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1.
Nature ; 595(7869): 718-723, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34082438

RESUMO

Resistance represents a major challenge for antibody-based therapy for COVID-191-4. Here we engineered an immunoglobulin M (IgM) neutralizing antibody (IgM-14) to overcome the resistance encountered by immunoglobulin G (IgG)-based therapeutics. IgM-14 is over 230-fold more potent than its parental IgG-14 in neutralizing SARS-CoV-2. IgM-14 potently neutralizes the resistant virus raised by its corresponding IgG-14, three variants of concern-B.1.1.7 (Alpha, which first emerged in the UK), P.1 (Gamma, which first emerged in Brazil) and B.1.351 (Beta, which first emerged in South Africa)-and 21 other receptor-binding domain mutants, many of which are resistant to the IgG antibodies that have been authorized for emergency use. Although engineering IgG into IgM enhances antibody potency in general, selection of an optimal epitope is critical for identifying the most effective IgM that can overcome resistance. In mice, a single intranasal dose of IgM-14 at 0.044 mg per kg body weight confers prophylactic efficacy and a single dose at 0.4 mg per kg confers therapeutic efficacy against SARS-CoV-2. IgM-14, but not IgG-14, also confers potent therapeutic protection against the P.1 and B.1.351 variants. IgM-14 exhibits desirable pharmacokinetics and safety profiles when administered intranasally in rodents. Our results show that intranasal administration of an engineered IgM can improve efficacy, reduce resistance and simplify the prophylactic and therapeutic treatment of COVID-19.


Assuntos
COVID-19/prevenção & controle , COVID-19/virologia , Imunoglobulina M/administração & dosagem , Imunoglobulina M/imunologia , SARS-CoV-2/classificação , SARS-CoV-2/imunologia , Administração Intranasal , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Proteínas Reguladoras de Apoptose/metabolismo , COVID-19/imunologia , Relação Dose-Resposta Imunológica , Feminino , Humanos , Imunoglobulina A/genética , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/efeitos adversos , Imunoglobulina M/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Engenharia de Proteínas , Receptores Virais/antagonistas & inibidores , Receptores Virais/metabolismo , SARS-CoV-2/genética , Tratamento Farmacológico da COVID-19
2.
Nat Mater ; 23(7): 960-968, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38514846

RESUMO

Limitations in electrochemical performance as well as supply chain challenges have rendered positive electrode materials a critical bottleneck for Li-ion batteries. State-of-the-art Li-ion batteries fall short of accessing theoretical capacities. As such, there is intense interest in the design of strategies that enable the more effective utilization of active intercalation materials. Pre-intercalation with alkali-metal ions has attracted interest as a means of accessing higher reversible capacity and improved rate performance. However, the structural basis for improvements in electrochemical performance remains mostly unexplored. Here we use topochemical single-crystal-to-single-crystal transformations in a tunnel-structured ζ-V2O5 positive electrode to illustrate the effect of pre-intercalation in modifying the host lattice and altering diffusion pathways. Furthermore, operando synchrotron X-ray diffraction is used to map Li-ion site preferences and occupancies as a function of the depth of discharge in pre-intercalated materials. Na- and K-ion intercalation 'props open' the one-dimensional tunnel, reduces electrostatic repulsions between inserted Li ions and entirely modifies diffusion pathways, enabling orders of magnitude higher Li-ion diffusivities and accessing higher capacities. Deciphering the atomistic origins of improved performance in pre-intercalated materials on the basis of single-crystal-to-single-crystal topochemical transformation and operando diffraction studies paves the way to site-selective modification approaches for positive electrode design.

