RESUMO
Protective Ebola virus (EBOV) antibodies have neutralizing activity and induction of antibody constant domain (Fc)-mediated innate immune effector functions. Efforts to enhance Fc effector functionality often focus on maximizing antibody-dependent cellular cytotoxicity, yet distinct combinations of functions could be critical for antibody-mediated protection. As neutralizing antibodies have been cloned from EBOV disease survivors, we sought to identify survivor Fc effector profiles to help guide Fc optimization strategies. Survivors developed a range of functional antibody responses, and we therefore applied a rapid, high-throughput Fc engineering platform to define the most protective profiles. We generated a library of Fc variants with identical antigen-binding fragments (Fabs) from an EBOV neutralizing antibody. Fc variants with antibody-mediated complement deposition and moderate natural killer (NK) cell activity demonstrated complete protective activity in a stringent in vivo mouse model. Our findings highlight the importance of specific effector functions in antibody-mediated protection, and the experimental platform presents a generalizable resource for identifying correlates of immunity to guide therapeutic antibody design.
Assuntos
Ebolavirus/imunologia , Doença pelo Vírus Ebola/imunologia , Fragmentos Fab das Imunoglobulinas/imunologia , Fragmentos Fc das Imunoglobulinas/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Feminino , Células HEK293 , Doença pelo Vírus Ebola/virologia , Humanos , Imunoglobulina G/imunologia , Camundongos Endogâmicos BALB C , Receptores Fc/imunologiaRESUMO
Chirality is a geometrical property described by continuous mathematical functions1-5. However, in chemical disciplines, chirality is often treated as a binary left or right characteristic of molecules rather than a continuity of chiral shapes. Although they are theoretically possible, a family of stable chemical structures with similar shapes and progressively tuneable chirality is yet unknown. Here we show that nanostructured microparticles with an anisotropic bowtie shape display chirality continuum and can be made with widely tuneable twist angle, pitch, width, thickness and length. The self-limited assembly of the bowties enables high synthetic reproducibility, size monodispersity and computational predictability of their geometries for different assembly conditions6. The bowtie nanoassemblies show several strong circular dichroism peaks originating from absorptive and scattering phenomena. Unlike classical chiral molecules, these particles show a continuum of chirality measures2 that correlate exponentially with the spectral positions of the circular dichroism peaks. Bowtie particles with variable polarization rotation were used to print photonically active metasurfaces with spectrally tuneable positive or negative polarization signatures for light detection and ranging (LIDAR) devices.
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Phagocytosis and degradation of photoreceptor outer segments (POS) by retinal pigment epithelium (RPE) is fundamental to vision. Autophagy is also responsible for bulk degradation of cellular components, but its role in POS degradation is not well understood. We report that the morning burst of RPE phagocytosis coincided with the enzymatic conversion of autophagy protein LC3 to its lipidated form. LC3 associated with single-membrane phagosomes containing engulfed POS in an Atg5-dependent manner that required Beclin1, but not the autophagy preinitiation complex. The importance of this process was verified in mice with Atg5-deficient RPE cells that showed evidence of disrupted lysosomal processing. These mice also exhibited decreased photoreceptor responses to light stimuli and decreased chromophore levels that were restored with exogenous retinoid supplementation. These results establish that the interplay of phagocytosis and autophagy within the RPE is required for both POS degradation and the maintenance of retinoid levels to support vision.
Assuntos
Autofagia , Células Fotorreceptoras de Vertebrados/metabolismo , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/metabolismo , Visão Ocular , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 5 Relacionada à Autofagia , Proteína Beclina-1 , Bovinos , Lisossomos/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Fagocitose , Fagossomos/metabolismo , Retinoides/metabolismoRESUMO
The unique topology and physics of chiral superlattices make their self-assembly from nanoparticles highly sought after yet challenging in regard to (meta)materials1-3. Here we show that tetrahedral gold nanoparticles can transform from a perovskite-like, low-density phase with corner-to-corner connections into pinwheel assemblies with corner-to-edge connections and denser packing. Whereas corner-sharing assemblies are achiral, pinwheel superlattices become strongly mirror asymmetric on solid substrates as demonstrated by chirality measures. Liquid-phase transmission electron microscopy and computational models show that van der Waals and electrostatic interactions between nanoparticles control thermodynamic equilibrium. Variable corner-to-edge connections among tetrahedra enable fine-tuning of chirality. The domains of the bilayer superlattices show strong chiroptical activity as identified by photon-induced near-field electron microscopy and finite-difference time-domain simulations. The simplicity and versatility of substrate-supported chiral superlattices facilitate the manufacture of metastructured coatings with unusual optical, mechanical and electronic characteristics.
