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1.
Mol Cell ; 84(9): 1802-1810.e4, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38701741

RESUMO

Polyphosphate (polyP) is a chain of inorganic phosphate that is present in all domains of life and affects diverse cellular phenomena, ranging from blood clotting to cancer. A study by Azevedo et al. described a protein modification whereby polyP is attached to lysine residues within polyacidic serine and lysine (PASK) motifs via what the authors claimed to be covalent phosphoramidate bonding. This was based largely on the remarkable ability of the modification to survive extreme denaturing conditions. Our study demonstrates that lysine polyphosphorylation is non-covalent, based on its sensitivity to ionic strength and lysine protonation and absence of phosphoramidate bond formation, as analyzed via 31P NMR. Ionic interaction with lysine residues alone is sufficient for polyP modification, and we present a new list of non-PASK lysine repeat proteins that undergo polyP modification. This work clarifies the biochemistry of polyP-lysine modification, with important implications for both studying and modulating this phenomenon. This Matters Arising paper is in response to Azevedo et al. (2015), published in Molecular Cell. See also the Matters Arising Response by Azevedo et al. (2024), published in this issue.


Assuntos
Amidas , Lisina , Ácidos Fosfóricos , Polifosfatos , Lisina/metabolismo , Lisina/química , Polifosfatos/química , Polifosfatos/metabolismo , Fosforilação , Humanos , Processamento de Proteína Pós-Traducional , Proteínas/química , Proteínas/metabolismo , Proteínas/genética
2.
Mol Cell ; 84(9): 1811-1815.e3, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38701742

RESUMO

Post-translational modifications of proteins (PTMs) introduce an extra layer of complexity to cellular regulation. Although phosphorylation of serine, threonine, and tyrosine residues is well-known as PTMs, lysine is, in fact, the most heavily modified amino acid, with over 30 types of PTMs on lysine having been characterized. One of the most recently discovered PTMs on lysine residues is polyphosphorylation, which sees linear chains of inorganic polyphosphates (polyP) attached to lysine residues. The labile nature of phosphoramidate bonds raises the question of whether this modification is covalent in nature. Here, we used buffers with very high ionic strength, which would disrupt any non-covalent interactions, and confirmed that lysine polyphosphorylation occurs covalently on proteins containing PASK domains (polyacidic, serine-, and lysine-rich), such as the budding yeast protein nuclear signal recognition 1 (Nsr1) and the mammalian protein nucleolin. This Matters Arising Response paper addresses the Neville et al. (2024) Matters Arising paper, published concurrently in Molecular Cell.


Assuntos
Lisina , Fosfoproteínas , Processamento de Proteína Pós-Traducional , Proteínas de Ligação a RNA , Fosforilação , Lisina/metabolismo , Fosfoproteínas/metabolismo , Fosfoproteínas/química , Fosfoproteínas/genética , Humanos , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/química , Nucleolina , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/química , Animais , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Polifosfatos/metabolismo , Polifosfatos/química , Concentração Osmolar
3.
Comput Struct Biotechnol J ; 21: 238-250, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36544476

RESUMO

The process of designing biomolecules, in particular proteins, is witnessing a rapid change in available tooling and approaches, moving from design through physicochemical force fields, to producing plausible, complex sequences fast via end-to-end differentiable statistical models. To achieve conditional and controllable protein design, researchers at the interface of artificial intelligence and biology leverage advances in natural language processing (NLP) and computer vision techniques, coupled with advances in computing hardware to learn patterns from growing biological databases, curated annotations thereof, or both. Once learned, these patterns can be used to provide novel insights into mechanistic biology and the design of biomolecules. However, navigating and understanding the practical applications for the many recent protein design tools is complex. To facilitate this, we 1) document recent advances in deep learning (DL) assisted protein design from the last three years, 2) present a practical pipeline that allows to go from de novo-generated sequences to their predicted properties and web-powered visualization within minutes, and 3) leverage it to suggest a generated protein sequence which might be used to engineer a biosynthetic gene cluster to produce a molecular glue-like compound. Lastly, we discuss challenges and highlight opportunities for the protein design field.