3.
Syst Biol ; 2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38970781

RESUMO

Due to the hierarchical structure of the tree of life, closely related species often resemble each other more than distantly related species; a pattern termed phylogenetic signal. Numerous univariate statistics have been proposed as measures of phylogenetic signal for single phenotypic traits, but the study of phylogenetic signal for multivariate data, as is common in modern biology, remains challenging. Here we introduce a new method to explore phylogenetic signal in multivariate phenotypes. Our approach decomposes the data into linear combinations with maximal (or minimal) phylogenetic signal, as measured by Blomberg's K. The loading vectors of these phylogenetic components or K-components can be biologically interpreted, and scatterplots of the scores can be used as a low-dimensional ordination of the data that maximally (or minimally) preserves phylogenetic signal. We present algebraic and statistical properties, along with two new summary statistics, KA and KG, of phylogenetic signal in multivariate data. Simulation studies showed that KA and KG have higher statistical power than the previously suggested statistic Kmult, especially if phylogenetic signal is low or concentrated in a few trait dimensions. In two empirical applications to vertebrate cranial shape (crocodyliforms and papionins), we found statistically significant phylogenetic signal concentrated in a few trait dimensions. The finding that phylogenetic signal can be highly variable across the dimensions of multivariate phenotypes has important implications for current maximum likelihood approaches to phylogenetic signal in multivariate data.

4.
Oncologist ; 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38982622

RESUMO

Despite recent efforts to issue clinical guidelines outlining strategies to define the pathogenicity of genomic variants, there is currently no standardized framework for which to make these assertions. This review does not present a step-by-step methodology, but rather takes a holistic approach to discuss many aspects which should be taken into consideration when determining variant pathogenicity. Categorization should be curated to reflect relevant findings within the scope of the specific medical context. Functional characterization should evaluate all available information, including results from literature reviews, different classes of genomic data repositories, and applicable computational predictive algorithms. This article further proposes a multidimensional view to infer pathogenic status from many genomic measurements across multiple axes. Notably, tumor suppressors and oncogenes exhibit fundamentally different biology which helps refine the importance of effects on splicing, mutation interactions, copy number thresholds, rearrangement annotations, germline status, and genome-wide signatures. Understanding these relevant datapoints with thoughtful perspective could aid in the reclassification of variants of unknown significance (VUS), which are ambiguously understood and currently have uncertain clinical implications. Ongoing assessments of VUS examining these relevant biological axes could lead to more accurate classification of variant pathogenicity interpretation in diagnostic oncology.

5.
Oncologist ; 29(6): 493-503, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38330461

RESUMO

BACKGROUND: One of the most common sporadic homozygous deletions in cancers is 9p21 loss, which includes the genes methylthioadenosine phosphorylase (MTAP), CDKN2A, and CDKN2B, and has been correlated with worsened outcomes and immunotherapy resistance. MTAP-loss is a developing drug target through synthetic lethality with MAT2A and PMRT5 inhibitors. The purpose of this study is to investigate the prevalence and genomic landscape of MTAP-loss in advanced gastrointestinal (GI) tumors and investigate its role as a prognostic biomarker. MATERIALS AND METHODS: We performed next-generation sequencing and comparative genomic and clinical analysis on an extensive cohort of 64 860 tumors comprising 5 GI cancers. We compared the clinical outcomes of patients with GI cancer harboring MTAP-loss and MTAP-intact tumors in a retrospective study. RESULTS: The prevalence of MTAP-loss in GI cancers is 8.30%. MTAP-loss was most prevalent in pancreatic ductal adenocarcinoma (PDAC) at 21.7% and least in colorectal carcinoma (CRC) at 1.1%. MTAP-loss tumors were more prevalent in East Asian patients with PDAC (4.4% vs 3.2%, P = .005) or intrahepatic cholangiocarcinoma (IHCC; 6.4% vs 4.3%, P = .036). Significant differences in the prevalence of potentially targetable genomic alterations (ATM, BRAF, BRCA2, ERBB2, IDH1, PIK3CA, and PTEN) were observed in MTAP-loss tumors and varied according to tumor type. MTAP-loss PDAC, IHCC, and CRC had a lower prevalence of microsatellite instability or elevated tumor mutational burden. Positive PD-L1 tumor cell expression was less frequent among MTAP-loss versus MTAP-intact IHCC tumors (23.2% vs 31.2%, P = .017). CONCLUSION: In GI cancers, MTAP-loss occurs as part of 9p21 loss and has an overall prevalence of 8%. MTAP-loss occurs in 22% of PDAC, 15% of IHCC, 8.7% of gastroesophageal adenocarcinoma, 2.4% of hepatocellular carcinoma, and 1.1% of CRC and is not mutually exclusive with other targetable mutations.


