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1.
Trends Biochem Sci ; 47(9): 730-731, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35501234

RESUMO

The signal recognition particle (SRP) cotranslationally targets a large and diverse portion of the nascent proteome to the endoplasmic reticulum (ER). A recent study by Jomaa et al. reveals an unexpected function for the ribosome-bound nascent chain-associated complex (NAC) in sensing ER-targeting signals and recruiting SRP to the appropriate ribosomes for high-fidelity targeting.


Assuntos
Retículo Endoplasmático , Partícula de Reconhecimento de Sinal , Retículo Endoplasmático/metabolismo , Biossíntese de Proteínas , Ribossomos/metabolismo , Partícula de Reconhecimento de Sinal/metabolismo
2.
EMBO J ; 41(24): e110959, 2022 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-36314723

RESUMO

One-third of the human proteome is comprised of membrane proteins, which are particularly vulnerable to misfolding and often require folding assistance by molecular chaperones. Calnexin (CNX), which engages client proteins via its sugar-binding lectin domain, is one of the most abundant ER chaperones, and plays an important role in membrane protein biogenesis. Based on mass spectrometric analyses, we here show that calnexin interacts with a large number of nonglycosylated membrane proteins, indicative of additional nonlectin binding modes. We find that calnexin preferentially bind misfolded membrane proteins and that it uses its single transmembrane domain (TMD) for client recognition. Combining experimental and computational approaches, we systematically dissect signatures for intramembrane client recognition by calnexin, and identify sequence motifs within the calnexin TMD region that mediate client binding. Building on this, we show that intramembrane client binding potentiates the chaperone functions of calnexin. Together, these data reveal a widespread role of calnexin client recognition in the lipid bilayer, which synergizes with its established lectin-based substrate binding. Molecular chaperones thus can combine different interaction modes to support the biogenesis of the diverse eukaryotic membrane proteome.


Assuntos
Chaperonas Moleculares , Proteoma , Humanos , Calnexina/metabolismo , Proteoma/metabolismo , Chaperonas Moleculares/metabolismo , Lectinas/metabolismo , Proteínas de Membrana/metabolismo , Dobramento de Proteína , Proteínas de Ligação ao Cálcio/metabolismo
3.
Nat Chem Biol ; 20(7): 877-884, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38172604

RESUMO

Translation termination is an essential cellular process, which is also of therapeutic interest for diseases that manifest from premature stop codons. In eukaryotes, translation termination requires eRF1, which recognizes stop codons, catalyzes the release of nascent proteins from ribosomes and facilitates ribosome recycling. The small molecule SRI-41315 triggers eRF1 degradation and enhances translational readthrough of premature stop codons. However, the mechanism of action of SRI-41315 on eRF1 and translation is not known. Here we report cryo-EM structures showing that SRI-41315 acts as a metal-dependent molecular glue between the N domain of eRF1 responsible for stop codon recognition and the ribosomal subunit interface near the decoding center. Retention of eRF1 on ribosomes by SRI-41315 leads to ribosome collisions, eRF1 ubiquitylation and a higher frequency of translation termination at near-cognate stop codons. Our findings reveal a new mechanism of release factor inhibition and additional implications for pharmacologically targeting eRF1.


Assuntos
Códon de Terminação , Fatores de Terminação de Peptídeos , Ribossomos , Fatores de Terminação de Peptídeos/metabolismo , Fatores de Terminação de Peptídeos/genética , Fatores de Terminação de Peptídeos/química , Ribossomos/metabolismo , Ribossomos/genética , Humanos , Códon de Terminação/genética , Microscopia Crioeletrônica , Ubiquitinação , Terminação Traducional da Cadeia Peptídica , Modelos Moleculares , Biossíntese de Proteínas
4.
Nature ; 580(7805): 597-601, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32161364