4.
Evol Bioinform Online ; 18: 11769343221128540, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36458150

RESUMO

It is postulated that the human digestive tract (DT) from mouth to intestine is differentiated into diverse niches. For example, Segata et al. discovered that the microbiomes of diverse habitats along the DT could be distinguished as 4 types (niches) including (i) stool; (ii) sub-gingival plaques (SubP) and supra-gingival plaques (SupP); (iii) tongue dorsum (TD), throat (TH), palatine tonsils (PT), and saliva (Sal); and (iv) hard palate (HP) and buccal mucosa (BM), and keratinized gingiva (KG). These niches are different not only in composition, but also in metabolic potentials. In a previous study, we applied Harris et al's multi-site neutral and Tang and Zhou's niche-neutral hybrid models to characterize the DT niches discovered by Segata et al. Here, we complement the previous study by applying Sloan's near-neural model and Ning et al's stochasticity analysis framework to quantify the niche-neutral continuum of the DT microbiome distribution to shed light on the possible ecological/evolutionary mechanism that shapes the continuum. Overall but excluding the stool site, the proportion of neutral OTUs (46%) is slightly higher than that of the positive selection (38%), but significantly higher than negative selection (15%). The gut (stool) exhibited 3 to 12 times lower neutrality than other DT sites. The analysis also cross-verified our previous hypothesis that the KG (keratinized gingiva) is of distinct assembly dynamics in the DT microbiome, should be treated as a fifth niche. Our findings offer new insight on the long-standing debate concerning whether a minimum of 2-mm of KG width is necessary for marginal periodontal health.

5.
Ann Med Surg (Lond) ; 84: 104867, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36536708

RESUMO

Introduction: Rheumatic heart disease (RHD), is a common cause of mitral stenosis (MS) in developing nations. As per current recommendation, Percutaneous Transvenous Mitral Commissurotomy (PTMC) is advised as a Class IA (I-Class Of Recommendation, COR; A-Level Of Evidence, LOE) indication in patients with symptomatic severe mitral stenosis. We aim to examine the clinical profile and in-hospital results of PTMC for mitral stenosis. Methods: A cross-sectional retrospective study was conducted at Manmohan Cardiothoracic Vascular and Transplant Center from April 2020 to May 2022. A structured questionnaire was used to collect the data and ethical approval for conducting the study was taken from the Institutional Review Committee (IRC) of Institute of Medicine (IOM). The data was collected in Microsoft Excel (Ver. 2013). For statistical analysis, SPSS 21 (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.) Association was measured using a parametric and non-parametric test (depending upon the distribution of data) and p value < 0.05 was considered significant. Results: A total of 104 patients who met the inclusion criteria underwent PTMC during the study period. The mean age group of the patient was 41.7 ± 12.5 years, of which 23 (22.1%) were males and 81 (78.9%) were females. Mean mitral valve area prior to PTMC was 0.98 ± 0.19 mm2 that increased to 1.69 ± 0.19 mm2 after the procedure and it was statistically significant (p=<0.001). The post PTMC MVA varied with PTMC Wilkin's score with less than or equal to 8 having favorable outcomes. Conclusion: Successful PTMC is highly influenced by the patients' increasing age, valve morphology (calcification, thickness, mobility), Left atrial dimensions, Pre PTMC mitral valve area, Degree of Baseline mitral regurgitation. Post procedure development of MR is usually well tolerated but rarely be severe enough requiring surgical valve replacement.

6.
Case Rep Womens Health ; 36: e00469, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36425248

RESUMO

Mirror syndrome is the phenomenon of fetal hydrops causing maternal edema and weight gain. Here, we report a case of arrhythmia as the primary maternal symptom. A 36-year-old woman, G2P1001, at 34.5 weeks of gestation presented with new-onset fetal hydrops combined with maternal weight gain and edema. She developed atrial fibrillation with rapid ventricular response; cardiac workup was unremarkable. Rate control was achieved with diltiazem. She underwent delivery and reverted to normal sinus rhythm on post-operative day 1. Volume overload causes atrial wall stress and neurohormonal changes that may trigger atrial fibrillation. Optimization with rate control facilitated good maternal and fetal outcomes in this case.

