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Abstract Background As previously published, the MMPOWER-3 clinical trial did not demonstrate a significant benefit of elamipretide treatment in a genotypically diverse population of adults with primary mitochondrial myopathy (PMM). However, the prespecified subgroup of subjects with disease-causing nuclear DNA (nDNA) pathogenic variants receiving elamipretide experienced an improvement in the six-minute walk test (6MWT), while the cohort of subjects with mitochondrial DNA (mtDNA) pathogenic variants showed no difference versus placebo. These published findings prompted additional genotype-specific post hoc analyses of the MMPOWER-3 trial. Here, we present these analyses to further investigate the findings and to seek trends and commonalities among those subjects who responded to treatment, to build a more precise Phase 3 trial design for further investigation in likely responders. Results Subjects with mtDNA pathogenic variants or single large-scale mtDNA deletions represented 74% of the MMPOWER-3 population, with 70% in the mtDNA cohort having either single large-scale mtDNA deletions or MT-TL1 pathogenic variants. Most subjects in the nDNA cohort had pathogenic variants in genes required for mtDNA maintenance (mtDNA replisome), the majority of which were in POLG and TWNK. The mtDNA replisome post-hoc cohort displayed an improvement on the 6MWT, trending towards significant, in the elamipretide group when compared with placebo (25.2 ± 8.7 m versus 2.0 ± 8.6 m for placebo group; p = 0.06). The 6MWT results at week 24 in subjects with replisome variants showed a significant change in the elamipretide group subjects who had chronic progressive external ophthalmoplegia (CPEO) (37.3 ± 9.5 m versus − 8.0 ± 10.7 m for the placebo group; p = 0.0024). Pharmacokinetic (exposure–response) analyses in the nDNA cohort showed a weak positive correlation between plasma elamipretide concentration and 6MWT improvement. Conclusions Post hoc analyses indicated that elamipretide had a beneficial effect in PMM patients with mtDNA replisome disorders, underscoring the importance of considering specific genetic subtypes in PMM clinical trials. These data serve as the foundation for a follow-up Phase 3 clinical trial (NuPOWER) which has been designed as described in this paper to determine the efficacy of elamipretide in patients with mtDNA maintenance-related disorders. Classification of evidence Class I ClinicalTrials.gov identifier NCT03323749

Abstract Statins, widely used cardiovascular drugs that lower cholesterol by inhibiting HMG-CoA reductase, have been increasingly recognized for their potential anticancer properties. This study elucidates the underlying mechanism, revealing that statins exploit Synthetic Lethality, a principle where the co-occurrence of two non-lethal events leads to cell death. Our computational analysis of approximately 37,000 SL pairs identified statins as potential drugs targeting genes involved in SL pairs with metastatic genes. In vitro validation on various cancer cell lines confirmed the anticancer efficacy of statins. This data-driven drug repurposing strategy provides a molecular basis for the anticancer effects of statins, offering translational opportunities in oncology.

Introduction: The World Health Organization (WHO) has proposed to monitor intrinsic capacity (IC) in the older population as a public health strategy through the Integrated Care for Older People (ICOPE) program. Although the program has been developed based on solid concepts, scientific evidence on its practical applicability is still scarce. Objectives: To evaluate IC in Brazilian older adults, its progress over time, and its association with sociodemographic and health factors and outcomes. To evaluate the psychometric properties of the WHO/ICOPE screening tool. Methods: This is a prospective multicenter cohort study with a 36-month follow-up. We will recruit 3838 people aged ≥ 60 years, registered in the health care units included in the study by the participating centers. We will collect sociodemographic and health data and will administer tools to assess IC domains, both those provided for in the ICOPE screening tool and the sequence of confirmatory assessments provided for in the program. Participants will be reassessed every 6 months for 36 months. Expected results: To establish the profile of IC in the study population and to understand its progress and the variables associated with the clinical outcomes of interest. To reveal the diagnostic and psychometric properties of the WHO/ICOPE screening tool. The project is funded by the Brazilian National Council for Scientific and Technological Development (CNPq). Relevance: Understanding the potential use of the ICOPE public health strategy proposed by the WHO within the scope of the Brazilian Unified Health System (SUS) by integrating several research centers in the field of Geriatrics and Gerontology throughout Brazil.

Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G>A mutation in the MT-ND4 gene being the most common disease-causing mtDNA variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G>A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary end point was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary end point). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (P < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (P < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G>A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.