RESUMO

Ultrahot giant exoplanets receive thousands of times Earth's insolation1,2. Their high-temperature atmospheres (greater than 2,000 kelvin) are ideal laboratories for studying extreme planetary climates and chemistry3-5. Daysides are predicted to be cloud-free, dominated by atomic species6 and much hotter than nightsides5,7,8. Atoms are expected to recombine into molecules over the nightside9, resulting in different day and night chemistries. Although metallic elements and a large temperature contrast have been observed10-14, no chemical gradient has been measured across the surface of such an exoplanet. Different atmospheric chemistry between the day-to-night ('evening') and night-to-day ('morning') terminators could, however, be revealed as an asymmetric absorption signature during transit4,7,15. Here we report the detection of an asymmetric atmospheric signature in the ultrahot exoplanet WASP-76b. We spectrally and temporally resolve this signature using a combination of high-dispersion spectroscopy with a large photon-collecting area. The absorption signal, attributed to neutral iron, is blueshifted by -11 ± 0.7 kilometres per second on the trailing limb, which can be explained by a combination of planetary rotation and wind blowing from the hot dayside16. In contrast, no signal arises from the nightside close to the morning terminator, showing that atomic iron is not absorbing starlight there. We conclude that iron must therefore condense during its journey across the nightside.

5.
EMBO Rep ; 24(9): e56463, 2023 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-37462213

RESUMO

Mitotic chromatin is largely assumed incompatible with transcription due to changes in the transcription machinery and chromosome architecture. However, the mechanisms of mitotic transcriptional inactivation and their interplay with chromosome assembly remain largely unknown. By monitoring ongoing transcription in Drosophila early embryos, we reveal that eviction of nascent mRNAs from mitotic chromatin occurs after substantial chromosome compaction and is not promoted by condensin I. Instead, we show that the timely removal of transcripts from mitotic chromatin is driven by the SNF2 helicase-like protein Lodestar (Lds), identified here as a modulator of sister chromatid cohesion defects. In addition to the eviction of nascent transcripts, we uncover that Lds cooperates with Topoisomerase 2 to ensure efficient sister chromatid resolution and mitotic fidelity. We conclude that the removal of nascent transcripts upon mitotic entry is not a passive consequence of cell cycle progression and/or chromosome compaction but occurs via dedicated mechanisms with functional parallelisms to sister chromatid resolution.


Assuntos
Cromátides , Drosophila , Mitose , Animais , Proteínas de Ciclo Celular/metabolismo , Cromátides/metabolismo , Cromatina , DNA Topoisomerases Tipo II/genética , Drosophila/citologia , Drosophila/genética
6.
EMBO J ; 39(10): e104880, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32239769

RESUMO

Eukaryotic cells have evolved multiple responses that allow endoplasmic reticulum (ER) homeostasis to be maintained even in the face of acute or chronic stresses. In this issue, Yu et al (2020) describe how site-specific phosphorylation switches protein disulfide isomerase (PDI) from a folding enzyme to a holdase chaperone which regulates ER stress responses, thus highlighting PDI as a key player in ER homeostasis.


Assuntos
Oxirredutases , Isomerases de Dissulfetos de Proteínas , Retículo Endoplasmático/metabolismo , Oxirredutases/metabolismo , Fosforilação , Isomerases de Dissulfetos de Proteínas/metabolismo , Proteostase
7.
Ann Surg ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38953528

RESUMO

OBJECTIVE: To report the first European series of full robotic whole liver transplantation (RLT) with technical details and future perspectives. SUMMARY BACKGROUND DATA: Few cases of liver transplantation with a minimally invasive approach using partial grafts have been reported so far, and no cases of robotic whole liver transplantation have been reported in the scientific literature. METHODS: The adopted technique was full robotic liver hepatectomy, followed by robotic implantation after graft introduction through a small midline incision. Patients presenting with Hepatocellular Carcinoma (HCC) in liver cirrhosis with a small caudate lobe, low degree of portal hypertension, no porto-mesenteric thrombosis, as well as low MELD patients have been considered ideal candidates. RESULTS: Six patients underwent RLT between February and March 2024 at Lisbon and Modena University Liver Transplant Centers. Warm ischemia time during RLT ranged between 55 and 90 min, with a total surgery duration between 440 and 710 min. The median total operative time was 595 (±111,3) minutes. Only one recipient had prolonged hyperbilirubinemia, which was safely treated. The median in-hospital stay was 7.5 days, (±4.8 days). CONCLUSIONS: RLT is a promising technique to further reduce the impact of liver transplantation thanks to smaller incision, gentle tissue manipulation, high magnification and precision for vascular and biliary anastomosis, and reduced postoperative pain. This is the first step toward the demonstration of the feasibility of minimally invasive surgery in liver transplantation, although further selection and technical refinements are needed to improve reproducibility.

