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Transendothelial migration of neutrophils in postcapillary venules is a key event in the inflammatory response against pathogens and tissue damage. The precise regulation of this process is incompletely understood. We report that perivascular macrophages are critical for neutrophil migration into skin infected with the pathogen Staphylococcus aureus. Using multiphoton intravital microscopy we showed that neutrophils extravasate from inflamed dermal venules in close proximity to perivascular macrophages, which are a major source of neutrophil chemoattractants. The virulence factor α-hemolysin produced by S. aureus lyses perivascular macrophages, which leads to decreased neutrophil transmigration. Our data illustrate a previously unrecognized role for perivascular macrophages in neutrophil recruitment to inflamed skin and indicate that S. aureus uses hemolysin-dependent killing of these cells as an immune evasion strategy.
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Macrófagos/imunologia , Neutrófilos/imunologia , Pele/imunologia , Infecções Estafilocócicas/imunologia , Animais , Toxinas Bacterianas/imunologia , Toxinas Bacterianas/metabolismo , Vasos Sanguíneos/imunologia , Vasos Sanguíneos/metabolismo , Citometria de Fluxo , Expressão Gênica/imunologia , Proteínas Hemolisinas/imunologia , Proteínas Hemolisinas/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Microscopia de Fluorescência por Excitação Multifotônica , Infiltração de Neutrófilos/imunologia , Neutrófilos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/irrigação sanguínea , Pele/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Staphylococcus aureus/imunologia , Staphylococcus aureus/metabolismo , Imagem com Lapso de Tempo/métodos , Migração Transendotelial e Transepitelial/imunologia , Vênulas/imunologia , Vênulas/metabolismoRESUMO
The liver is positioned at the interface between two routes traversed by pathogens in disseminating infection. Whereas blood-borne pathogens are efficiently cleared in hepatic sinusoids by Kupffer cells (KCs), it is unknown how the liver prevents dissemination of peritoneal pathogens accessing its outer membrane. We report here that the hepatic capsule harbors a contiguous cellular network of liver-resident macrophages phenotypically distinct from KCs. These liver capsular macrophages (LCMs) were replenished in the steady state from blood monocytes, unlike KCs that are embryonically derived and self-renewing. LCM numbers increased after weaning in a microbiota-dependent process. LCMs sensed peritoneal bacteria and promoted neutrophil recruitment to the capsule, and their specific ablation resulted in decreased neutrophil recruitment and increased intrahepatic bacterial burden. Thus, the liver contains two separate and non-overlapping niches occupied by distinct resident macrophage populations mediating immunosurveillance at these two pathogen entry points to the liver.
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Células de Kupffer/fisiologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Fígado/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Peritônio/microbiologia , Animais , Comunicação Celular , Autorrenovação Celular , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Células de Kupffer/microbiologia , Fígado/microbiologia , Fígado/patologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Infiltração de Neutrófilos , Peritônio/patologiaRESUMO
Type 2 immunity is critical for defense against cutaneous infections but also underlies the development of allergic skin diseases. We report the identification in normal mouse dermis of an abundant, phenotypically unique group 2 innate lymphoid cell (ILC2) subset that depended on interleukin 7 (IL-7) and constitutively produced IL-13. Intravital multiphoton microscopy showed that dermal ILC2 cells specifically interacted with mast cells, whose function was suppressed by IL-13. Treatment of mice deficient in recombination-activating gene 1 (Rag1(-/-)) with IL-2 resulted in the population expansion of activated, IL-5-producing dermal ILC2 cells, which led to spontaneous dermatitis characterized by eosinophil infiltrates and activated mast cells. Our data show that ILC2 cells have both pro- and anti-inflammatory properties and identify a previously unknown interactive pathway between two innate populations of cells of the immune system linked to type 2 immunity and allergic diseases.