7.
Genetics ; 222(2)2022 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-36005881

RESUMO

Aspergillus nidulans snxA, an ortholog of Saccharomyces cerevisiae Hrb1/Gbp2 messenger RNA shuttle proteins, is-in contrast to budding yeast-involved in cell cycle regulation, in which snxA1 and snxA2 mutations as well as a snxA deletion specifically suppress the heat sensitivity of mutations in regulators of the CDK1 mitotic induction pathway. snxA mutations are strongly cold sensitive, and at permissive temperature snxA mRNA and protein expression are strongly repressed. Initial attempts to identify the causative snxA mutations revealed no defects in the SNXA protein. Here, we show that snxA1/A2 mutations resulted from an identical chromosome I-II reciprocal translocation with breakpoints in the snxA first intron and the fourth exon of a GYF-domain gene, gyfA. Surprisingly, a gyfA deletion and a reconstructed gyfA translocation allele suppressed the heat sensitivity of CDK1 pathway mutants in a snxA+ background, demonstrating that 2 unrelated genes, snxA and gyfA, act through the CDK1-CyclinB axis to restrain the G2-M transition, and for the first time identifying a role in G2-M regulation for a GYF-domain protein. To better understand snxA1/A2-reduced expression, we generated suppressors of snxA cold sensitivity in 2 genes: (1) loss of the abundant nucleolar protein Nsr1/nucleolin bypassed the requirement for snxA and (2) loss of the Set2 histone H3 lysine36 (H3K36) methyltransferase or a nonmethylatable histone H3K36L mutant rescued hypomorphic snxA mutants by restoring full transcriptional proficiency, indicating that methylation of H3K36 acts normally to repress snxA transcription. These observations are in line with known Set2 functions in preventing excessive and cryptic transcription of active genes.


Assuntos
Aspergillus nidulans , Proteínas de Saccharomyces cerevisiae , Aspergillus nidulans/genética , Aspergillus nidulans/metabolismo , Regulação Fúngica da Expressão Gênica , Histona Metiltransferases/genética , Histona Metiltransferases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/genética , Histonas/metabolismo , Lisina/metabolismo , RNA Mensageiro , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Transcrição Gênica
8.
Comput Struct Biotechnol J ; 20: 2029-2041, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35521546

RESUMO

It is estimated that human body is inhabited by approximately 380 trillions of viruses, which exist in the form of viral communities and are collectively termed as human virome. How virome is assembled and what kind of forces maintain the composition and diversity of viral communities is still an open question. The question is of obvious importance because of its implications to human health and diseases. Here we address the question by harnessing the power of Hubbell's unified neutral theory of biodiversity (UNTB) in terms of three neutral models including standard Hubbell's neutral model (HNM), Sloan's near-neutral model (SNM) and Harris et al. (2017) multi-site neutral model (MSN), further augmented by Ning et al. (2019) normalized stochasticity ratio (NSR) and Hammal et al. (2015) power analysis for the neutral test (PNT). With the five models applied to 179 virome samples, we aim to obtain robust findings given both Type-I and Type-II errors are addressed and possible alternative, non-neutral processes are detected. It was found that stochastic neutral drifts seem prevalent: approximately 65-92% at metacommunity/landscape scales and 67-80% at virus species scale. The non-neutral selection is approximately 26-28% at community scale and 23% at species scale. The false negative rate is about 2-3%, which suggested rather limited confounding effects of non-neutral process on neutrality tests. We postulate that prevalence of neutrality in human virome is likely due to extremely simple structure of viruses (stands of DNA/RNA) and their inter-species homogeneities, forming the foundation of species equivalence-the hallmark of neutral theory.