8.
Am J Physiol Heart Circ Physiol ; 326(5): H1193-H1203, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38334973

RESUMO

Pressure overload-induced hypertrophy compromises cardiac stretch-induced compliance (SIC) after acute volume overload (AVO). We hypothesized that SIC could be enhanced by physiological hypertrophy induced by pregnancy's chronic volume overload. This study evaluated SIC-cardiac adaptation in pregnant women with or without cardiovascular risk (CVR) factors. Thirty-seven women (1st trimester, 1stT) and a separate group of 31 (3rd trimester, 3rdT) women [healthy or with CVR factors (obesity and/or hypertension and/or with gestational diabetes)] underwent echocardiography determination of left ventricular end-diastolic volume (LVEDV) and E/e' before (T0), immediately after (T1), and 15 min after (T2; SIC) AVO induced by passive leg elevation. Blood samples for NT-proBNP quantification were collected before and after the AVO. Acute leg elevation significantly increased inferior vena cava diameter and stroke volume from T0 to T1 in both 1stT and 3rdT, confirming AVO. LVEDV and E/e' also increased immediately after AVO (T1) in both 1stT and 3rdT. SIC adaptation (T2, 15 min after AVO) significantly decreased E/e' in both trimesters, with additional expansion of LVEDV only in the 1stT. NT-pro-BNP increased slightly after AVO but only in the 1stT. CVR factors, but not parity or age, significantly impacted SIC cardiac adaptation. A distinct functional response to SIC was observed between 1stT and 3rdT, which was influenced by CVR factors. The LV of 3rdT pregnant women was hypertrophied, showing a structural limitation to dilate with AVO, whereas the lower LV filling pressure values suggest increased diastolic compliance.NEW & NOTEWORTHY The sudden increase of volume overload triggers an acute myocardial stretch characterized by an immediate rise in contractility by the Frank-Starling mechanism, followed by a progressive increase known as the slow force response. The present study is the first to characterize echocardiographically the stretch-induced compliance (SIC) mechanism in the context of physiological hypertrophy induced by pregnancy. A distinct functional adaptation to SIC was observed between first and third trimesters, which was influenced by cardiovascular risk factors.


Assuntos
Adaptação Fisiológica , Fatores de Risco de Doenças Cardíacas , Humanos , Feminino , Gravidez , Adulto , Função Ventricular Esquerda , Cardiomegalia/fisiopatologia , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/etiologia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Complicações Cardiovasculares na Gravidez/fisiopatologia , Complicações Cardiovasculares na Gravidez/diagnóstico por imagem , Complicações Cardiovasculares na Gravidez/sangue , Volume Sistólico , Terceiro Trimestre da Gravidez , Diabetes Gestacional/fisiopatologia , Complacência (Medida de Distensibilidade) , Primeiro Trimestre da Gravidez , Obesidade/fisiopatologia , Obesidade/complicações , Fatores de Risco
9.
Ann Surg Oncol ; 31(1): 81-89, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37718337