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Dermatite/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Pele/imunologia , Animais , Comunicação Celular/imunologia , Células Cultivadas , Dermatite/genética , Dermatite/metabolismo , Derme/citologia , Derme/imunologia , Derme/metabolismo , Eosinófilos/imunologia , Eosinófilos/metabolismo , Citometria de Fluxo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Proteínas de Homeodomínio/metabolismo , Imunidade Inata/genética , Interleucina-13/imunologia , Interleucina-13/metabolismo , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-2/imunologia , Interleucina-2/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Mastócitos/imunologia , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia de Fluorescência por Excitação Multifotônica , Pele/metabolismo , Gravação de VideoteipeRESUMO
Small molecules containing the N-nitroso group, such as the bacterial natural product streptozotocin, are prominent carcinogens1,2 and important cancer chemotherapeutics3,4. Despite the considerable importance of this functional group to human health, enzymes dedicated to the assembly of the N-nitroso unit have not been identified. Here we show that SznF, a metalloenzyme from the biosynthesis of streptozotocin, catalyses an oxidative rearrangement of the guanidine group of Nω-methyl-L-arginine to generate an N-nitrosourea product. Structural characterization and mutagenesis of SznF reveal two separate active sites that promote distinct steps in this transformation using different iron-containing metallocofactors. This biosynthetic reaction, which has little precedent in enzymology or organic synthesis, expands the catalytic capabilities of non-haem-iron-dependent enzymes to include N-N bond formation. We find that biosynthetic gene clusters that encode SznF homologues are widely distributed among bacteria-including environmental organisms, plant symbionts and human pathogens-which suggests an unexpectedly diverse and uncharacterized microbial reservoir of bioactive N-nitroso metabolites.
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Metaloproteínas/metabolismo , Estreptozocina/biossíntese , Estreptozocina/química , Arginina/análogos & derivados , Domínio Catalítico/genética , Coenzimas/metabolismo , Cristalografia por Raios X , Guanidina/metabolismo , Ferro/metabolismo , Metaloproteínas/química , Metaloproteínas/genética , Modelos Moleculares , Família Multigênica , Compostos de Nitrosoureia/metabolismo , Streptomyces/enzimologia , Streptomyces/genéticaRESUMO
Sunlight penetrates the ice surfaces of glaciers and ice sheets, forming a water-bearing porous ice matrix known as the weathering crust. This crust is home to a significant microbial community. Despite the potential implications of microbial processes in the weathering crust for glacial melting, biogeochemical cycles, and downstream ecosystems, there have been few explorations of its microbial communities. In our study, we used 16S rRNA gene sequencing and shotgun metagenomics of a Svalbard glacier surface catchment to characterise the microbial communities within the weathering crust, their origins and destinies, and the functional potential of the weathering crust metagenome. Our findings reveal that the bacterial community in the weathering crust is distinct from those in upstream and downstream habitats. However, it comprises two separate micro-habitats, each with different taxa and functional categories. The interstitial porewater is dominated by Polaromonas, influenced by the transfer of snowmelt, and exported via meltwater channels. In contrast, the ice matrix is dominated by Hymenobacter, and its metagenome exhibits a diverse range of functional adaptations. Given that the global weathering crust area and the subsequent release of microbes from it are strongly responsive to climate projections for the rest of the century, our results underscore the pressing need to integrate the microbiome of the weathering crust with other communities and processes in glacial ecosystems.
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Camada de Gelo , Microbiota , Camada de Gelo/microbiologia , RNA Ribossômico 16S/genética , Microbiota/genética , Bactérias/genética , Regiões ÁrticasRESUMO
Melanocytes are dendritic cells localized in skin, eyes, hair follicles, ears, heart and central nervous system. They are characterized by the presence of melanosomes enriched in melanin which are responsible for skin, eye and hair pigmentation. They also have different functions in photoprotection, immunity and sound perception. Melanocyte dysfunction can cause pigmentary disorders, hearing and vision impairments or increased cancer susceptibility. This review focuses on the role of melanocytes in homeostasis and disease, before discussing their potential in regenerative medicine applications, such as for disease modeling, drug testing or therapy development using stem cell technologies, tissue engineering and extracellular vesicles.