9.
Med Phys ; 49(1): 682-701, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34796512

RESUMO

PURPOSE: Focused ultrasound (FUS) is a promising tool to develop new modalities of therapeutic neurostimulation. The ability of FUS to stimulate the nervous system, in a noninvasive and spatiotemporally precise manner, has been demonstrated in animals and human subjects, but the underlying biomechanisms are not fully understood yet. The objective of the present study was to investigate the bioeffects involved in the generation of trains of action potentials (APs) by repetitive-pulse FUS stimuli in a simple invertebrate neural model. METHODS: The respective influences of different acoustic parameters on the neurostimulation success rate (NSR), defined as the rate of FUS stimuli capable of evoking at least one AP, were explored using the system of afferent nerves and giant fibers of Lumbricus terrestris as neural model. Each parameter was studied independently by administering random FUS sequences while keeping all but one FUS parameter constant. The NSR was evaluated as a function of (i) the spatial-average pulse-average intensity (Isapa ); (ii) the pulse duration (PD); (iii) the pulse repetition frequency (PRF); iv) the number of cycles per pulse (Ncycles ); (v) two ultrasound frequencies, f0  = 1.1 MHz and f3  = 3.3 MHz, corresponding to the fundamental and third-harmonic resonant frequencies of the FUS transducer, respectively (spherical, radius of curvature: 50 mm); and (vi) levels of emerging stable cavitation and inertial cavitation. RESULTS: The NSR associated to 1.1 MHz repetitive-pulse FUS stimuli was found to increase as a function of increasing Isapa , PD, PRF, and Ncycles . When evaluating each parameter at f = 1.1 MHz, it was observed that NSRs close to 100% were achieved when sufficiently elevating their respective values. When computing the NSR as a function of the spatial-average, temporal-average intensity (Isata ), defined as the product of PRF, PD, and Isapa , a significant elevation of the NSR from 0% to close to 100% was measured by increasing Isata from values approximate to 4 W/cm2 to values higher than 12 W/cm2 . No clear and consistent trend was observed in trials aimed at exploring the effects of different levels of stable and inertial acoustic cavitation on the NSR. Finally, the feasibility of inducing neural responses with 3.3 MHz repetitive-pulse FUS stimuli was also demonstrated with NSRs reaching up to 60%, in the range of FUS parameters studied. CONCLUSION: The time-averaged value of the radiation force per unit volume of tissue is proportional to the acoustic intensity. As a result, the observations from this study suggest that the neural structure responding to the stimulus is sensitive to the mean radiation force carried by the FUS sequence, regardless of the combination of FUS parameters giving rise to such force. The results from this study further revealed the existence of a minimal activation threshold with regard to Isapa .


Assuntos
Acústica , Axônios , Animais , Humanos , Som , Transdutores , Ultrassonografia
10.
Appl Environ Microbiol ; 87(16): e0039121, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34105992

RESUMO

Antimicrobial peptides are evolving as novel therapeutic options against the increasing problem of multidrug-resistant microorganisms, and nisin is one such avenue. However, some bacteria possess a specific nisin resistance system (NSR), which cleaves the peptide reducing its bactericidal efficacy. NSR-based resistance was identified in strains of Streptococcus uberis, a ubiquitous pathogen that causes mastitis in dairy cattle. Previous studies have demonstrated that a nisin A derivative termed nisin PV, featuring S29P and I30V, exhibits enhanced resistance to proteolytic cleavage by NSR. Our objective was to investigate the ability of this nisin derivative to eradicate and inhibit biofilms of S. uberis DPC 5344 and S. uberis ATCC 700407 (nsr+) using crystal violet (biomass), 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) (viability) assays, and confocal microscopy (viability and architecture). When preestablished biofilms were assessed, both peptides reduced biofilm biomass by over 60% compared to that of the untreated controls. However, a 42% higher reduction in viability was observed following treatment with nisin PV compared to that of nisin A. Accordingly, confocal microscopy analysis revealed significantly more dead cells on the biofilm upper surface and a reduced thickness following treatment with nisin PV. When biofilm inhibition was assessed, nisin PV inhibited biofilm formation and decreased viability up to 56% and 85% more than nisin A, respectively. Confocal microscopy analysis revealed a lack of biofilm for S. uberis ATCC 700407 and only dead cells for S. uberis DPC 5344. These results suggest that nisin PV is a promising alternative to effectively reduce the biofilm formation of S. uberis strains carrying NSR. IMPORTANCE One of the four most prevalent species of bovine mastitis-causing pathogens is S. uberis. Its ability to form biofilms confers on the bacteria greater resistance to antibiotics, requiring higher doses to be more effective. In a bid to limit antibiotic resistance development, the need for alternative antimicrobials is paramount. Bacteriocins such as nisin represent one such alternative that could alleviate the impact of mastitis caused by S. uberis. However, many strains of S. uberis have been shown to possess nisin resistance determinants, such as the nisin resistance protein (NSR). In this study, we demonstrate the ability of nisin and a nisin derivative termed PV that is insensitive to NSR to prevent and remove biofilms of NSR-producing S. uberis strains. These findings will add new information to the antimicrobial bacteriocins and control of S. uberis research fields specifically in relation to biofilms and nsr+ mastitis-associated strains.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Nisina/química , Nisina/farmacologia , Streptococcus/efeitos dos fármacos , Bioengenharia , Farmacorresistência Bacteriana , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Nisina/genética , Streptococcus/crescimento & desenvolvimento , Streptococcus/fisiologia
11.
Stud Russ Econ Dev ; 32(2): 160-168, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33976526