Resumo As diretrizes estabelecidas pelo Estatuto da Cidade determinam a garantia do direito a cidades sustentáveis, à gestão democrática e à inclusão da política patrimonial no planejamento e na gestão do desenvolvimento urbano. O objetivo deste trabalho é realizar uma pesquisa do estado da arte, em bancos de dados, sobre a produção acadêmica nacional relacionada à abordagem do patrimônio cultural entre 2011-2020, nos planos diretores municipais. Por meio da metodologia estado da arte foi possível concluir que há pouca produção acadêmica relacionando o plano diretor ao patrimônio cultural.

Introdução: A Medicina Narrativa emerge como uma metodologia que utiliza a leitura de obras literárias e a escrita para desenvolver a empatia, a autorreflexão e o entendimento das complexidades sociais e emocionais dos pacientes. A partir desses princípios, enfatiza-se a importância de uma abordagem humanizada na formação médica, que valorize tanto a escuta quanto a interpretação das histórias dos pacientes. Objetivo: O presente ensaio tem como objetivo explorar a intersecção entre Medicina e narrativa, investigando como a literatura pode ser utilizada na educação médica. Desenvolvimento: O ensaio parte da experiência de um grupo de estudos em Medicina Narrativa formado por estudantes de Medicina, que, com orientação pedagógica, selecionaram livros para refletir sobre temas sociais e éticos. Três obras literárias foram discutidas – “O Quinze”, de Raquel de Queiroz, “Memórias da Água”, de Emmi Itäranta e “A Trança”, de Laetitia Colombani. Cada obra suscitou debates sobre questões como vulnerabilidade social, impactos das mudanças climáticas na saúde e a diversidade cultural. A análise de cada texto conecta as trajetórias dos personagens a reflexões sobre prática médica, destacando o potencial da literatura para sensibilizar os futuros médicos sobre a pluralidade das condições sociais. Conclusão: A educação médica pode se beneficiar do uso de narrativas ao proporcionar uma compreensão mais aprofundada do sofrimento humano, bem como da complexidade das realidades socioculturais dos pacientes. A Medicina Narrativa oferece ferramentas para aprimorar a capacidade de escuta e de interpretação, auxiliando os estudantes de Medicina a se tornarem mais atentos e empáticos às histórias das pessoas. Este ensaio reforça a ideia de que a literatura e a narrativa parecem constituir um exercício para produzir cuidado humanizado e responsável em saúde, promovendo uma prática clínica que respeite a individualidade de cada paciente sem perder de vista as interferências sociais nos processos de saúde e adoecimento.

The potential for reusing different waste in building material manufacture has been extensively explored in recent years, reducing their disposal and the natural resources consumption. The main objective of this research is to investigate the advantage of adding graphene oxide nanoparticles (GON) to a mortar made with Portland cement, sand, silica fume, marble powder, and the addition of polymeric fibers (obtained through crushing of the N-95 facial protection mask (FM)). The experimental program added 0 %, 0.7 %, 1.4 %, 2.0 % FM, and 0.02 % GON (both about the cement weight) in the mortars, which were investigated for their physical, mechanical, and chemical properties. The results indicate the possibility of 0.7 % FM since it has GON addition. Finally, the GON addition in mortars will allow the addition of other types of recycled polymeric fibers.

Abstract Background A reliable preclinical model of patient-derived organoids (PDOs) was developed in a case study of a 69-year-old woman diagnosed with breast cancer (BC) to investigate the tumour evolution before and after neoadjuvant chemotherapy and surgery. The results were achieved due to the development of PDOs from tissues collected before (O-PRE) and after (O-POST) treatment. Methods PDO cultures were characterized by histology, immunohistochemistry (IHC), transmission electron microscopy (TEM), scanning electron microscopy (SEM), confocal microscopy, flow cytometry, real-time PCR, bulk RNA-seq, single-cell RNA sequencing (scRNA-seq) and drug screening. Results Both PDO cultures recapitulated the histological and molecular profiles of the original tissues, and they showed typical mammary gland organization, confirming their reliability as a personalized in vitro model. Compared with O-PRE, O-POST had a greater proliferation rate with a significant increase in the Ki67 proliferation index. Moreover O-POST exhibited a more stem-like and aggressive phenotype, with increases in the CD24low/CD44low and EPCAMlow/CD49fhigh cell populations characterized by increased tumour initiation potential and multipotency and metastatic potential in invasive lobular carcinoma. Analysis of ErbB receptor expression indicated a decrease in HER-2 expression coupled with an increase in EGFR expression in O-POST. In this context, deregulation of the PI3K/Akt signalling pathway was assessed by transcriptomic analysis, confirming the altered transcriptional profile. Finally, transcriptomic single-cell analysis identified 11 cell type clusters, highlighting the selection of the luminal component and the decrease in the number of Epithelial–mesenchymal transition cell types in O-POST. Conclusion Neoadjuvant treatment contributed to the enrichment of cell populations with luminal phenotypes that were more resistant to chemotherapy in O-POST. PDOs represent an excellent 3D cell model for assessing disease evolution.