Assuntos
Ouro , Nanopartículas Metálicas , Eletrônica , FísicaRESUMO
Chirality is a unifying structural metric of biological and abiological forms of matter. Over the past decade, considerable clarity has been achieved in understanding the chemistry and physics of chiral inorganic nanoparticles1-4; however, little is known about their effects on complex biochemical networks5,6. Intermolecular interactions of biological molecules and inorganic nanoparticles show some commonalities7-9, but these structures differ in scale, in geometry and in the dynamics of chiral shapes, which can both impede and strengthen their mirror-asymmetric complexes. Here we show that achiral and left- and right-handed gold biomimetic nanoparticles show different in vitro and in vivo immune responses. We use irradiation with circularly polarized light (CPL) to synthesize nanoparticles with controllable nanometre-scale chirality and optical anisotropy factors (g-factors) of up to 0.4. We find that binding of nanoparticles to two proteins from the family of adhesion G-protein-coupled receptors (AGPCRs)-namely cluster-of-differentiation 97 (CD97) and epidermal-growth-factor-like-module receptor 1 (EMR1)-results in the opening of mechanosensitive potassium-efflux channels, the production of immune signalling complexes known as inflammasomes, and the maturation of mouse bone-marrow-derived dendritic cells. Both in vivo and in vitro immune responses depend monotonically on the g-factors of the nanoparticles, indicating that nanoscale chirality can be used to regulate the maturation of immune cells. Finally, left-handed nanoparticles show substantially higher (1,258-fold) efficiency compared with their right-handed counterparts as adjuvants for vaccination against the H9N2 influenza virus, opening a path to the use of nanoscale chirality in immunology.
Assuntos
Proteínas de Ligação ao Cálcio , Células Dendríticas , Inflamassomos , Nanopartículas Metálicas , Receptores Acoplados a Proteínas G , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Células Dendríticas/imunologia , Ouro , Vírus da Influenza A Subtipo H9N2 , Mecanotransdução Celular , Nanopartículas Metálicas/química , Camundongos , Canais de Potássio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , EstereoisomerismoRESUMO
In the adult hippocampus, synapses are constantly formed and eliminated1,2. However, the exact function of synapse elimination in the adult brain, and how it is regulated, are largely unknown. Here we show that astrocytic phagocytosis3 is important for maintaining proper hippocampal synaptic connectivity and plasticity. By using fluorescent phagocytosis reporters, we find that excitatory and inhibitory synapses are eliminated by glial phagocytosis in the CA1 region of the adult mouse hippocampus. Unexpectedly, we found that astrocytes have a major role in the neuronal activity-dependent elimination of excitatory synapses. Furthermore, mice in which astrocytes lack the phagocytic receptor MEGF10 show a reduction in the elimination of excitatory synapses; as a result, excessive but functionally impaired synapses accumulate. Finally, Megf10-knockout mice show defective long-term synaptic plasticity and impaired formation of hippocampal memories. Together, our data provide strong evidence that astrocytes eliminate unnecessary excitatory synaptic connections in the adult hippocampus through MEGF10, and that this astrocytic function is crucial for maintaining circuit connectivity and thereby supporting cognitive function.
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Envelhecimento , Astrócitos/citologia , Região CA1 Hipocampal/citologia , Homeostase , Vias Neurais , Fagocitose , Sinapses/metabolismo , Animais , Potenciais Pós-Sinápticos Excitadores , Feminino , Potenciais Pós-Sinápticos Inibidores , Masculino , Proteínas de Membrana/metabolismo , Memória/fisiologia , Camundongos , Plasticidade Neuronal/fisiologiaRESUMO
Growth deficiency is a characteristic feature of both Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), Mendelian disorders of the epigenetic machinery with similar phenotypes but distinct genetic etiologies. We previously described skeletal growth deficiency in a mouse model of KS1 and further established that a Kmt2d-/- chondrocyte model of KS1 exhibits precocious differentiation. Here we characterized growth deficiency in a mouse model of KS2, Kdm6atm1d/+. We show that Kdm6atm1d/+ mice have decreased femur and tibia length compared to controls and exhibit abnormalities in cortical and trabecular bone structure. Kdm6atm1d/+ growth plates are also shorter, due to decreases in hypertrophic chondrocyte size and hypertrophic zone height. Given these disturbances in the growth plate, we generated Kdm6a-/- chondrogenic cell lines. Similar to our prior in vitro model of KS1, we found that Kdm6a-/- cells undergo premature, enhanced differentiation towards chondrocytes compared to Kdm6a+/+ controls. RNA-seq showed that Kdm6a-/- cells have a distinct transcriptomic profile that indicates dysregulation of cartilage development. Finally, we performed RNA-seq simultaneously on Kmt2d-/-, Kdm6a-/-, and control lines at Days 7 and 14 of differentiation. This revealed surprising resemblance in gene expression between Kmt2d-/- and Kdm6a-/- at both time points and indicates that the similarity in phenotype between KS1 and KS2 also exists at the transcriptional level.