RESUMO

INTRODUCTION: Perihilar cholangiocarcinoma is a difficult cancer to treat with frequent vascular invasion, local recurrence, and poor survival. Due to the need for biliary anastomosis and potential vascular resection, the standard approach is an open operation. Suboptimal outcomes after laparoscopic resection had been sporadically reported by high-volume centers. In this first, Trans-Atlantic, multicenter study, we report our outcomes of robotic resection for perihilar cholangiocarcinoma. This is the largest study of its kind in the Western hemisphere. METHODS: Between 2016 and 2023, we prospectively followed patients undergoing robotic resection for perihilar cholangiocarcinoma at three, high-volume, robotic, liver-surgery centers. RESULTS: Thirty-eight patients underwent perihilar cholangiocarcinoma utilizing the robotic technique; Klatskin type-3 was the most common. The median age was 72 years, and 82% of the patients underwent preoperative biliary drainage. Median operative time was 481 minutes with a median estimated blood loss of 200 mL. The number of harvested lymph nodes was seven, and 11 (28%) patients yielded positive lymph nodes. Three patients required vascular reconstruction; 18% of patients had >1 biliary anastomosis. R0 resection margins were achieved in 82% of patients. Clavien-Dindo Grade ≥3 complications were seen in 16% of patients. The length of stay was 6 days. Five patients had an unplanned readmission within 30 days. One patient died within 30 days. With a median follow-up of 15 months, 68% of patients are alive without disease, 13% recurred, and 19% died. CONCLUSIONS: Application of the robotic platform for perihilar cholangiocarcinoma is safe and feasible with acceptable short-term clinical and oncological outcomes.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Tumor de Klatskin , Procedimentos Cirúrgicos Robóticos , Robótica , Humanos , Idoso , Tumor de Klatskin/patologia , Procedimentos Cirúrgicos Robóticos/métodos , Hepatectomia/métodos , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/cirurgia , Resultado do Tratamento , Estudos Retrospectivos
10.
Osteoporos Int ; 35(4): 575-588, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38055051

RESUMO

PURPOSE: Osteoporosis is a metabolic bone disease characterized by decreased bone strength and mass, which predisposes patients to fractures and is associated with high morbidity and mortality. Like osteoporosis, obesity and diabetes are systemic metabolic diseases associated with modifiable risk factors and lifestyle, and their prevalence is increasing. They are related to decreased quality of life, functional loss and increased mortality, generating high costs for health systems and representing a worldwide public health problem. Growing evidence reinforces the role of bone marrow adipose tissue (BMAT) as an influential factor in the bone microenvironment and systemic metabolism. Given the impact of obesity and diabetes on metabolism and their possible effect on the bone microenvironment, changes in BMAT behavior may explain the risk of developing osteoporosis in the presence of these comorbidities. METHODS: This study reviewed the scientific literature on the behavior of BMAT in pathological metabolic conditions, such as obesity and diabetes, and its potential involvement in the pathogenesis of bone fragility. RESULTS: Published data strongly suggest a relationship between increased BMAT adiposity and the risk of bone fragility in the context of obesity and diabetes. CONCLUSION: By secreting a broad range of factors, BMAT modulates the bone microenvironment and metabolism, ultimately affecting skeletal health. A better understanding of the relationship between BMAT expansion and metabolic disturbances observed in diabetic and obese patients will help to identify regulatory pathways and new targets for the treatment of bone-related diseases, with BMAT as a potential therapeutic target.


Assuntos
Diabetes Mellitus , Osteoporose , Humanos , Medula Óssea/patologia , Densidade Óssea , Qualidade de Vida , Tecido Adiposo/patologia , Obesidade/complicações , Obesidade/patologia , Osteoporose/epidemiologia , Osteoporose/etiologia , Osteoporose/metabolismo
11.
Am J Primatol ; 86(5): e23603, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38293796

RESUMO

Identifying novel medicinal resources in chimpanzee diets has historically presented challenges, requiring extensive behavioral data collection and health monitoring, accompanied by expensive pharmacological analyses. When putative therapeutic self-medicative behaviors are observed, these events are often considered isolated occurrences, with little attention paid to other resources ingested in combination. For chimpanzees, medicinal resource combinations could play an important role in maintaining well-being by tackling different symptoms of an illness, chemically strengthening efficacy of a treatment, or providing prophylactic compounds that prevent future ailments. We call this concept the self-medicative resource combination hypothesis. However, a dearth of methodological approaches for holistically investigating primate feeding ecology has limited our ability to identify nonrandom resource combinations and explore potential synergistic relationships between medicinal resource candidates. Here we present two analytical tools that test such a hypothesis and demonstrate these approaches on feeding data from the Sonso chimpanzee community in Budongo Forest, Uganda. Using 4 months of data, we establish that both collocation and APRIORI analyses are effective exploratory tools for identifying binary combinations, and that APRIORI is effective for multi-item rule associations. We then compare outputs from both methods, finding up to 60% agreement, and propose APRIORI as more effective for studies requiring control over confidence intervals and those investigating nonrandom associations between more than two resources. These analytical tools, which can be extrapolated across the animal kingdom, can provide a cost-effective and efficient method for targeting resources for further pharmacological investigation, potentially aiding in the discovery of novel medicines.


