLHL40, which regulates skeletal muscle myogenesis, has been identified as a frequent cause of severe autosomal-recessive nemaline myopathy (NM). We use all-atom molecular dynamics simulations to characterize the dynamic behaviour of the β-propeller of the wild-type protein and identify correlated motions underlying the in vivo functionality. We also modelled the NM-associated mutation and we found that it does not lead to dramatic disruption of the β-propeller architecture; yet, residue 528 is a hub in the correlated motions of the domain, and mutation-induced local structural alterations are propagated to the whole protein, affecting its dynamics and physicochemical properties, which are fundamental for in vivo interaction with partners. Our results indicate that rational design of drugs can be envisioned as a strategy for restoring the internal network of communication and resetting KLHL40 to its physiological state

Pre-amyloid oligomers budding:a metastatic mechanism of proteotoxicity

The pathological hallmark of misfolded protein diseases and aging is the accumulation of proteotoxic aggregates. However, the mechanisms of proteotoxicity and the dynamic changes in fiber formation and dissemination remain unclear, preventing a cure. Here we adopted a reductionist approach and used atomic force microscopy to define the temporal and spatial changes of amyloid aggregates, their modes of dissemination and the biochemical changes that may influence their growth. We show that pre-amyloid oligomers (PAO) mature to form linear and circular protofibrils, and amyloid fibers, and those can break reforming PAO that can migrate invading neighbor structures. Simulating the effect of immunotherapy modifies the dynamics of PAO formation. Anti-fibers as well as anti-PAO antibodies fragment the amyloid fibers, however the fragmentation using anti-fibers antibodies favored the migration of PAO. In conclusion, we provide evidence for the mechanisms of misfolded protein maturation and propagation and the effects of interventions on the resolution and dissemination of amyloid pathology

An Unusual Hypopharyngeal Foreign Body Causing Dyspnea After Vertebroplasty

n/

Bone Modeling after Orthodontic Extrusion: A Histomorphometric Pilot Study

During osteogenesis and bone modeling, high vascularity and osteoblastic/osteoclastic cell activity have been detected. A decrease in this activity is a sign of complete bone formation and maturation. Alveolar bone maturation seems to occur within weeks and months; however, the precise timing of the alveolar bone modeling is still unknown. The aim of this clinical pilot study was to investigate the bone modeling of neo-apposed tissue during orthodontic extrusive movements, through a histomorphometric analysis of human biopsies. This study was conducted on third mandibular molars sockets, and all teeth were extracted after orthodontic extrusion between 2010 and 2014. After different stabilization timings, extractions were performed, and a specimen of neo-deposed bone was harvested from each socket for the histomorphometric analysis. Histological parameters were evaluated to identify bone quantity and quality. This study included 12 teeth extracted from 9 patients. All specimens were composed of bone tissue. Bone samples taken after 1 and 1.5 months of stabilization presented remarkable percentages of woven bone, while after 2 months, a relevant decrease was observed. Histomorphometric analysis suggested that after orthodontic extrusion, a period of stabilization of 2 months allows the neo-deposed bone to mature

The self-confinement of electrons and positrons from dark matter

Radiative emissions from electrons and positrons generated by dark matter (DM) annihilation or decay are one of the most investigated signals in indirect searches of WIMPs. Ideal targets must have large ratio of DM to baryonic matter. However, such ``dark'' systems have a poorly known level of magnetic turbulence, which determines the residence time of the electrons and positrons and therefore also the strength of the expected signal. This typically leads to significant uncertainties in the derived DM bounds. In a novel approach, we compute the self-confinement of the DM-induced electrons and positrons. Indeed, they themselves generate irregularities in the magnetic field, thus setting a lower limit on the presence of the magnetic turbulence. We specifically apply this approach to dwarf spheroidal galaxies. Finally, by comparing the expected synchrotron emission with radio data from the direction of the Draco galaxy collected at the Giant Metre Radio Telescope, we show that the proposed approach can be used to set robust and competitive bounds on WIMP DM.Comment: 18 pages, 10 figures. v2: minor revision, matches published versio

Una “ciudad fantasma” como espacio de posibilidad: luchar por el derecho a la ciudad en contextos de pobreza urbana