RESUMO

The article examines the problems and development prospects for the international transit of goods along the NSR. The existing restrictions on increasing freight traffic up to 80 million tons per year declared in program documents are identified. An option for its enhancement based on the domestic fleet of Arctic cargo ships is proposed. The article summarizes the main shortcomings of earlier studies assessing the transit capabilities of the NSR. A model for assessing the optimal number of ships for the transportation of goods is proposed taking into account climatic, physical-geographical, technological, and temporal constraints and risks. Within the framework of the model, the cost of goods transportation was estimated for implementing two scenarios of transit traffic.

12.
Front Bioeng Biotechnol ; 9: 622835, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33748081

RESUMO

Lactococcus lactis cheese starter cultures typically contain a mix of many strains and may include variants that produce and/or tolerate the antimicrobial bacteriocin nisin. Nisin is well-established as an effective agent against several undesirable Gram-positive bacteria in cheese and various other foods. In the current study, we have examined the effect of nisin on 710 individual L. lactis strains during milk fermentations. Changes in milk acidification profiles with and without nisin exposure, ranging from unaltered acidification to loss of acidification, could be largely explained by the type(s) and variants of nisin immunity and nisin degradation genes present, but surprisingly, also by genotypic lineage (L. lactis ssp. cremoris vs. ssp. lactis). Importantly, we identify that nisin degradation by NSR is frequent among L. lactis and therefore likely the main mechanism by which dairy-associated L. lactis strains tolerate nisin. Insights from this study on the strain-specific effect of nisin tolerance and degradation during milk acidification is expected to aid in the design of nisin-compatible cheese starter cultures.

13.
Infect Drug Resist ; 14: 613-626, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33628037

RESUMO

PURPOSE: Multi-drug resistant Klebsiella pneumoniae (MDR KP) is spreading worldwide and has posed a huge medical burden to public health. However, studies on drug resistance surveillance of KP, especially MDR KP, with a large longitudinal sample size in a tertiary hospital are rare. This study aims to investigate phenotypic epidemiology characteristics of 4128 KP isolates in a Chinese tertiary hospital covering a period of 5 years. METHODS: All the KP clinical isolates were retrospectively collected from a tertiary hospital in Hunan province of China from Jan 5, 2013 to Jul 24, 2018. All the isolates were identified by MALDI-TOF MS analysis. Twenty-four antimicrobial agents were tested by antimicrobial susceptibility testing. Fisher exact test and logistic regression were used to analyze the association between clinical factors and antimicrobial non-susceptibility for seven second-choice antimicrobials. RESULTS: A total of 4128 KP isolates were collected in our study. The non-susceptible rates (NSRs) to ertapenem, imipenem and tigecycline increased considerably from 2013 to 2018 (13.6% to 28.6%, 10.1% to 28.9%, 10.8% to 46.5%, respectively). Amikacin presents the lowest NSR among 3 aminoglycosides (3.8-22.8%). The multi-drug NSRs among KP isolates to second-choice antimicrobials (88.6-100%) were higher than to all drugs (68.0%). The NSRs varied significantly among departments and sample sources. Higher ETP/IPM/AK NSRs (39.8/39.7/30.6%) were observed in Intensive Care Unit, and ETP/IPM non-susceptible isolates tended to distribute in cerebrospinal fluid. From 2015 to 2017, the NSRs of ETP, IPM, and AK showed an opposite trend of seasonal fluctuations to SXT. CONCLUSION: Higher multi-drug resistance (MDR) rates were observed in KP isolates to second-choice antimicrobials than to others, among which MDR rates to carbapenems or AK are the highest. A unique pattern of MIC and time distributions of MDR were observed. Clinical factors including gender were correlated with MDR rates of KP. Isolates in ICU and CSF showed higher NSRs in carbapenems which should be paid more attention to, and temporal distribution of NSRs was observed.