Assuntos
Neoplasias Gastrointestinais , Purina-Núcleosídeo Fosforilase , Humanos , Purina-Núcleosídeo Fosforilase/genética , Masculino , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Biomarcadores Tumorais/genética , Adulto , Prognóstico , Genômica/métodos
6.
Appl Environ Microbiol ; 90(4): e0223423, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38497641

RESUMO

The primary objective of this study was to identify associations between the prepartum teat apex microbiome and the presence of Staphylococcus aureus intramammary infections (IMI) in primiparous cows during the first 5 weeks after calving. We performed a case-control study using shotgun metagenomics of the teat apex and culture-based milk data collected longitudinally from 710 primiparous cows on five organic dairy farms. Cases had higher odds of having S. aureus metagenomic DNA on the teat apex prior to parturition compared to controls (OR = 38.9, 95% CI: 14.84-102.21). Differential abundance analysis confirmed this association, with cases having a 23.8 higher log fold change (LFC) in the abundance of S. aureus in their samples compared to controls. Of the most prevalent microorganisms in controls, those associated with a lower risk of post-calving S. aureus IMI included Microbacterium phage Min 1 (OR = 0.37, 95% CI: 0.25-0.53), Corynebacterium efficiens (OR = 0.53, 95% CI: 0.30-0.94), Kocuria polaris (OR = 0.54, 95% CI: 0.35-0.82), Micrococcus terreus (OR = 0.64, 95% CI: 0.44-0.93), and Dietzia alimentaria (OR = 0.45, 95% CI: 0.26-0.75). Genes encoding for Microcin B17 AMPs were the most prevalent on the teat apex of cases and controls (99.7% in both groups). The predicted abundance of genes encoding for Microcin B17 was also higher in cases compared to controls (LFC 0.26). IMPORTANCE: Intramammary infections (IMI) caused by Staphylococcus aureus remain an important problem for the dairy industry. The microbiome on the external skin of the teat apex may play a role in mitigating S. aureus IMI risk, in particular the production of antimicrobial peptides (AMPs) by commensal microbes. However, current studies of the teat apex microbiome utilize a 16S approach, which precludes the detection of genomic features such as genes that encode for AMPs. Therefore, further research using a shotgun metagenomic approach is needed to understand what role prepartum teat apex microbiome dynamics play in IMI risk.


Assuntos
Mastite Bovina , Infecções Estafilocócicas , Feminino , Bovinos , Animais , Staphylococcus aureus/genética , Metagenoma , Estudos de Casos e Controles , Mastite Bovina/epidemiologia , Mastite Bovina/microbiologia , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/veterinária , Infecções Estafilocócicas/microbiologia , Leite/microbiologia , Glândulas Mamárias Animais/microbiologia
7.
Blood ; 140(14): 1592-1606, 2022 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-35767701

RESUMO

Adult hematopoietic stem cells (HSCs) are predominantly quiescent and can be activated in response to acute stress such as infection or cytotoxic insults. STAT1 is a pivotal downstream mediator of interferon (IFN) signaling and is required for IFN-induced HSC proliferation, but little is known about the role of STAT1 in regulating homeostatic hematopoietic stem/progenitor cells (HSPCs). Here, we show that loss of STAT1 altered the steady state HSPC landscape, impaired HSC function in transplantation assays, delayed blood cell regeneration following myeloablation, and disrupted molecular programs that protect HSCs, including control of quiescence. Our results also reveal STAT1-dependent functional HSC heterogeneity. A previously unrecognized subset of homeostatic HSCs with elevated major histocompatibility complex class II (MHCII) expression (MHCIIhi) displayed molecular features of reduced cycling and apoptosis and was refractory to 5-fluorouracil-induced myeloablation. Conversely, MHCIIlo HSCs displayed increased megakaryocytic potential and were preferentially expanded in CALR mutant mice with thrombocytosis. Similar to mice, high MHCII expression is a feature of human HSCs residing in a deeper quiescent state. Our results therefore position STAT1 at the interface of stem cell heterogeneity and the interplay between stem cells and the adaptive immune system, areas of broad interest in the wider stem cell field.