Assuntos
Dieta , Pan troglodytes , Animais , Dieta/veterinária , Alimentos , Ecologia , Florestas , Uganda
12.
Int J Mol Sci ; 25(8)2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38674073

RESUMO

Prostate cancer (PCA) is the second most common cancer diagnosis in men and the fifth leading cause of death worldwide. The conventional treatments available are beneficial to only a few patients and, in those, some present adverse side effects that eventually affect the quality of life of most patients. Thus, there is an urgent need for effective, less invasive and targeted specific treatments for PCA. Photothermal therapy (PTT) is a minimally invasive therapy that provides a localized effect for tumour cell ablation by activating photothermal agents (PTA) that mediate the conversion of the light beam's energy into heat at the site. As tumours are unable to easily dissipate heat, they become more susceptible to temperature increases. In the PTT field, gold nanoparticles (AuNPs) have been attracting interest as PTA. The aim of this study was to formulate AuNPs capable of remaining retained in the tumour and subsequently generating heat at the tumour site. AuNPs were synthesized and characterized in terms of size, polydispersity index (PdI), zeta potential (ZP), morphology and the surface plasmon resonance (SPR). The safety of AuNPs and their efficacy were assessed using in vitro models. A preliminary in vivo safety assessment of AuNPs with a mean size lower than 200 nm was confirmed. The morphology was spherical-like and the SPR band showed good absorbance at the laser wavelength. Without laser, AuNPs proved to be safe both in vitro (>70% viability) and in vivo. In addition, with laser irradiation, they proved to be relatively effective in PCA cells. Overall, the formulation appears to be promising for use in PTT.


Assuntos
Ouro , Nanopartículas Metálicas , Neoplasias da Próstata , Ouro/química , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Masculino , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Humanos , Animais , Terapia Fototérmica/métodos , Linhagem Celular Tumoral , Camundongos , Ressonância de Plasmônio de Superfície , Lasers
13.
Ann Surg ; 278(5): 748-755, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37465950

RESUMO

OBJECTIVE: This study aims at establishing benchmark values for best achievable outcomes following open major anatomic hepatectomy for liver tumors of all dignities. BACKGROUND: Outcomes after open major hepatectomies vary widely lacking reference values for comparisons among centers, indications, types of resections, and minimally invasive procedures. METHODS: A standard benchmark methodology was used covering consecutive patients, who underwent open major anatomic hepatectomy from 44 high-volume liver centers from 5 continents over a 5-year period (2016-2020). Benchmark cases were low-risk non-cirrhotic patients without significant comorbidities treated in high-volume centers (≥30 major liver resections/year). Benchmark values were set at the 75th percentile of median values of all centers. Minimum follow-up period was 1 year in each patient. RESULTS: Of 8044 patients, 2908 (36%) qualified as benchmark (low-risk) cases. Benchmark cutoffs for all indications include R0 resection ≥78%; liver failure (grade B/C) ≤10%; bile leak (grade B/C) ≤18%; complications ≥grade 3 and CCI ® ≤46% and ≤9 at 3 months, respectively. Benchmark values differed significantly between malignant and benign conditions so that reference values must be adjusted accordingly. Extended right hepatectomy (H1, 4-8 or H4-8) disclosed a higher cutoff for liver failure, while extended left (H1-5,8 or H2-5,8) were associated with higher cutoffs for bile leaks, but had superior oncologic outcomes, when compared to formal left hepatectomy (H1-4 or H2-4). The minimal follow-up for a conclusive outcome evaluation following open anatomic major resection must be 3 months. CONCLUSION: These new benchmark cutoffs for open major hepatectomy provide a powerful tool to convincingly evaluate other approaches including parenchymal-sparing procedures, laparoscopic/robotic approaches, and alternative treatments, such as ablation therapy, irradiation, or novel chemotherapy regimens.