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Melanócitos , Medicina Regenerativa , Pigmentação/fisiologia , Melaninas/fisiologia , Folículo Piloso/fisiologiaRESUMO
Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the Bcell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax. To test this hypothesis, we conducted a pre-clinical investigation of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition to minimize platelet toxicity. This study demonstrated that LP-118 induces efficient BAK activation, cytochrome C release, and apoptosis in both venetoclax naïve and resistant CLL cells. Significantly, LP-118 is effective in cell lines expressing the BCL2 G101V mutation and in cells expressing BCLXL but lacking BCL2 dependence. Using an immunocompetent mouse model, Eµ-TCL1, LP-118 demonstrates low platelet toxicity, which hampered earlier BCLXL inhibitors. Finally, LP-118 in the RS4;11 and OSU-CLL xenograft models results in decreases in tumor burden and survival advantage, respectively. These results provide a mechanistic rationale for the evaluation of LP-118 for the treatment of venetoclax responsive and relapsed CLL.
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INTRODUCTION: Research on athletic footwear familiarisation within an older population is sparse. This is problematic because unfamiliar footwear may act as a new perturbation and modify older adults' walking gait and stability. In addition, while athletic footwear has been suggested to enhance older adults' comfort and support during activities of daily living, the necessary period for familiarisation with athletic footwear is unknown. Therefore, this study aimed to identify the number of steps required for older adults to be familiarised with athletic footwear of different midsole thicknesses. METHODS: Twenty-six healthy and physically active community-dwelling older adults, 21 females (71.1 ± 4.5 years; 164.5 ± 5.3 cm; 68.4 ± 11.4 kg) and five males (70.6 ± 2.3 years; 175.2 ± 7.8 cm; 72.8 ± 9.7 kg), completed a walking-based protocol. Participants walked two trials of 200 steps at their habitual speed on a 10-m track of an optical measurement system in three footwear conditions: (1) New Balance® REVlite 890v6 (thick midsole); (2) New Balance® REVlite 1400v5 (moderate midsole); and (3) New Balance® Minimus 20v7 (thin midsole). Gait speed (m.s-1) and walking time (min) were analysed for each participant over the 400 steps. Number of required familiarisation steps were established over three analysis phases, consisting of steady-state gait assessment, averaging and analysis of blocks of 40 steps, and sequentially comparing these steps with a predetermined threshold. Footwear familiarisation was assumed when the mean gait speed fell within an acceptable level (±2 SD from 320 to 360 step values) and subsequently maintained. RESULTS: Most participants were familiarised with all three footwear conditions (thick n = 18; moderate and thin n = 20) after walking 80 steps. For all participants, the moderate midsole had the shortest familiarisation period (160 steps). The highest number of familiarisation steps was found in the thick (320 steps) and thin midsoles (240 steps) for some participants. CONCLUSION: A minimum of 320 familiarisation steps is recommended to account for both individual differences and midsole thicknesses. Implementing this walking-based footwear familiarisation protocol would improve validity of future studies, ensuring they analyse footwear effects rather than familiarisation with the footwear.
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Enzymes in multistep metabolic pathways utilize an array of regulatory mechanisms to maintain a delicate homeostasis [K. Magnuson, S. Jackowski, C. O. Rock, J. E. Cronan, Jr, Microbiol. Rev. 57, 522-542 (1993)]. Carrier proteins in particular play an essential role in shuttling substrates between appropriate enzymes in metabolic pathways. Although hypothesized [E. Ploskon et al., Chem. Biol. 17, 776-785 (2010)], allosteric regulation of substrate delivery has never before been demonstrated for any acyl carrier protein (ACP)-dependent pathway. Studying these mechanisms has remained challenging due to the transient and dynamic nature of protein-protein interactions, the vast diversity of substrates, and substrate instability [K. Finzel, D. J. Lee, M. D. Burkart, ChemBioChem 16, 528-547 (2015)]. Here we demonstrate a unique communication mechanism between the ACP and partner enzymes using solution NMR spectroscopy and molecular dynamics to elucidate allostery that is dependent on fatty acid chain length. We demonstrate that partner enzymes can allosterically distinguish between chain lengths via protein-protein interactions as structural features of substrate sequestration are translated from within the ACP four-helical bundle to the protein surface, without the need for stochastic chain flipping. These results illuminate details of cargo communication by the ACP that can serve as a foundation for engineering carrier protein-dependent pathways for specific, desired products.