Assuntos
Células-Tronco Hematopoéticas , Megacariócitos , Fator de Transcrição STAT1 , Animais , Proliferação de Células , Fluoruracila/farmacologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Interferons , Megacariócitos/metabolismo , Camundongos , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo
8.
Langmuir ; 40(1): 1117-1129, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38115197

RESUMO

This study demonstrated the importance of identifying the optimal balance of hydrophilic and hydrophobic moieties in amphiphilic coatings to achieve fouling-release (FR) performance that surpasses that of traditional hydrophobic marine coatings. While there have been many reports on fouling-release properties of amphiphilic surfaces, the offered understanding is often limited. Hence, this work is focused on further understanding of the amphiphilic surfaces. Poly(ethylene glycol) (PEG) and polydimethylsiloxane (PDMS) were used to create a series of noncross-linked amphiphilic additives that were then added to a hydrophobic-designed siloxane-polyurethane (SiPU) FR system. After being characterized by ATR-FTIR, XPS, contact angle analysis, and AFM, the FR performance was evaluated by using different marine organisms. The assessments showed that the closer the hydrophilic and hydrophobic moieties in a system reached a relatively equalized level, the more desirable the FR performance of the coating system became. A balanced ratio of hydrophilicity-hydrophobicity in the system at around 10-15 wt % of each component had the best FR performance and was comparable to or better than commercial FR coatings.

9.
Macromol Rapid Commun ; 45(12): e2300665, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38444218

RESUMO

Glycidyl ethers are prepared from a series of furan-based diols and cured with a diamine to form thermosets. The furan diols demonstrate lower toxicity than bisphenol-A in a prior study. The diglycidyl ethers show improved thermal stability compared to the parent diols. Cured thermosets are prepared at elevated temperature using isophorone diamine (IPDA). Glass transition temperatures are in the range of 30-54 °C and depend on the structure of the furan diol. Coatings are prepared on steel substrates and show very high hardness, good adhesion, and a range of flexibility. Properties compare favorably with a control based on a bisphenol-A epoxy resin. The study demonstrates that epoxy resins based on furan diols, which have been shown to have lower toxicity than bisphenol-A, can form thermosets having properties comparable to a standard epoxy resin system; and thus, are viable as replacements for bisphenol-A epoxy resins.


Assuntos
Resinas Epóxi , Furanos , Resinas Epóxi/química , Furanos/química , Compostos Benzidrílicos/química , Temperatura , Estrutura Molecular , Compostos de Epóxi/química , Fenóis/química
10.
Phys Chem Chem Phys ; 26(5): 4541-4554, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38241021

RESUMO

The bottom-up prediction of thermodynamic and mechanical behaviors of polymeric materials based on molecular dynamics (MD) simulation is of critical importance in polymer physics. Although the atomistically informed coarse-grained (CG) model can access greater spatiotemporal scales and retain essential chemical specificity, the temperature-transferable CG model is still a big challenge and hinders widespread application of this technique. Herein, we use a silicone polymer, i.e., polydimethylsiloxane (PDMS), having an incredibly low chain rigidity as a model system, combined with an energy-renormalization (ER) approach, to systematically develop a temperature-transferable CG model. Specifically, by introducing temperature-dependent ER factors to renormalize the effective distance and cohesive energy parameters, the developed CG model faithfully preserved the dynamics, mechanical and conformational behaviors compared with the target all-atomistic (AA) model from glassy to melt regimes, which was further validated by experimental data. With the developed CG model featuring tremendously improved computational efficiency, we systematically explored the influences of cohesive interaction strength and temperature on the dynamical heterogeneity and mechanical response of polymers, where we observed consistent trends with other linear polymers with varying chain rigidity and monomeric structures. This study serves as an extension of our proposed ER approach of developing temperature transferable CG models with diverse segmental structures, highlighting the critical role of cohesive interaction strength on CG modeling of polymer dynamics and thermomechanical behaviors.

11.
Nature ; 557(7706): 530-533, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29795255

RESUMO

Plasmon polaritons are hybrid excitations of light and mobile electrons that can confine the energy of long-wavelength radiation at the nanoscale. Plasmon polaritons may enable many enigmatic quantum effects, including lasing 1 , topological protection2,3 and dipole-forbidden absorption 4 . A necessary condition for realizing such phenomena is a long plasmonic lifetime, which is notoriously difficult to achieve for highly confined modes 5 . Plasmon polaritons in graphene-hybrids of Dirac quasiparticles and infrared photons-provide a platform for exploring light-matter interaction at the nanoscale6,7. However, plasmonic dissipation in graphene is substantial 8 and its fundamental limits remain undetermined. Here we use nanometre-scale infrared imaging to investigate propagating plasmon polaritons in high-mobility encapsulated graphene at cryogenic temperatures. In this regime, the propagation of plasmon polaritons is primarily restricted by the dielectric losses of the encapsulated layers, with a minor contribution from electron-phonon interactions. At liquid-nitrogen temperatures, the intrinsic plasmonic propagation length can exceed 10 micrometres, or 50 plasmonic wavelengths, thus setting a record for highly confined and tunable polariton modes. Our nanoscale imaging results reveal the physics of plasmonic dissipation and will be instrumental in mitigating such losses in heterostructure engineering applications.