Assuntos
Laparoscopia , Falência Hepática , Neoplasias Hepáticas , Humanos , Hepatectomia/métodos , Benchmarking , Complicações Pós-Operatórias/etiologia , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/etiologia , Falência Hepática/etiologia , Laparoscopia/métodos , Estudos Retrospectivos , Tempo de Internação
14.
Sensors (Basel) ; 23(2)2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36679804

RESUMO

This article presents the results regarding a systematic literature review procedure on digital twins applied to precision agriculture. In particular, research and development activities aimed at the use of digital twins, in the context of predictive control, with the purpose of improving soil quality. This study was carried out through an exhaustive search of scientific literature on five different databases. A total of 158 articles were extracted as a result of this search. After a first screening process, only 11 articles were considered to be aligned with the current topic. Subsequently, these articles were categorised to extract all relevant information, using the preferred reporting items for systematic reviews and meta-analyses methods. Based on the obtained results, there are two main conclusions to draw: First, when compared with industrial processes, there is only a very slight rising trend regarding the use of digital twins in agriculture. Second, within the time frame in which this work was carried out, it was not possible to find any published paper on the use of digital twins for soil quality improvement within a model predictive control context.


Assuntos
Solo
15.
Int J Legal Med ; 136(5): 1483-1494, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35624167

RESUMO

The accurate age at death assessment of unidentified adult skeletal individuals is a critical research task in forensic anthropology, being a key feature for the determination of biological profiles of individual skeletal remains. We have previously shown that the age-related decrease of bone mineral density (BMD) in the proximal femur could be used to assess age at death in women (Navega et al., J Forensic Sci 63:497-503, 2018). The present study aims to generate models for age estimation in both sexes through bone densitometry of the femur and radiogrammetry of the second metacarpal. The training sample comprised 224 adults (120 females, 104 males) from the "Coimbra Identified Skeletal Collection," and different models were generated through least squares regression and general regression neural networks (GRNN). The models were operationalized in a user-friendly online interface at https://osteomics.com/DXAGE2/ . The mean absolute difference between the known and estimated age at death ranges from 9.39 to 13.18 years among women and from 10.33 to 15.76 among men with the least squares regression models. For the GRNN models, the mean absolute difference between documented and projected age ranges from 8.44 to 12.58 years in women and from 10.56 to 16.18 years in men. DXAGE 2.0 enables age estimation in incomplete and/or fragmentary skeletal remains, using alternative skeletal regions, with reliable results.


Assuntos
Ossos Metacarpais , Absorciometria de Fóton , Adulto , Restos Mortais , Densidade Óssea , Criança , Feminino , Fêmur/anatomia & histologia , Fêmur/diagnóstico por imagem , Humanos , Masculino , Ossos Metacarpais/diagnóstico por imagem
16.
Exp Cell Res ; 403(2): 112617, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33930402

RESUMO

A healthy and functional proteome is essential to cell physiology. However, this is constantly being challenged as most steps of protein metabolism are error-prone and changes in the physico-chemical environment can affect protein structure and function, thereby disrupting proteome homeostasis. Among a variety of potential mistakes, proteins can be targeted to incorrect compartments or subunits of protein complexes may fail to assemble properly with their partners, resulting in the formation of mislocalized and orphan proteins, respectively. Quality control systems are in place to handle these aberrant proteins, and to minimize their detrimental impact on cellular functions. Here, we discuss recent findings on quality control mechanisms handling mislocalized and orphan proteins. We highlight common principles involved in their recognition and summarize how accumulation of these aberrant molecules is associated with aging and disease.