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Proteína de Transporte de Acila/metabolismo , Proteína de Transporte de Acila/ultraestrutura , Regulação Alostérica/fisiologia , Proteína de Transporte de Acila/fisiologia , Sequência de Aminoácidos , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas/fisiologia , Mapas de Interação de Proteínas/fisiologiaRESUMO
Synanthropic silverfish are the best-known and most widely distributed insects of the order Zygentoma. However, there is a great gap in the knowledge and confusion about the geographic distribution and the diagnostic characteristics that allow their identification. In this work, we provide an exhaustive and deep analysis of the most common 9 synanthropic silverfish of the world, combining previously published and newly derived morphological and molecular data. Updated descriptions of Ctenolepisma calvum (Ritter, 1910) and Ctenolepisma (Sceletolepisma) villosum (Fabricius, 1775) are included, and morphological remarks, illustrations, and photographs of the remaining synanthropic species are provided to clarify their diagnosis and differentiation among them and from other free-living species. In addition, Ctenolepisma targionii (Grassi and Rovelli, 1889) is synonymized with C. villosum. A molecular phylogeny is presented based on the COI sequences of all the synanthropic species deposited in BOLD and GenBank, with 15 new sequences provided by this study. This has allowed us to detect and correct a series of identification errors based on the lack of morphological knowledge of several species. Moreover, 2 different lineages of Ctenolepisma longicaudatumEscherich, 1905 have also been detected. To help future studies, we also provide a taxonomic interpretation guide for the most important diagnostic characters of the order Zygentoma, as well as an identification key for all the Synanthropic studied species. Finally, an approximation of the global distribution of synanthropic silverfish is discussed. Several new records indicate that the expansion of these species, generally associated with the transport of goods and people, is still far from over.
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Insetos , Filogenia , Animais , Insetos/genética , Insetos/anatomia & histologia , Insetos/classificação , Feminino , Masculino , Distribuição AnimalRESUMO
We study regularity properties of frequency measures arising from random substitutions, which are a generalisation of (deterministic) substitutions where the substituted image of each letter is chosen independently from a fixed finite set. In particular, for a natural class of such measures, we derive a closed-form analytic formula for the Lq-spectrum and prove that the multifractal formalism holds. This provides an interesting new class of measures satisfying the multifractal formalism. More generally, we establish results concerning the Lq-spectrum of a broad class of frequency measures. We introduce a new notion called the inflation word Lq-spectrum of a random substitution and show that this coincides with the Lq-spectrum of the corresponding frequency measure for all q≥0. As an application, we obtain closed-form formulas under separation conditions and recover known results for topological and measure theoretic entropy.
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BACKGROUND: Pain-free bite force (PFBF) is a promising measure to evaluate bite function in temporomandibular disorders (TMDs), yet the reliability of the measure is unknown. OBJECTIVES: Establish the (1) within-session test-retest reliability of PFBF in a healthy population for a single and mean of three trials in supported and unsupported sitting; (2) standard error of measurement (SEM) and minimal detectable change (MDC). METHODS: Thirty healthy participants (n = 15 female, mean [SD] age = 34.4 [11.0] years) completed two sessions (30-60 min apart) comprising three PFBF trials on each side, in both supported and unsupported sitting, to provide data for 60 (30 participants × two sides) test-retest assessments. Test-retest reliability for the first trial and mean of three trials in each position were determined using intraclass correlation coefficients (ICCs), before calculating the corresponding SEM and MDC for males (M) and females (F) respectively. RESULTS: Within-session reliability was considered excellent for a single trial in supported sitting (ICC = 0.85; SEM M/F = 99/84 N; MDC M/F = 275/232 N) and unsupported sitting (ICC = 0.91; SEM M/F = 72/59 N, MDC M/F = 200/163 N), and for a mean of three trials in supported sitting (ICC = 0.89; SEM M/F = 66/79 N, MDC M/F = 182/220 N) and unsupported sitting (ICC = 0.92; SEM M/F = 64/59 N, MDC M/F = 177/164 N). CONCLUSION: Single and a mean of three trials in supported and unsupported sitting appear reliable methods to measure PFBF in a healthy population. Testing PFBF using a mean of three trials in unsupported sitting appears superior over other methods though due to higher test-retest reliability, and lower SEM and MDC. Future studies should examine the reliability of PFBF in TMD populations.