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Anormalidades Múltiplas , Condrócitos , Modelos Animais de Doenças , Face , Doenças Hematológicas , Histona Desmetilases , Doenças Vestibulares , Animais , Doenças Vestibulares/genética , Doenças Vestibulares/patologia , Camundongos , Face/anormalidades , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Doenças Hematológicas/genética , Doenças Hematológicas/patologia , Condrócitos/metabolismo , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Diferenciação Celular/genética , Condrogênese/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/deficiência , Humanos , Camundongos Knockout , Fenótipo , Histona-Lisina N-Metiltransferase , Proteína de Leucina Linfoide-MieloideRESUMO
Chiral plasmonic surfaces with 3D "forests" from nanohelicoids should provide strong optical rotation due to alignment of helical axis with propagation vector of photons. However, such three-dimensional nanostructures also demand multi-step nanofabrication, which is incompatible with many substrates. Large-scale photonic patterns on polymeric and flexible substrates remain unattainable. Here, we demonstrate the substrate-tolerant direct-write printing and patterning of silver nanohelicoids with out-of-plane 3D orientation using circularly polarized light. Centimeter-scale chiral plasmonic surfaces can be produced within minutes using inexpensive medium-power lasers. The growth of nanohelicoids is driven by the symmetry-broken site-selective deposition and self-assembly of the silver nanoparticles (NPs). The ellipticity and wavelength of the incident photons control the local handedness and size of the printed nanohelicoids, which enables on-the-fly modulation of nanohelicoid chirality during direct writing and simple pathways to complex multifunctional metasurfaces. Processing simplicity, high polarization rotation, and fine spatial resolution of the light-driven printing of stand-up helicoids provide a rapid pathway to chiral plasmonic surfaces, accelerating the development of chiral photonics for health and information technologies.
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Spinal opioid-induced itch, a prevalent side effect of pain management, has been proposed to result from pain inhibition. We now report that the µ-opioid receptor (MOR) isoform MOR1D is essential for morphine-induced scratching (MIS), whereas the isoform MOR1 is required only for morphine-induced analgesia (MIA). MOR1D heterodimerizes with gastrin-releasing peptide receptor (GRPR) in the spinal cord, relaying itch information. We show that morphine triggers internalization of both GRPR and MOR1D, whereas GRP specifically triggers GRPR internalization and morphine-independent scratching. Providing potential insight into opioid-induced itch prevention, we demonstrate that molecular and pharmacologic inhibition of PLCß3 and IP3R3, downstream effectors of GRPR, specifically block MIS but not MIA. In addition, blocking MOR1D-GRPR association attenuates MIS but not MIA. Together, these data suggest that opioid-induced itch is an active process concomitant with but independent of opioid analgesia, occurring via the unidirectional cross-activation of GRPR signaling by MOR1D heterodimerization.
Assuntos
Analgesia , Analgésicos Opioides/administração & dosagem , Morfina/administração & dosagem , Dor/tratamento farmacológico , Prurido/induzido quimicamente , Receptores da Bombesina/metabolismo , Receptores Opioides mu/metabolismo , Sequência de Aminoácidos , Animais , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Receptores da Bombesina/genética , Receptores Opioides mu/genética , Transdução de SinaisRESUMO
Blood vessels support tumours by providing nutrients and oxygen, while also acting as conduits for the dissemination of cancer1. Here we use mouse models of breast and lung cancer to investigate whether endothelial cells also have active 'instructive' roles in the dissemination of cancer. We purified genetically tagged endothelial ribosomes and their associated transcripts from highly and poorly metastatic tumours. Deep sequencing revealed that metastatic tumours induced expression of the axon-guidance gene Slit2 in endothelium, establishing differential expression between the endothelial (high Slit2 expression) and tumoural (low Slit2 expression) compartments. Endothelial-derived SLIT2 protein and its receptor ROBO1 promoted the migration of cancer cells towards endothelial cells and intravasation. Deleting endothelial Slit2 suppressed metastatic dissemination in mouse models of breast and lung cancer. Conversely, deletion of tumoural Slit2 enhanced metastatic progression. We identified double-stranded RNA derived from tumour cells as an upstream signal that induces expression of endothelial SLIT2 by acting on the RNA-sensing receptor TLR3. Accordingly, a set of endogenous retroviral element RNAs were upregulated in metastatic cells and detected extracellularly. Thus, cancer cells co-opt innate RNA sensing to induce a chemotactic signalling pathway in endothelium that drives intravasation and metastasis. These findings reveal that endothelial cells have a direct instructive role in driving metastatic dissemination, and demonstrate that a single gene (Slit2) can promote or suppress cancer progression depending on its cellular source.
Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Endotélio/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metástase Neoplásica , Proteínas do Tecido Nervoso/metabolismo , Receptor 3 Toll-Like/metabolismo , Animais , Quimiotaxia , Modelos Animais de Doenças , Progressão da Doença , Células Endoteliais/metabolismo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Camundongos , Metástase Neoplásica/genética , Proteínas do Tecido Nervoso/genética , RNA de Cadeia Dupla , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Transdução de Sinais , Receptor 3 Toll-Like/deficiência , Receptor 3 Toll-Like/genética , Células Tumorais Cultivadas , Proteínas RoundaboutRESUMO
BACKGROUND: Human breast cancer most frequently originates within a well-defined anatomical structure referred to as the terminal duct lobular unit (TDLU). This structure is endowed with its very own lobular fibroblasts representing one out of two steady-state fibroblast subtypes-the other being interlobular fibroblasts. While cancer-associated fibroblasts (CAFs) are increasingly appreciated as covering a spectrum of perturbed states, we lack a coherent understanding of their relationship-if any-with the steady-state fibroblast subtypes. To address this, we here established two autologous CAF lines representing inflammatory CAFs (iCAFs) and myofibroblast CAFs (myCAFs) and compared them with already established interlobular- and lobular fibroblasts with respect to their origin and impact on tumor formation. METHODS: Primary breast tumor-derived CAFs were transduced to express human telomerase reverse transcriptase (hTERT) and sorted into CD105low and CD105high populations using fluorescence-activated cell sorting (FACS). The two populations were tested for differentiation similarities to iCAF and myCAF states through transcriptome-wide RNA-Sequencing (RNA-Seq) including comparison to an available iCAF-myCAF cell state atlas. Inference of origin in interlobular and lobular fibroblasts relied on RNA-Seq profiles, immunocytochemistry and growth characteristics. Osteogenic differentiation and bone formation assays in culture and in vivo were employed to gauge for origin in bone marrow-derived mesenchymal stem cells (bMSCs). Functional characteristics were assessed with respect to contractility in culture and interaction with tumor cells in mouse xenografts. The cells' gene expression signatures were tested for association with clinical outcome of breast cancer patients using survival data from The Cancer Genome Atlas database. RESULTS: We demonstrate that iCAFs have properties in common with interlobular fibroblasts while myCAFs and lobular fibroblasts are related. None of the CAFs qualify as bMSCs as revealed by lack of critical performance in bone formation assays. Functionally, myCAFs and lobular fibroblasts are almost equally tumor promoting as opposed to iCAFs and interlobular fibroblasts. A myCAF gene signature is found to associate with poor breast cancer-specific survival. CONCLUSIONS: We propose that iCAFs and myCAFs originate in interlobular and lobular fibroblasts, respectively, and more importantly, that the tumor-promoting properties of lobular fibroblasts render the TDLU an epicenter for breast cancer evolution.