Abstract Low serum 25(OH)D levels (

Summary: Background: The concomitant loss of lean muscle mass and bone mineral density is known as osteosarcopenia. This disorder can result in increased physical impairment in addition to an increased risk of falls and fractures. Although the diagnostic of osteoporosis and sarcopenia has been described, the inflammatory mediators that identify the presence of osteosarcopenia and propose possible inflammatory mechanisms implicated in muscle and bone loss are unknown. The objective of this study was to evaluate a panel of inflammatory biomarkers and investigate its relationship with the presence of osteosarcopenia. Methods: Body composition was assessed using Dual X-ray absorptiometry and handgrip strength using a Jamar dynamometer. Blood samples were collected for evaluation the plasmatic concentrations of adiponectin, brain-derived neurotrophic factor (BDNF), interferon ɣ (IFN), interleukins 2, 4, 5, 6, 8 and 10, leptin, resistin, tumour necrosis factor (TNF) and its soluble receptors (sTNFr) 1 and 2. Results: In seventy-one older women the age was 75 (±7) years, BMI 26.1 (±4.5) kg/m2, handgrip strength 19 (±6) kgf and the muscle mass index was 6.39 (±1.05) kg/m2. The diagnosis of osteosarcopenia was found in 25% of the sample. Analysis of the distribution of biomarkers demonstrate the osteosarcopenia group presented greater concentrations among all markers measured, and significant differences was found in plasmatic concentrations of interleukin 8 (p = 0.02). Subgroup analysis showed that group with osteopenia plus sarcopenia had significantly greater IL-6 (p = 0.03) and IL-8 (p = 0.007) concentrations. Conclusions: In a panel of biomarkers, IL-6 and IL-8 were found to be related with diagnosis of osteosarcopenia in community-dwelling older women. These results may contribute to understand the inflammatory mechanisms and suggest a diagnostic strategy for these patients, also informing new strategies for prevention, monitoring, and treatment of osteosarcopenia.

Background: Real-world evidence (RWE) can reinforce clinical trial evidence in health technology assessment (HTA). Objectives: Review HTA bodies’ (HTAbs) requirements for RWE, real uses, and acceptance across seven countries (Brazil, Canada, France, Germany, Italy, Spain, and the United Kingdom) and outline recommendations that may improve acceptance of RWE in efficacy/effectiveness assessments and appraisals processes. Methods: RWE requirements were summarized based on HTAbs’ guidelines. Acceptance by HTAbs was evaluated based on industry experience and case studies. Results: As of June 2022, RWE methodological guidelines were in place in three of the seven countries. HTAbs typically requested analyses based on local data sources, but the preferred study design and data sources differed. HTAbs had individual submission, assessment, and appraisal processes; some allowed early meetings for the protocol and/or results validation, though few involved external experts or medical societies to provide input to assessment and appraisal. The extent of submission, assessment, and appraisal requirements did not necessarily reflect the degree of acceptance. Conclusion: All the countries reviewed face common challenges regarding the use of RWE. Our proposals address the need to facilitate collaboration and communication with industry and regulatory agencies and the need for specific guidelines describing RWE design and criteria of acceptance throughout the assessment and appraisal processes.