12.
Arthroscopy ; 40(3): 726-731.e6, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-37567487

RESUMO

PURPOSE: To analyze the quality and readability of information regarding shoulder stabilization surgery available using an online AI software (ChatGPT), using standardized scoring systems, as well as to report on the given answers by the AI. METHODS: An open AI model (ChatGPT) was used to answer 23 commonly asked questions from patients on shoulder stabilization surgery. These answers were evaluated for medical accuracy, quality, and readability using The JAMA Benchmark criteria, DISCERN score, Flesch-Kincaid Reading Ease Score (FRES) & Grade Level (FKGL). RESULTS: The JAMA Benchmark criteria score was 0, which is the lowest score, indicating no reliable resources cited. The DISCERN score was 60, which is considered a good score. The areas that open AI model did not achieve full marks were also related to the lack of available source material used to compile the answers, and finally some shortcomings with information not fully supported by the literature. The FRES was 26.2, and the FKGL was considered to be that of a college graduate. CONCLUSIONS: There was generally high quality in the answers given on questions relating to shoulder stabilization surgery, but there was a high reading level required to comprehend the information presented. However, it is unclear where the answers came from with no source material cited. It is important to note that the ChatGPT software repeatedly references the need to discuss these questions with an orthopaedic surgeon and the importance of shared discussion making, as well as compliance with surgeon treatment recommendations. CLINICAL RELEVANCE: As shoulder instability is an injury that predominantly affects younger individuals who may use the Internet for information, this study shows what information patients may be getting online.


Assuntos
Instabilidade Articular , Articulação do Ombro , Humanos , Inteligência Artificial , Ombro/cirurgia , Compreensão , Idioma
13.
Arthroscopy ; 40(2): 515-522, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37146663

RESUMO

PURPOSE: To systematically review the current evidence in the literature to compare return to play following arthroscopic Bankart repair versus open Latarjet procedure for the treatment of anterior shoulder instability. METHODS: A literature search was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Comparative studies reporting return to play following arthroscopic Bankart repair versus open Latarjet procedure were included. Return to play was compared, with all statistical analysis performed using Review Manager, Version 5.3. RESULTS: Nine studies with 1,242 patients (mean age: 15-30 years) were included. The rate of return to play was 61% to 94.1% among those undergoing arthroscopic Bankart repair and 72% to 96.8% in those undergoing an open Latarjet procedure. Two studies (Bessiere et al. and Zimmerman et al.) found a significant difference in favor of the Latarjet procedure (P < .05 for both, I2 = 37%). The rate of return to play at preinjury level was 9% to 83.8% among those undergoing arthroscopic Bankart repair and 19.4% to 80.6% in those undergoing an open Latarjet procedure, with no study finding a significant difference (P > .05 for all, I2 = 0%). The mean time of return to play was 5.4 to 7.3 months among those undergoing arthroscopic Bankart repair and 5.5 to 6.2 months in those undergoing an open Latarjet procedure, with no study finding a significant difference (P > .05 for all, I2 = 39%). CONCLUSIONS: Overall, the majority of studies showed no significant difference in rates of return to play or timing following arthroscopic Bankart repair or open Latarjet procedure. Furthermore, no study has found a significant difference in rate of return to play at pre-injury level, or rate of return to play among collision athletes. LEVEL OF EVIDENCE: Level III, systematic review of Level I-III studies.