14.
Front Microbiol ; 11: 588427, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042103

RESUMO

The use of high-throughput sequencing (HTS) for virus diagnostics, as well as the importance of this technology as a valuable tool for discovery of novel viruses has been extensively investigated. In this review, we consider the application of HTS approaches to uncover novel plant viruses with a focus on the negative-sense, single-stranded RNA virosphere. Plant viruses with negative-sense and ambisense RNA (NSR) genomes belong to several taxonomic families, including Rhabdoviridae, Aspiviridae, Fimoviridae, Tospoviridae, and Phenuiviridae. They include both emergent pathogens that infect a wide range of plant species, and potential endophytes which appear not to induce any visible symptoms. As a consequence of biased sampling based on a narrow focus on crops with disease symptoms, the number of NSR plant viruses identified so far represents only a fraction of this type of viruses present in the virosphere. Detection and molecular characterization of NSR viruses has often been challenging, but the widespread implementation of HTS has facilitated not only the identification but also the characterization of the genomic sequences of at least 70 NSR plant viruses in the last 7 years. Moreover, continuing advances in HTS technologies and bioinformatic pipelines, concomitant with a significant cost reduction has led to its use as a routine method of choice, supporting the foundations of a diverse array of novel applications such as quarantine analysis of traded plant materials and genetic resources, virus detection in insect vectors, analysis of virus communities in individual plants, and assessment of virus evolution through ecogenomics, among others. The insights from these advancements are shedding new light on the extensive diversity of NSR plant viruses and their complex evolution, and provide an essential framework for improved taxonomic classification of plant NSR viruses as part of the realm Riboviria. Thus, HTS-based methods for virus discovery, our 'new eyes,' are unraveling in real time the richness and magnitude of the plant RNA virosphere.

15.
Neurosurg Focus ; 48(3): E6, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32114562

RESUMO

OBJECTIVE: Postgraduate training in medicine has been under scrutiny in the last 10 years, with a focus on improving residents' education. The aim of this study was to quantify trends in neurosurgery residency (NSR) training and education over the last 10 years. METHODS: The authors assessed Accreditation Council for Graduate Medical Education (ACGME), National Resident Matching Program, and American Board of Neurological Surgeons records and searched PubMed to collate 2009-2019 data. Analyzed trends included residents' demographic data, programs' characteristics, graduation and attrition rates, match data, resident case logs, and qualitative educational curriculum changes. RESULTS: Significant increases in residents' demographic data (p < 0.05) included the number of female residents (from 12.7% to 17.6%) and the absolute number of residents (from 1112 to 1462). Age (mean 28.8 years), ethnicity, and number of residents per program (mean 13 residents per program) were unchanged. There were 16 new ACGME NSR programs, with currently 115 programs nationwide. The number of applicants per year (324 applicants per year) and the matching rate (mean 64%) remained stable. The mean attrition rate of 2.6% (range 2%-4%) was higher than the mean 2.1% ACGME attrition rate, a rate that decreased from 3% in 2009 to 1.6% in 2019. Education curriculum changes aimed at the standardization of training across the US included residents' boot camp (2009), the Milestones project (2012), and mandatory 7-year training initiated in 2013. An increase in endovascular, functional, trauma, and spine resident caseload was noted. The number of yearly publications about US NSR education has significantly increased (p < 0.05). CONCLUSIONS: NSR education has received greater attention over the last decade in the US. Standardization of training has been implemented. A steady number of students remain interested in neurosurgery, with an increased number of women entering the field. Attention to wellness, in addition to high-quality education, should be further assessed as a factor to improve the overall NSR training and retention rate.