Abstract Background Epilepsy, a challenging neurological condition, is often present with comorbidities that significantly impact diagnosis and management. In the Pakistani population, where financial limitations and geographical challenges hinder access to advanced diagnostic methods, understanding the genetic underpinnings of epilepsy and its associated conditions becomes crucial. Methods This study investigated four distinct Pakistani families, each presenting with epilepsy and a spectrum of comorbidities, using a combination of whole exome sequencing (WES) and Sanger sequencing. The epileptic patients were prescribed multiple antiseizure medications (ASMs), yet their seizures persist, indicating the challenging nature of ASM-resistant epilepsy. Results Identified genetic variants contributed to a diverse range of clinical phenotypes. In the family 1, which presented with epilepsy, developmental delay (DD), sleep disturbance, and aggressive behavior, a homozygous splice site variant, c.1339–6 C > T, in the COL18A1 gene was detected. The family 2 exhibited epilepsy, intellectual disability (ID), DD, and anxiety phenotypes, a homozygous missense variant, c.344T > A (p. Val115Glu), in the UFSP2 gene was identified. In family 3, which displayed epilepsy, ataxia, ID, DD, and speech impediment, a novel homozygous frameshift variant, c.1926_1941del (p. Tyr643MetfsX2), in the ZFYVE26 gene was found. Lastly, family 4 was presented with epilepsy, ID, DD, deafness, drooling, speech impediment, hypotonia, and a weak cry. A homozygous missense variant, c.1208 C > A (p. Ala403Glu), in the ATP13A2 gene was identified. Conclusion This study highlights the genetic heterogeneity in ASM-resistant epilepsy and comorbidities among Pakistani families, emphasizing the importance of genotype-phenotype correlation and the necessity for expanded genetic testing in complex clinical cases.

Ship weather routing, which involves suggesting low-emission routes, holds potential for contributing to the decarbonisation of maritime transport. However, including because of a lack of readily deployable open-source and open-language computational models, its quantitative impact has been explored only to a limited extent. As a response, the graph-search VISIR (discoVerIng Safe and effIcient Routes) model has been refactored in Python, incorporating novel features. For motor vessels, the angle of attack of waves has been considered, while for sailboats the combined effects of wind and sea currents are now accounted for. The velocity composition with currents has been refined, now encompassing leeway as well. Provided that the performance curve is available, no restrictions are imposed on the vessel type. A cartographic projection has been introduced. The graph edges are quickly screened for coast intersection via a K-dimensional tree. A least-CO2 algorithm in the presence of dynamic graph edge weights has been implemented and validated, proving a quasi-linear computational performance. The software suite's modularity has been significantly improved, alongside a thorough validation against various benchmarks. For the visualisation of the dynamic environmental fields along the route, isochrone-bounded sectors have been introduced. The resulting VISIR-2 model has been employed in numerical experiments within the Mediterranean Sea for the entirety of 2022, utilising meteo-oceanographic analysis fields. For a 125 m long ferry, the percentage saving of overall CO2 expenditure follows a bi-exponential distribution. Routes with a carbon dioxide saving of at least 2 % with respect to the least-distance route were found for prevailing beam or head seas. Two-digit savings, up to 49 %, were possible for about 10 d in a year. In the case of an 11 m sailboat, time savings increased with the extent of path elongation, particularly during upwind sailing. The sailboat's routes were made approximately 2.4 % faster due to optimisation, with the potential for an additional 0.8 % in savings by factoring in currents. VISIR-2 serves as an integrative model, uniting expertise from meteorology, oceanography, ocean engineering, and computer science, to evaluate the influence of ship routing on decarbonisation efforts within the shipping industry.

INTRODUCTION: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174. METHODS: The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies. RESULTS: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was - 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P

ABSTRACT In 2000, Cleide Costa published a paper presenting the state of knowledge of the Neotropical Coleopte ra, with a focus on the Brazilian fauna. Twenty-four years later, thanks to the development of the Coleoptera section of the Taxonomic Catalog of the Brazilian Fauna (CTFB - Catálogo Taxonômico da Fauna do Brasil) through the collaboration of 100 coleopterists from all over the globe, we can build on Costa’s work and present an updated overview of the state of knowledge of the beetles from Brazil. There are currently 35,699 species in 4,958 genera and 116 families known to occur in the country, including representatives of all extant suborders and superfamilies. Our data show that the Brazilian beetle fauna is the richest on the planet, concentrating 9% of the world species diversity, with some estimates accounting to up to 15% of the global total. The most diverse family in numbers of genera is Cerambycidae (1,056 genera), while in number of species it is Chrysomelidae (6,079 species). Conotrachelus Dejean, 1835 (Curculionidae) is the most species-rich genus, with 570 species. The French entomologist Maurice Pic is the author who has contributed the most to the naming of species recorded from Brazil, with 1,794 valid names in 36 families, whereas the Brazilians Ubirajara R. Martins and Maria Helena M. Galileo are the only ones among the top-ten authors to have named species in the 21st century. Currently, approximately 144 new species of Brazilian beetles are described each year, and this average is projected to increase in the next decade to 180 species per year, or about one new Brazilian beetle every two days.