Assuntos
Instabilidade Articular , Luxação do Ombro , Articulação do Ombro , Humanos , Adolescente , Adulto Jovem , Adulto , Luxação do Ombro/cirurgia , Articulação do Ombro/cirurgia , Volta ao Esporte , Instabilidade Articular/cirurgia , Estudos Retrospectivos , Recidiva , Artroscopia/métodos
14.
J Shoulder Elbow Surg ; 33(8): e443-e450, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38522776

RESUMO

BACKGROUND: The purpose of this study is to systematically review the evidence in the literature to ascertain the functional outcomes, recurrence rates, and subsequent revision rates following type V superior labrum anterior to posterior (SLAP) repair. METHODS: Two independent reviewers performed a literature search based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, utilizing the EMBASE, MEDLINE, and the Cochrane Library Databases. Studies were included if they had clinical outcomes on the patients undergoing type V SLAP repair. Statistical analysis was performed using SPSS (IBM, Armonk, NY, USA). A P value of <.05 was considered to be statistically significant. RESULTS: Our review found 13 studies, including 451 shoulders meeting our inclusion criteria. The majority of patients were males (89.3%), with an average age of 25.9 years (range 15-58) and a mean follow-up of 53.8 months. The Rowe score was the most utilized functional outcome score, with a weighted mean of 88.5. Additionally, the mean Constant score was 91.0, the mean American Shoulder and Elbow Surgeons score was 88.3, the mean subjective shoulder value score was 85.5%, and the mean visual analog scale pain score was 1.2. The overall rate of return to play was 84.8%, with 80.2% returning to the same level of play. The overall reoperation rate was 6.1%, with a recurrent dislocation rate of 8.2%. In the studies comparing type V SLAP and isolated Bankart repair, there were statistically insignificant differences in visual analog scale pain scores (mean difference; 0.15, 95% confidence interval, -0.13 to 0.44, I2 = 0%, P = .29) and recurrence rates (risk ratio; 1.38, 95% confidence interval, 0.88-2.15, I2 = 0%, P = .16). CONCLUSION: Arthroscopic repair of type V SLAP tears results in excellent functional outcomes, with high return to play rates in athletes. There are low rates of reoperations and recurrent dislocations. Additionally, in comparison to an isolated Bankart repair, SLAP repair does not increase recurrence rates or postoperative pain.


Assuntos
Articulação do Ombro , Humanos , Articulação do Ombro/cirurgia , Lesões do Ombro/cirurgia , Artroscopia/métodos , Reoperação/estatística & dados numéricos , Recidiva
15.
J Bacteriol ; 205(1): e0042422, 2023 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-36541811

RESUMO

The peptidoglycan of mycobacteria has two types of direct cross-links, classical 4-3 cross-links that occur between diaminopimelate (DAP) and alanine residues, and nonclassical 3-3 cross-links that occur between DAP residues on adjacent peptides. The 3-3 cross-links are synthesized by the concerted action of d,d-carboxypeptidases and l,d-transpeptidases (Ldts). Mycobacterial genomes encode several Ldt proteins that can be classified into six classes based upon sequence identity. As a group, the Ldt enzymes are resistant to most ß-lactam antibiotics but are susceptible to carbapenem antibiotics, with the exception of LdtC, a class 5 enzyme. In previous work, we showed that loss of LdtC has the greatest effect on the carbapenem susceptibility phenotype of Mycobacterium smegmatis (also known as Mycolicibacterium smegmatis) compared to other ldt deletion mutants. In this work, we show that a M. smegmatis mutant lacking the five ldt genes other than ldtC has a wild-type phenotype with the exception of increased susceptibility to rifampin. In contrast, a mutant lacking all six ldt genes has pleiotropic cell envelope defects, is temperature sensitive, and has increased susceptibility to a variety of antibiotics. These results indicate that LdtC is capable of functioning as the sole l,d-transpeptidase in M. smegmatis and suggest that it may represent a carbapenem-resistant pathway for peptidoglycan biosynthesis. IMPORTANCE Mycobacteria have several enzymes to catalyze nonclassical 3-3 linkages in the cell wall peptidoglycan. Understanding the biology of these cross-links is important for the development of antibiotic therapies to target peptidoglycan biosynthesis. Our work provides evidence that LdtC can function as the sole enzyme for 3-3 cross-link formation in M. smegmatis and suggests that LdtC may be part of a carbapenem-resistant l,d-transpeptidase pathway.