Assuntos
Internato e Residência/tendências , Neurocirurgiões/educação , Neurocirurgia/educação , Procedimentos Neurocirúrgicos/economia , Acreditação/normas , Currículo/tendências , Educação de Pós-Graduação em Medicina/normas , Educação de Pós-Graduação em Medicina/estatística & dados numéricos , Humanos , Neurocirurgia/tendências , Estados Unidos
16.
Mol Cell ; 77(6): 1176-1192.e16, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-31999954

RESUMO

Microexons represent the most highly conserved class of alternative splicing, yet their functions are poorly understood. Here, we focus on closely related neuronal microexons overlapping prion-like domains in the translation initiation factors, eIF4G1 and eIF4G3, the splicing of which is activity dependent and frequently disrupted in autism. CRISPR-Cas9 deletion of these microexons selectively upregulates synaptic proteins that control neuronal activity and plasticity and further triggers a gene expression program mirroring that of activated neurons. Mice lacking the Eif4g1 microexon display social behavior, learning, and memory deficits, accompanied by altered hippocampal synaptic plasticity. We provide evidence that the eIF4G microexons function as a translational brake by causing ribosome stalling, through their propensity to promote the coalescence of cytoplasmic granule components associated with translation repression, including the fragile X mental retardation protein FMRP. The results thus reveal an autism-disrupted mechanism by which alternative splicing specializes neuronal translation to control higher order cognitive functioning.


Assuntos
Transtorno Autístico/fisiopatologia , Disfunção Cognitiva/patologia , Fator de Iniciação Eucariótico 4G/fisiologia , Éxons/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Neuroblastoma/patologia , Neurônios/patologia , Animais , Comportamento Animal , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neurogênese , Neurônios/metabolismo , Biossíntese de Proteínas , Splicing de RNA , Células Tumorais Cultivadas
17.
Environ Sci Pollut Res Int ; 26(27): 27888-27896, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31346940

RESUMO

This study evaluated the NOx adsorption and desorption performance as well as the casual relationship underlying a Mn-incorporated catalyst (Pt/Ba/Ce/xMn/γ-Al2O3). NOx adsorption and desorption are regarded as a prominent index for the NOx removal performance of NOx storage and reduction; we utilized NOx storage experiments with various inlet NO and O2 concentrations and cycling adsorption/desorption experiments with a couple of adsorption time protocols for performance evaluation. In-suit DRIFT and NOx-TPD tests were implemented to reveal the instant stored species and their thermal stability. Eight percent of Mn catalyst at 350 °C was adopted in the described experiments for its desirable NOx adsorption characteristics. The optimal NOx storage performance was found under 10% O2, deteriorating when the concentration was further increased. Furthermore, elevating NO concentration impaired the NOx adsorption due to the low NO2/NOx ratio. It was also found that shorter adsorption time facilitated NOx removal via maintaining an unsaturated state for active storage components in terms of a fixed desorption time. The stored species existed as nitrites and nitrates with a good low-temperature thermal stability which however decayed at higher temperatures as exhibited in the DRIFT and NOx-TPD tests. These findings provided invaluable information for the application of Mn-incorporated catalyst for NOx removal in diesel exhaust purification to relieve the aerial pollution.


Assuntos
Metais/química , Nitratos/metabolismo , Óxidos de Nitrogênio/metabolismo , Adsorção , Catálise , Temperatura Baixa , Nitratos/química , Óxidos de Nitrogênio/química , Emissões de Veículos
18.
Data Brief ; 24: 103925, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31061864

RESUMO

This data article includes the datasets of the mean and the standard deviation of ice thickness in a set of sailing zones for a sailing route that goes through the Northern Sea Route (NSR) between Murmansk and Pusan. The route under consideration is between the longitudes 33° 45' 0″ and 129° 3' 60″ and the latitudes 69° 24' 27″ and 35° 6' 0″ that correspond to the ports of Murmansk (Russia) in the west and Pusan (China) in the east respectively. Within this area, the part that is between the longitude 57° 0' 0″ and -168° 58' 0″ and the latitude 70° 27' 18″ and 69° 6' 0″ correspond to the NSR. This route has been divided into 49 subzones, and each subzone into squares of 12.5km of side following the data structure of the database Copernicus [1]. The detailed coordinates of the subzones (longitude and latitude) are provided in the article. The daily ice thickness for the period between January 1, 2006 and December 31, 2016 has been obtained for each of the 12.5km sided squares. This data article provides the normality test outcomes and the corresponding p-value of the ice thickness data for each subzone on each calendar day. Moreover, the mean and the standard deviation of the ice thickness in each subzone are also provided. The data provided in this data article can be very helpful for researchers for different applications related to the weather conditions in the NSR zone or to shipping related issues. For instance, the data provided in this paper can be used to investigate the change in ice thickness in the NSR over the period 2006-2016 and to estimate future changes. Another potential application is the estimation of the need for icebreaker assistance as well as the possible ranges for the vessel sailing speed based on the vessel type and for any navigation day in any of the NSR zones. In addition, this data can be used to estimate the risk of blockage for any vessel type because of ice conditions in the NSR zones. It can be helpful to estimate the economic viability of shipping through the NSR since the icebreaker assistance, the speed and the risk of blockage have an effect on the profitability of the shipping lines that may use the NSR.