Assuntos
Envelhecimento/metabolismo , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteoma/química , Deficiências na Proteostase/metabolismo , Envelhecimento/genética , Animais , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Complexo de Golgi/genética , Complexo de Golgi/metabolismo , Humanos , Neoplasias/genética , Neoplasias/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Complexo de Endopeptidases do Proteassoma/genética , Dobramento de Proteína , Estabilidade Proteica , Transporte Proteico , Proteólise , Proteoma/genética , Proteoma/metabolismo , Proteostase/genética , Deficiências na Proteostase/genética , Deficiências na Proteostase/patologia , Ubiquitina/genética , Ubiquitina/metabolismo
17.
Retina ; 42(4): 775-781, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-34923509

RESUMO

PURPOSE: To compare the choroidal characteristics between the eyes of patients with and without hereditary transthyretin amyloidosis. METHODS: Case-control observational study with choroidal thickness and vasculature evaluation by optical coherence tomography with enhanced depth imaging protocol of the macula. RESULTS: The study included 332 eyes: 166 eyes of hereditary transthyretin amyloidosis patients and 166 eyes of healthy patients. Mean age was similar between groups (P = 0.979). For hereditary transthyretin amyloidosis patients, on average, in all sectors analyzed (in the full 5 mm-width image [G] and also in 1-mm-width central [C], nasal [N], and temporal [T] sectors), there was a higher stromal area, a lower choroidal thickness, and a lower choroidal vascularity index, compared with the control group. The linear mixed models revealed no differences according to the systemic treatment groups. CONCLUSION: Hereditary transthyretin amyloidosis patients showed statistically significant differences in choroidal characteristics, compared with eyes without pathology. These age-related and statistically significant changes compared with the healthy eyes may help in the future to better monitor the systemic hereditary transthyretin amyloidosis disease and complement other systemic evaluations, including on clinical trials to analyze more objectively, the results of new therapies.


Assuntos
Neuropatias Amiloides Familiares , Macula Lutea , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/patologia , Corioide/patologia , Humanos , Tomografia de Coerência Óptica/métodos
18.
Ophthalmologica ; 245(4): 376-384, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35196665

RESUMO

PURPOSE: Eye trauma is an important cause of monocular visual loss worldwide. This study aimed to describe the structural and functional characteristics and outcomes of 281 globe ruptures. METHODS: Medical records of all patients undergoing surgery for a ruptured globe at Centro Hospitalar Universitário do Porto in the last 17 years were retrospectively reviewed. RESULTS: 281 eyes of 277 patients were included. The majority of them were males (71%) with a mean age of 59.7 ± 20.5. In 38.8% of the cases, the cause was a fall. At the time of admission, 29.5% of the eyes had a visual acuity (VA) greater than 20/200 and 12.5% had no light perception. The median time between trauma and primary repair was less than 8 h (interquartile range 5-12 h). A primary reconstruction was always attempted. Primary evisceration was performed in 14 cases (5%). In multivariable analysis, independent predictors of vision survival were male gender, shorter wound size, and absence of vitreous hemorrhage. CONCLUSION: In this large, retrospective study on globe ruptures, we identified male gender, short wound length, and the absence of vitreous hemorrhage or retinal detachment as predictors of improved functional outcome. We found a correlation between the presenting and final VAs. The Ocular Trauma Score predicted the outcome well. Our determination to reconstruct the traumatized eyes as early and as completely as possible was justified by the functional results: despite the severity of the injuries, one out of four eyes reached a final VA greater than 20/200.