Assuntos
Mycobacterium , Peptidil Transferases , Peptidil Transferases/genética , Peptidil Transferases/química , Peptidil Transferases/metabolismo , Mycobacterium smegmatis/metabolismo , Peptidoglicano/metabolismo , Proteínas de Bactérias/metabolismo , Antibacterianos/farmacologia , Antibacterianos/metabolismo , Carbapenêmicos , Parede Celular/metabolismo
16.
Oncologist ; 28(1): 33-39, 2023 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-35962742

RESUMO

OBJECTIVE: The majority of tumor sequencing currently performed on cancer patients does not include a matched normal control, and in cases where germline testing is performed, it is usually run independently of tumor testing. The rates of concordance between variants identified via germline and tumor testing in this context are poorly understood. We compared tumor and germline sequencing results in patients with breast, ovarian, pancreatic, and prostate cancer who were found to harbor alterations in genes associated with homologous recombination deficiency (HRD) and increased hereditary cancer risk. We then evaluated the potential for a computational somatic-germline-zygosity (SGZ) modeling algorithm to predict germline status based on tumor-only comprehensive genomic profiling (CGP) results. METHODS: A retrospective chart review was performed using an academic cancer center's databases of somatic and germline sequencing tests, and concordance between tumor and germline results was assessed. SGZ modeling from tumor-only CGP was compared to germline results to assess this method's accuracy in determining germline mutation status. RESULTS: A total of 115 patients with 146 total alterations were identified. Concordance rates between somatic and germline alterations ranged from 0% to 85.7% depending on the gene and variant classification. After correcting for differences in variant classification and filtering practices, SGZ modeling was found to have 97.2% sensitivity and 90.3% specificity for the prediction of somatic versus germline origin. CONCLUSIONS: Mutations in HRD genes identified by tumor-only sequencing are frequently germline. Providers should be aware that technical differences related to assay design, variant filtering, and variant classification can contribute to discordance between tumor-only and germline sequencing test results. In addition, SGZ modeling had high predictive power to distinguish between mutations of somatic and germline origin without the need for a matched normal control, and could potentially be considered to inform clinical decision-making.


Assuntos
Neoplasias , Masculino , Humanos , Estudos Retrospectivos , Atenção Terciária à Saúde , Neoplasias/patologia , Genômica , Mutação , Mutação em Linhagem Germinativa
17.
Proc Biol Sci ; 290(2011): 20231914, 2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-37964520

RESUMO

Convergent evolution is widely regarded as a signature of adaptation. However, testing the adaptive consequences of convergent phenotypes is challenging, making it difficult to exclude non-adaptive explanations for convergence. Here, we combined feather reflectance spectra and phenotypic trajectory analyses with visual and thermoregulatory modelling to test the adaptive significance of dark plumage in songbirds of the California Channel Islands. By evolving dark dorsal plumage, island birds are generally less conspicuous to visual-hunting raptors in the island environment than mainland birds. Dark dorsal plumage also reduces the energetic demands associated with maintaining homeothermy in the cool island climate. We also found an unexpected pattern of convergence, wherein the most divergent island populations evolved greater reflectance of near-infrared radiation. However, our heat flux models indicate that elevated near-infrared reflectance is not adaptive. Analysis of feather microstructure suggests that mainland-island differences are related to coloration of feather barbs and barbules rather than their structure. Our results indicate that adaptive and non-adaptive mechanisms interact to drive plumage evolution in this system. This study sheds light on the mechanisms driving the association between dark colour and wet, cold environments across the tree of life, especially in island birds.


Assuntos
Aves Canoras , Animais , Aves Canoras/genética , Plumas , Fenótipo , Regulação da Temperatura Corporal , Ilhas Anglo-Normandas , Pigmentação/genética , Ilhas
18.
J Evol Biol ; 36(5): 829-841, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37129372