The objective of this text is to reconstruct the ways in which secondary school students denounce situations of vulnerability associated with pollution and the precariousness they experience in their neighborhoods. This research uses creative methods based on artistic and audiovisual co-production workshops in and with schools in two neighborhoods in the Metropolitan Region of Buenos Aires (RMBA) characterized by urban poverty and environmental degradation. The final productions identified ways of denouncing everyday urban inequalities, a commitment to a different city, and a political demand for the right to the city.El objetivo del presente texto consiste en reponer los modos en que estudiantes de escuelas secundarias denuncian situaciones de vulneración asociadas a la contaminación y la precariedad que viven en sus barrios. Esta investigación utiliza métodos creativos basados en talleres de coproducción artística y audiovisual en y con escuelas de dos barrios de la Región Metropolitana de Buenos Aires (RMBA) caracterizados por la pobreza urbana y la degradación ambiental. En las producciones finales se lograron identificar modos de denuncia de las desigualdades cotidianas urbanas, una apuesta por una ciudad otra y un reclamo político por el derecho a la ciudad

Pseudoperoxidase activity, conformational stability and aggregation propensity of the His98Tyr myoglobin variant. Implications for the onset of myoglobinopathy.

The autosomal dominant striated muscle disease myoglobinopathy is due to the single point mutation His98Tyr in human myoglobin (MB) [Olivè et al. Nat. Comm, 2019, 10, 1396], the heme-protein responsible for binding, storage and controlled release of O2 in striated muscle. In order to understand the molecular bases of this disease, a comprehensive biochemical and biophysical study on wt MB and the variant H98Y has been performed. Although only small differences exist between the active site architectures of the two proteins, the mutant exhibits an (i) increased reactivity towards hydrogen peroxide, (ii) a higher tendency to form high-molecular weight aggregates and (iii) is more prone to heme bleaching, possibly as a consequence of the observed H2O2-induced formation of the Tyr98 radical close to the metal center. These effects add to the impaired oxygen binding capacity and faster heme dissociation of the H98Y variant compared to wt MB. As the above effects result from bond formation/cleavage events occurring at the distal and proximal heme sites, it appears that the molecular determinants of the disease are localized there. These findings set the bases for clarifying the onset of the cascade of chemical events that are responsible for the pathological symptoms of myoglobinopathy

Relationship between low Ankle-Brachial Index and rapid renal function decline in patients with atrial fibrillation: A prospective multicentre cohort study

OBJECTIVE: To investigate the relationship between Ankle-Brachial Index (ABI) and renal function progression in patients with atrial fibrillation (AF). DESIGN: Observational prospective multicentre cohort study. SETTING:Atherothrombosis Center of I Clinica Medica of 'Sapienza' University of Rome; Department of Medical and Surgical Sciences of University Magna Græcia of Catanzaro; Atrial Fibrillation Registry for Ankle-Brachial Index Prevalence Assessment-Collaborative Italian Study. PARTICIPANTS: 897 AF patients on treatment with vitamin K antagonists. MAIN OUTCOME MEASURES: The relationship between basal ABI and renal function progression, assessed by the estimated Glomerular Filtration Rate (eGFR) calculated with the CKD-EPI formula at baseline and after 2 years of follow-up. The rapid decline in eGFR, defined as a decline in eGFR >5 mL/min/1.73 m(2)/year, and incident eGFR<60 mL/min/1.73 m(2) were primary and secondary end points, respectively. RESULTS: Mean age was 71.8±9.0 years and 41.8% were women. Low ABI (ie, ≤0.90) was present in 194 (21.6%) patients. Baseline median eGFR was 72.7 mL/min/1.73 m(2), and 28.7% patients had an eGFR60 mL/min/1.73 m(2), 153 (23.9%) had a reduction of the eGFR <60 mL/min/1.73 m(2). ABI ≤0.90 was also an independent predictor for incident eGFR<60 mL/min/1.73 m(2) (HR 1.851, 95% CI 1.205 to 2.845, p=0.005). CONCLUSIONS: In patients with AF, an ABI ≤0.90 is independently associated with a rapid decline in renal function and incident eGFR<60 mL/min/1.73 m(2). ABI measurement may help identify patients with AF at risk of renal function deterioration