Assuntos
Traumatismos Oculares , Hemorragia Vítrea , Adulto , Idoso , Idoso de 80 Anos ou mais , Traumatismos Oculares/complicações , Traumatismos Oculares/diagnóstico , Traumatismos Oculares/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Acuidade Visual , Hemorragia Vítrea/cirurgia
19.
Mikrochim Acta ; 190(1): 40, 2022 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-36585475

RESUMO

Laser-induced graphene (LIG) is as a promising material for flexible microsupercapacitors (MSCs) due to its simple and cost-effective processing. However, LIG-MSC research and production has been centered on non-sustainable polymeric substrates, such as polyimide. In this work, it is presented a cost-effective, reproducible, and robust approach for the preparation of LIG structures via a one-step laser direct writing on chromatography paper. The developed strategy relies on soaking the paper in a 0.1 M sodium tetraborate solution (borax) prior to the laser processing. Borax acts as a fire-retardant agent, thus allowing the laser processing of sensitive substrates that other way would be easily destroyed under the high-energy beam. LIG on paper exhibiting low sheet resistance (30 Ω sq-1) and improved electrode/electrolyte interface was obtained by the proposed method. When used as microsupercapacitor electrodes, this laser-induced graphene resulted in specific capacitances of 4.6 mF cm-2 (0.015 mA cm-2). Furthermore, the devices exhibit excellent cycling stability (> 10,000 cycles at 0.5 mA cm-2) and good mechanical properties. By connecting the devices in series and parallel, it was also possible to control the voltage and energy delivered by the system. Thus, paper-based LIG-MSC can be used as energy storage devices for flexible, low-cost, and portable electronics. Additionally, due to their flexible design and architecture, they can be easily adapted to other circuits and applications with different power requirements.


Assuntos
Grafite , Capacitância Elétrica , Eletrodos , Lasers
20.
Radiology ; 299(3): 715-724, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33825512

RESUMO

Background In patients with liver cancer, portal vein embolization (PVE) is recommended to promote liver growth before major hepatectomies. However, the optimal embolization strategy has not been established. Purpose To compare liver regeneration as seen at CT in participants with liver cancer, before major hepatectomies, with N-butyl-cyanoacrylate (NBCA) plus iodized oil versus standard polyvinyl alcohol (PVA) particles plus coils, for PVE. Materials and Methods In this single-center, prospective, randomized controlled trial (Best Future Liver Remnant, or BestFLR, trial; International Standard Randomized Controlled Trial Number 16062796), PVE with NBCA plus iodized oil was compared with standard PVE with PVA particles plus coils in participants with liver cancer. Participant recruitment started in November 2017 and ended in March 2020. Participants were randomly assigned to undergo PVE with PVA particles plus coils or PVE with NBCA plus iodized oil. The primary end point was liver growth assessed with CT 14 days and 28 days after PVE. Secondary outcomes included posthepatectomy liver failure, surgical complications, and length of intensive care treatment and hospital stay. The Mann-Whitney U test was used to compare continuous outcomes according to PVE material, whereas the Χ2 test or Fisher exact test was used for categoric variables. Results Sixty participants (mean age, 61 years ± 11 [standard deviation]; 32 men) were assigned to the PVA particles plus coils group (n = 30) or to the NBCA plus iodized oil group (n = 30). Interim analysis revealed faster and superior liver hypertrophy for the NBCA plus iodized oil group versus the PVA particles plus coils group 14 days and 28 days after PVE (absolute hypertrophy of 46% vs 30% [P < .001] and 57% vs 37% [P < .001], respectively). Liver growth for the proposed hepatectomy was achieved in 87% of participants (26 of 30) in the NBCA plus iodized oil group versus 53% of participants (16 of 30) in the PVA particles plus coils group (P = .008) 14 days after PVE. Liver failure occurred in 13% of participants (three of 24) in the NBCA plus iodized oil group and in 27% of participants (six of 22) in the PVA particles plus coils group (P = .27). Conclusion Portal vein embolization with N-butyl-cyanoacrylate plus iodized oil produced greater and faster liver growth as seen at CT in participants with liver cancer, compared with portal vein embolization with polyvinyl alcohol particles plus coils, allowing for earlier surgical intervention. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Arellano in this issue.


Assuntos
Embolização Terapêutica/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , Regeneração Hepática , Tomografia Computadorizada por Raios X , Terapia Combinada , Embucrilato , Feminino , Hepatectomia , Humanos , Óleo Iodado , Masculino , Pessoa de Meia-Idade , Álcool de Polivinil , Veia Porta , Estudos Prospectivos
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