RESUMO

Sexual dimorphism (SD) is a common feature of animals, and selection for sexually dimorphic traits may affect both functional morphological traits and organismal performance. Trait evolution through natural selection can also vary across environments. However, whether the evolution of organismal performance is distinct between the sexes is rarely tested in a phylogenetic comparative context. Anurans commonly exhibit sexual size dimorphism, which may affect jumping performance given the effects of body size on locomotion. They also live in a wide variety of microhabitats. Yet the relationships among dimorphism, performance, and ecology remain underexamined in anurans. Here, we explore relationships between microhabitat use, body size, and jumping performance in males and females to determine the drivers of dimorphic patterns in jumping performance. Using methods for predicting jumping performance through anatomical measurements, we describe how fecundity selection and natural selection associated with body size and microhabitat have likely shaped female jumping performance. We found that the magnitude of sexual size dimorphism (where females are about 14% larger than males) was much lower than dimorphism in muscle volume, where females had 42% more muscle than males (after accounting for body size). Despite these sometimes-large averages, phylogenetic t-tests failed to show the statistical significance of SD for any variable, indicating sexually dimorphic species tend to be closely related. While SD of jumping performance did not vary among microhabitats, we found female jumping velocity and energy differed across microhabitats. Overall, our findings indicate that differences in sex-specific reproductive roles, size, jumping-related morphology, and performance are all important determinants in how selection has led to the incredible ecophenotypic diversity of anurans.


Assuntos
Evolução Biológica , Caracteres Sexuais , Masculino , Animais , Feminino , Filogenia , Ecologia , Anuros/anatomia & histologia
19.
J Chem Phys ; 159(18)2023 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-37955325

RESUMO

Many modern anti-icing and anti-fouling coatings rely on soft, low surface energy elastomeric materials such as polydimethylsiloxane for their functionality. While the low surface energy is desirable for reducing adhesion, very little work considers the larger contribution to adhesive failure caused by the viscoelastic nature of elastomers. Here we examine several different siloxane elastomers using a JKR adhesion test, which was operated over a range of different speeds and temperatures. Additionally, we characterize the dynamic mechanical modulus over a large range of frequencies for each material. We note that surface energies of the materials are all similar, but variation in adhesion strength is clear in the data. The variation at low speeds is related to elastomer architecture but the speed dependence itself is independent of architecture. Qualitative correlations are noted between the JKR adhesion measurements and the dynamic moduli. Finally, an attempt is made to directly compare moduli and adhesion through the recent Persson-Brener model. Approximations of the model are shown to be inaccurate. The full model is found to be accurate at low speeds, although it fails to precisely capture higher speed behaviour.

20.
Eur Spine J ; 32(8): 2670-2678, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36867253

RESUMO

PURPOSE: While anterior cervical discectomy and fusion as well as cervical disk arthroplasty are gold standard treatments for the surgical treatment of cervical radiculopathy, posterior endoscopic cervical foraminotomy (PECF) as a substitute procedure is gaining popularity. To date, studies investigating the number of surgeries needed to achieve proficiency in this procedure are lacking. The purpose of the study is to examine the learning curve for PECF. METHODS: The learning curve in operative time for two fellowship-trained spine surgeons at independent institutions was retrospectively assessed for 90 uniportal PECF procedures (PBD: n = 26, CPH: n = 64) performed from 2015 to 2022. Operative time was assessed across consecutive cases using a nonparametric monotone regression, and a plateau in operative time was used as a proxy to define the learning curve. Secondary outcomes assessing achievement of endoscopic prowess before and after the initial learning curve included number of fluoroscopy images, visual analog scale (VAS) for neck and arm, Neck Disability Index (NDI), and the need for reoperation. RESULTS: There was no significant difference in operative time between surgeons (p = 0.420). The start of a plateau for Surgeon 1 occurred at 9 cases and 111.6 min. The start of a plateau for Surgeon 2 occurred at 29 cases and 114.7 min. A second plateau for Surgeon 2 occurred at 49 cases and 91.8 min. Fluoroscopy use did not significantly change before and after surmounting the learning curve. The majority of patients achieved minimally clinically important differences in VAS and NDI after PECF, but postoperative VAS and NDI did not significantly differ before and after achieving the learning curve. There were no significant differences in revisions or postoperative cervical injections before and after reaching a steady state in the learning curve. CONCLUSION: PECF is an advanced endoscopic technique with an initial improvement in operative time that occurred after as few as 8 cases to as many as 28 cases in this series. A second learning curve may occur with additional cases. Patient-reported outcomes improve following surgery, and these outcomes are independent of the surgeon's position on the learning curve. Fluoroscopy use does not change significantly along the learning curve. PECF is a safe and effective technique that current and future spine surgeons should consider as part of their armamentarium.


Assuntos
Endoscopia , Foraminotomia , Curva de Aprendizado , Endoscopia/educação , Endoscopia/métodos , Foraminotomia/educação , Foraminotomia/métodos , Vértebras Cervicais/cirurgia
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