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Força de Mordida , Voluntários Saudáveis , Postura Sentada , Humanos , Feminino , Reprodutibilidade dos Testes , Masculino , Adulto , Transtornos da Articulação Temporomandibular/fisiopatologia , Adulto Jovem , Pessoa de Meia-IdadeRESUMO
Mycobacterium bovis (M. bovis) is a causative agent of bovine tuberculosis, a significant source of morbidity and mortality in the global cattle industry. The Randomised Badger Culling Trial was a field experiment carried out between 1998 and 2005 in the South West of England. As part of this trial, M. bovis isolates were collected from contemporaneous and overlapping populations of badgers and cattle within ten defined trial areas. We combined whole genome sequences from 1,442 isolates with location and cattle movement data, identifying transmission clusters and inferred rates and routes of transmission of M. bovis. Most trial areas contained a single transmission cluster that had been established shortly before sampling, often contemporaneous with the expansion of bovine tuberculosis in the 1980s. The estimated rate of transmission from badger to cattle was approximately two times higher than from cattle to badger, and the rate of within-species transmission considerably exceeded these for both species. We identified long distance transmission events linked to cattle movement, recurrence of herd breakdown by infection within the same transmission clusters and superspreader events driven by cattle but not badgers. Overall, our data suggests that the transmission clusters in different parts of South West England that are still evident today were established by long-distance seeding events involving cattle movement, not by recrudescence from a long-established wildlife reservoir. Clusters are maintained primarily by within-species transmission, with less frequent spill-over both from badger to cattle and cattle to badger.
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Reservatórios de Doenças/microbiologia , Mustelidae/microbiologia , Mycobacterium bovis/isolamento & purificação , Tuberculose Bovina/transmissão , Animais , Bovinos , Ensaios Clínicos Veterinários como Assunto , Inglaterra/epidemiologia , Distribuição Aleatória , Tuberculose Bovina/epidemiologia , Tuberculose Bovina/microbiologiaRESUMO
Quantum impurity models with frustrated Kondo interactions can support quantum critical points with fractionalized excitations. Recent experiments [W. Pouse et al., Nat. Phys. (2023)NPAHAX1745-247310.1038/s41567-022-01905-4] on a circuit containing two coupled metal-semiconductor islands exhibit transport signatures of such a critical point. Here, we show using bosonization that the double charge-Kondo model describing the device can be mapped in the Toulouse limit to a sine-Gordon model. Its Bethe-ansatz solution shows that a Z_{3} parafermion emerges at the critical point, characterized by a fractional 1/2ln(3) residual entropy, and scattering fractional charges e/3. We also present full numerical renormalization group calculations for the model and show that the predicted behavior of conductance is consistent with experimental results.
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External biometrics such as thumbprint and facial recognition have become standard tools for securing our digital devices and protecting our data. These systems, however, are potentially prone to copying and cybercrime access. Researchers have therefore explored internal biometrics, such as the electrical patterns within an electrocardiogram (ECG). The heart's electrical signals carry sufficient distinctiveness to allow the ECG to be used as an internal biometric for user authentication and identification. Using the ECG in this way has many potential advantages and limitations. This article reviews the history of ECG biometrics and explores some of the technical and security considerations. It also explores current and future uses of the ECG as an internal biometric.
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Identificação Biométrica , Humanos , Frequência Cardíaca , Eletrocardiografia , BiometriaRESUMO
The influence of cultural background on the soundscape experience in public spaces has been widely acknowledged. However, most studies have not used standardized protocols for soundscape perception data collection, nor have they gathered large datasets across different regions of the world to investigate possible cultural differences. This study explored the relationships between soundscape descriptors, perceived dominance of sound sources, and overall soundscape qualities and whether these relationships differ across world regions. A database of over 2000 soundscape surveys was collected in situ in outdoor public spaces in Europe and China. Results highlighted differences in how European and Chinese participants perceived the pleasantness and dominance of different sound sources. Specifically, the positive correlation between perceived pleasantness and natural sounds was stronger for European participants. For Chinese participants, vibrant soundscapes were positively correlated with perceived dominance of natural sounds, whereas in Europe, they were associated more with human-generated sounds. Perceived loudness had a greater effect on the appropriateness dimension for the Chinese sample than that for the European sample. This study provides a deeper understanding of how the geographical/cultural context can influence soundscape perception in public spaces and suggests that such country-specific factors should be considered when designing urban soundscapes.