19.
Int J Biochem Cell Biol ; 110: 143-148, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30880168

RESUMO

S. cerevisiae ribosomal DNA (rDNA) locus hosts a series of highly complex regulatory machineries for RNA polymerase I, II and III transcription, DNA replication and units recombination, all acting in the Non Transcribed Spacers (NTSs) interposed between the repeated units by which it is composed. DNA topoisomerase I (Top1p) contributes, recruiting Sir2p, to the maintenance of transcriptional silencing occurring at the RNA Polymerase II cryptic promoters, located in the NTS region. In this paper we found that Fob1p presence is crucial for Top1p recruitment at NTS, allowing transcriptional silencing to be established and maintained. We also showed the role of Nsr1p in Top1p recruitment to rDNA locus. Our work allows to hypothesize that Nsr1p targets Top1p into the nucleolus while Fob1p is responsible for its preferential distribution at RFB.


Assuntos
DNA Topoisomerases Tipo I/metabolismo , Proteínas de Ligação a DNA/metabolismo , Inativação Gênica , Loci Gênicos/genética , Ribossomos/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Transcrição Gênica/genética , Replicação do DNA/genética , RNA Ribossômico/genética , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/genética
20.
J Stroke Cerebrovasc Dis ; 28(3): 665-671, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30503678

RESUMO

BACKGROUND: Antiplatelet drugs are administered before and after carotid endarterectomies (CEAs), but their efficacy for preventing restenosis remains unclear. Hence, this study aimed to identify associations between postoperative restenosis and platelet aggregability in CEA patients. METHODS: Thirty-six consecutive CEA patients treated at Tokyo Women's Medical University from May 2013 to March 2015 were included in this retrospective study. Restenosis was defined as a stenosis ratio greater than or equal to 50% per the European Carotid Surgery Trial criteria or peak systolic velocity of 150 cm/s on carotid ultrasound. Platelet aggregability was measured turbidimetrically using a light-transmission platelet aggregometer and analyzed in terms of aggregation profiles for 2 concentrations of collagen used to induce aggregation (.25 and 2.0 µg/mL). Patients were automatically divided into 9 classes (Class 1-9, from the lowest to the highest aggregability) using a software program according to area under their platelet aggregation curves. Each class was subdivided into 10 further gradations for a total of 90 possible scores (10-99) using a software program. Patients were divided into high- and low-platelet aggregability score groups (cut-off = 49). RESULTS: Data were analyzed for 36 of the 99 patients. Restenosis was observed in 10 (28%) patients. Restenosis incidence was significantly higher in patients with high-platelet aggregability score than in those with low-platelet aggregability score (50.0% [7/14] versus 13.6% [3 of 22]: P = .0176, odds ratio = 6.34, 95% CI: 1.27-31.57). CONCLUSIONS: Platelet aggregability is a useful metric for predicting and preventing restenosis after CEA. It has potential as an indicator for determining the optimal dose of antiplatelet drugs.


Assuntos
Estenose das Carótidas/cirurgia , Endarterectomia das Carótidas/efeitos adversos , Agregação Plaquetária , Idoso , Idoso de 80 Anos ou mais , Velocidade do Fluxo Sanguíneo , Estenose das Carótidas/sangue , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/fisiopatologia , Tomada de Decisão Clínica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Testes de Função Plaquetária , Recidiva , Fluxo Sanguíneo Regional , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Tóquio , Resultado do Tratamento , Ultrassonografia
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