OBJECTIVES:. Anemia has been associated with an increased risk of both cardiac arrest and stroke, frequent complications of COVID-19. The effect of hemoglobin level at ICU admission on a composite outcome of cardiac arrest or stroke in an international cohort of COVID-19 patients was investigated. DESIGN:. Retrospective analysis of prospectively collected database. SETTING:. A registry of COVID-19 patients admitted to ICUs at over 370 international sites was reviewed for patients diagnosed with cardiac arrest or stroke up to 30 days after ICU admission. Anemia was defined as: normal (hemoglobin ≥ 12.0 g/dL for women, ≥ 13.5 g/dL for men), mild (hemoglobin 10.0–11.9 g/dL for women, 10.0–13.4 g/dL for men), moderate (hemoglobin ≥ 8.0 and < 10.0 g/dL for women and men), and severe (hemoglobin < 8.0 g/dL for women and men). PATIENTS:. Patients older than 18 years with acute COVID-19 infection in the ICU. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Of 6926 patients (median age = 59 yr, male = 65%), 760 patients (11.0%) experienced stroke (2.0%) and/or cardiac arrest (9.4%). Cardiac arrest or stroke was more common in patients with low hemoglobin, occurring in 12.8% of patients with normal hemoglobin, 13.3% of patients with mild anemia, and 16.7% of patients with moderate/severe anemia. Time to stroke or cardiac arrest by anemia status was analyzed using Cox proportional hazards regression with death as a competing risk. Covariates selected through clinical knowledge were age, sex, comorbidities (diabetes, hypertension, obesity, and cardiac or neurologic conditions), pandemic era, country income, mechanical ventilation, and extracorporeal membrane oxygenation. Moderate/severe anemia was associated with a higher risk of cardiac arrest or stroke (hazard ratio, 1.32; 95% CI, 1.05–1.67). CONCLUSIONS:. In an international registry of ICU patients with COVID-19, moderate/severe anemia was associated with increased hazard of cardiac arrest or stroke.

Summary:. The “work horse” for the treatment of full-thickness defects of any etiology, including chronic nonhealing wounds and traumatic injuries, is generally autologous split-thickness skin grafts (STSGs), meshed, hand-fenestrated, or a sheet graft. Advancements in skin tissue engineering have allowed for the integration of dermal substitutes to be combined with autologous STSGs, adding valuable options for restoring the skin’s complex multilayered structure. Although dermal templates offer a promising avenue for more nuanced reconstruction in certain cases, their application is not without challenges, particularly when they are made from delicate materials. The following technique simplifies the application technique of single-stage dermal templates by using a composite approach. To demonstrate this technique, MatriDerm, a 1-mm-thick bovine collagen-elastin dermal template, is used to enable an STSG to be applied in a one-stage procedure.

Hypomyelinating leukodystrophies (HLD) are a group of heterogeneous genetic disorders characterized by a deficit in myelin deposition during brain development. Specifically, 4H-Leukodystrophy is a recessive disease due to biallelic mutations in the POLR3A gene, which encodes one of the subunits forming the catalytic core of RNA polymerase III (PolIII). The disease also presents non-neurological signs such as hypodontia and hypogonadotropic hypogonadism. Here, we report the generation of a human induced pluripotent stem cell (hiPSC) line from fibroblasts of the first identified carrier of the biallelic POLR3A variants c.1802 T > A and c.4072G > A.

Ribosomes frequently stall during mRNA translation, resulting in the context-dependent activation of quality control pathways to maintain proteostasis. However, surveillance mechanisms that specifically respond to stalled ribosomes with an occluded A site have not been identified. We discovered that the elongation factor-1α (eEF1A) inhibitor, ternatin-4, triggers the ubiquitination and degradation of eEF1A on stalled ribosomes. Using a chemical genetic approach, we unveiled a signaling network comprising two E3 ligases, RNF14 and RNF25, which are required for eEF1A degradation. Quantitative proteomics revealed the RNF14 and RNF25-dependent ubiquitination of eEF1A and a discrete set of ribosomal proteins. The ribosome collision sensor GCN1 plays an essential role by engaging RNF14, which directly ubiquitinates eEF1A. The site-specific, RNF25-dependent ubiquitination of the ribosomal protein RPS27A/eS31 provides a second essential signaling input. Our findings illuminate a ubiquitin signaling network that monitors the ribosomal A site and promotes the degradation of stalled translation factors, including eEF1A and the termination factor eRF1.