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Meio Ambiente , Som , Humanos , China , Bases de Dados Factuais , EmoçõesRESUMO
Soundscape studies typically attempt to capture the perception and understanding of sonic environments by surveying users. However, for long-term monitoring or assessing interventions, sound-signal-based approaches are required. To this end, most previous research focused on psycho-acoustic quantities or automatic sound recognition. Few attempts were made to include appraisal (e.g., in circumplex frameworks). This paper proposes an artificial intelligence (AI)-based dual-branch convolutional neural network with cross-attention-based fusion (DCNN-CaF) to analyze automatic soundscape characterization, including sound recognition and appraisal. Using the DeLTA dataset containing human-annotated sound source labels and perceived annoyance, the DCNN-CaF is proposed to perform sound source classification (SSC) and human-perceived annoyance rating prediction (ARP). Experimental findings indicate that (1) the proposed DCNN-CaF using loudness and Mel features outperforms the DCNN-CaF using only one of them. (2) The proposed DCNN-CaF with cross-attention fusion outperforms other typical AI-based models and soundscape-related traditional machine learning methods on the SSC and ARP tasks. (3) Correlation analysis reveals that the relationship between sound sources and annoyance is similar for humans and the proposed AI-based DCNN-CaF model. (4) Generalization tests show that the proposed model's ARP in the presence of model-unknown sound sources is consistent with expert expectations and can explain previous findings from the literature on soundscape augmentation.
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CONTEXT: Intervention studies for chronic ankle instability (CAI) often focus on improving physical impairments of the ankle complex. However, using an impairments-focused approach may miss psychological factors that may mediate function and recovery. Patient-reported outcome (PRO) measures can be used to assess several dimensions of the health-related quality of life (HRQoL) and deliver enhanced patient-centered care. Therefore, the purpose of this investigation was to evaluate group-level improvements in HRQoL and treatment response rates following various interventions in patients with CAI. DESIGN: Cross-sectional. METHODS: Data from 7 previous studies were pooled by the chronic ankle instability outcomes network for participant-level analysis, resulting in 136 patients with CAI. Several interventions were assessed including balance training, gait biofeedback, joint mobilizations, stretching, and strengthening, with treatment volume ranging from 1 to 4 weeks. Outcome measures were PROs that assessed ankle-specific function (Foot and Ankle Ability Measure), injury-related fear (Tampa Scale of Kinesiophobia and Fear Avoidance Belief Questionnaire), and global well-being (Disablement in the Physically Active); the PROs assessed varied between studies. Preintervention to postintervention changes were evaluated using separate Wilcoxon signed-rank tests and effect sizes, and a responder analysis was conducted for each PRO. RESULTS: Significant, moderate to large improvements were observed in PROs that assessed ankle-specific function, injury-related fear, and global well-being following intervention (P < .001). Responder rates ranged from 39.0% to 53.3%, 12.8% to 51.4%, and 37.8% for ankle specific function, injury-related fear, and global well-being, respectively. CONCLUSIONS: Various interventions can lead to positive improvements in HRQoL in patients with CAI. Treatment response rates at improving HRQoL are similar to response rates at improving impairments such as balance, further reinforcing the need for individualized treatment approaches when treating a patient with CAI.
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Tornozelo , Instabilidade Articular , Humanos , Qualidade de Vida , Estudos Transversais , Articulação do Tornozelo , Medidas de Resultados Relatados pelo Paciente , Doença Crônica , Equilíbrio Postural/fisiologiaRESUMO
STUDY QUESTION: Can the accuracy of timing of luteal phase endometrial biopsies based on urinary ovulation testing be improved by measuring the expression of a small number of genes and a continuous, non-categorical modelling approach? SUMMARY ANSWER: Measuring the expression levels of six genes (IL2RB, IGFBP1, CXCL14, DPP4, GPX3 and SLC15A2) is sufficient to obtain substantially more accurate timing estimates and to assess the reliability of timing estimates for each sample. WHAT IS KNOWN ALREADY: Commercially available endometrial timing approaches based on gene expression require large gene sets and use a categorical approach that classifies samples as pre-receptive, receptive or post-receptive. STUDY DESIGN, SIZE, DURATION: Gene expression was measured by RTq-PCR in different sample sets, comprising a total of 664 endometrial biopsies obtained 4-12 days after a self-reported positive home ovulation test. A further 36 endometrial samples were profiled by RTq-PCR as well as RNA-sequencing. PARTICIPANTS/MATERIALS, SETTING, METHODS: A computational procedure, named 'EndoTime', was established that models the temporal profile of each gene and estimates the timing of each sample. Iterating these steps, temporal profiles are gradually refined as sample timings are being updated, and confidence in timing estimates is increased. After convergence, the method reports updated timing estimates for each sample while preserving the overall distribution of time points. MAIN RESULTS AND THE ROLE OF CHANCE: The Wilcoxon rank-sum test was used to confirm that ordering samples by EndoTime estimates yields sharper temporal expression profiles for held-out genes (not used when determining sample timings) than ordering the same expression values by patient-reported times (GPX3: P < 0.005; CXCL14: P < 2.7e-6; DPP4: P < 3.7e-13). Pearson correlation between EndoTime estimates for the same sample set but based on RTq-PCR or RNA-sequencing data showed a high degree of congruency between the two (P = 8.6e-10, R2 = 0.687). Estimated timings did not differ significantly between control subjects and patients with recurrent pregnancy loss or recurrent implantation failure (P > 0.05). LARGE SCALE DATA: The RTq-PCR data files are available via the GitHub repository for the EndoTime software at https://github.com/AE-Mitchell/EndoTime, as is the code used for pre-processing of RTq-PCR data. The RNA-sequencing data are available on GEO (accession GSE180485). LIMITATIONS, REASONS FOR CAUTION: Timing estimates are informed by glandular gene expression and will only represent the temporal state of other endometrial cell types if in synchrony with the epithelium. Methods that estimate the day of ovulation are still required as these data are essential inputs in our method. Our approach, in its current iteration, performs batch correction such that larger sample batches impart greater accuracy to timing estimations. In theory, our method requires endometrial samples obtained at different days in the luteal phase. In practice, however, this is not a concern as timings based on urinary ovulation testing are associated with a sufficient level of noise to ensure that a variety of time points will be sampled. WIDER IMPLICATIONS OF THE FINDINGS: Our method is the first to assay the temporal state of luteal-phase endometrial samples on a continuous domain. It is freely available with fully shared data and open-source software. EndoTime enables accurate temporal profiling of any gene in luteal endometrial samples for a wide range of research applications and, potentially, clinical use. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by a Wellcome Trust Investigator Award (Grant/Award Number: 212233/Z/18/Z) and the Tommy's National Miscarriage Research Centre. None of the authors have any competing interests. J.L. was funded by the Biotechnology and Biological Sciences Research Council (UK) through the Midlands Integrative Biology Training Partnership (MIBTP, BB/M01116X/1).
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Aborto Habitual , Endométrio , Aborto Habitual/metabolismo , Endométrio/metabolismo , Feminino , Humanos , Fase Luteal/metabolismo , Gravidez , Reprodutibilidade dos Testes , Análise de Sequência de RNARESUMO
Fractional entropy is a signature of nonlocal degrees of freedom, such as Majorana zero modes or more exotic non-Abelian anyons. Although direct experimental measurements remain challenging, Maxwell relations provide an indirect route to the entropy through charge measurements. Here we consider multichannel charge-Kondo systems, which are predicted to host exotic quasiparticles due to a frustration of Kondo screening at low temperatures. In the absence of experimental data for the charge occupation, we derive relations connecting the latter to the conductance, for which experimental results have recently been obtained. Our analysis indicates that Majorana and Fibonacci anyon quasiparticles are well developed in existing two- and three-channel charge-Kondo devices, and that their characteristic k_{B}logsqrt[2] and k_{B}log[(1+sqrt[5])/2] entropies are experimentally measurable.