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Neoplasias da Mama , Fibroblastos Associados a Câncer , Humanos , Camundongos , Animais , Feminino , Neoplasias da Mama/patologia , Osteogênese , Fibroblastos/metabolismo , Fibroblastos Associados a Câncer/patologia , Mama/patologia , Microambiente TumoralRESUMO
BACKGROUND: In the myeloid compartment of the tumor microenvironment, CD244 signaling has been implicated in immunosuppressive phenotype of monocytes. However, the precise molecular mechanism and contribution of CD244 to tumor immunity in monocytes/macrophages remains elusive due to the co-existing lymphoid cells expressing CD244. METHODS: To directly assess the role of CD244 in tumor-associated macrophages, monocyte-lineage-specific CD244-deficient mice were generated using cre-lox recombination and challenged with B16F10 melanoma. The phenotype and function of tumor-infiltrating macrophages along with antigen-specific CD8 T cells were analyzed by flow cytometry and single cell RNA sequencing data analysis, and the molecular mechanism underlying anti-tumorigenic macrophage differentiation, antigen presentation, phagocytosis was investigated ex vivo. Finally, the clinical feasibility of CD244-negative monocytes as a therapeutic modality in melanoma was confirmed by adoptive transfer experiments. RESULTS: CD244fl/flLysMcre mice demonstrated a significant reduction in tumor volume (61% relative to that of the CD244fl/fl control group) 14 days after tumor implantation. Within tumor mass, CD244fl/flLysMcre mice also showed higher percentages of Ly6Clow macrophages, along with elevated gp100+IFN-γ+ CD8 T cells. Flow cytometry and RNA sequencing data demonstrated that ER stress resulted in increased CD244 expression on monocytes. This, in turn, impeded the generation of anti-tumorigenic Ly6Clow macrophages, phagocytosis and MHC-I antigen presentation by suppressing autophagy pathways. Combining anti-PD-L1 antibody with CD244-/- bone marrow-derived macrophages markedly improved tumor rejection compared to the anti-PD-L1 antibody alone or in combination with wild-type macrophages. Consistent with the murine data, transcriptome analysis of human melanoma tissue single-cell RNA-sequencing dataset revealed close association between CD244 and the inhibition of macrophage maturation and function. Furthermore, the presence of CD244-negative monocytes/macrophages significantly increased patient survival in primary and metastatic tumors. CONCLUSION: Our study highlights the novel role of CD244 on monocytes/macrophages in restraining anti-tumorigenic macrophage generation and tumor antigen-specific T cell response in melanoma. Importantly, our findings suggest that CD244-deficient macrophages could potentially be used as a therapeutic agent in combination with immune checkpoint inhibitors. Furthermore, CD244 expression in monocyte-lineage cells serve as a prognostic marker in cancer patients.
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Melanoma , Monócitos , Humanos , Animais , Camundongos , Monócitos/metabolismo , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Macrófagos/metabolismo , Linfócitos T CD8-Positivos , Carcinogênese/metabolismo , Microambiente Tumoral , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismoRESUMO
Pure laparoscopic donor hepatectomy (PLDH) has become a routine procedure at Seoul National University Hospital, and the pure laparoscopic method is now being applied to liver recipients as well. This study aimed to review the procedure and outcomes of PLDH to identify any areas that required improvement. Data from 556 donors who underwent PLDH between November 2015 and December 2021 and their recipients were retrospectively reviewed. Among these, 541 patients underwent pure laparoscopic donor right hepatectomy (PLDRH). The mean hospital stay of the donor was 7.2 days, and the rate of grade I, II, IIIa, and IIIb complications was 2.2%, 2.7%, 1.3%, and 0.9%, respectively, without any irreversible disabilities or mortalities. The most common early and late major complications in the recipient were intraabdominal bleeding (n = 47, 8.5%) and biliary problems (n = 198, 35.6%), respectively. Analysis of the PLDRH procedure showed that operative time, liver removal time, warm ischemic time, Δhemoglobin%, Δtotal bilirubin%, and postoperative hospital stay decreased significantly as the number of cases accumulated. In conclusion, the operative outcomes of PLDRH improved as the number of cases increased. However, continuous caution is needed because major complications still occur in donors and recipients even after hundreds of cases.
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Laparoscopia , Transplante de Fígado , Humanos , Hepatectomia/métodos , Seul , Estudos Retrospectivos , Transplante de Fígado/efeitos adversos , Doadores Vivos , Fígado/cirurgia , Coleta de Tecidos e Órgãos/efeitos adversos , Laparoscopia/métodos , Duração da Cirurgia , Hospitais , Complicações Pós-Operatórias/etiologiaRESUMO
TCP13 belongs to a subgroup of TCP transcription factors implicated in the shade avoidance syndrome (SAS), but its exact role remains unclear. Here, we show that TCP13 promotes the SAS-like response by enhancing hypocotyl elongation and suppressing flavonoid biosynthesis as a part of the incoherent feed-forward loop in light signaling. Shade is known to promote the SAS by activating PHYTOCHROME-INTERACTING FACTOR (PIF)-auxin signaling in plants, but we found no evidence in a transcriptome analysis that TCP13 activates PIF-auxin signaling. Instead, TCP13 mimics shade by activating the expression of a subset of shade-inducible and cell elongation-promoting SAUR genes including SAUR19, by direct targeting of their promoters. We also found that TCP13 and PIF4, a molecular proxy for shade, repress the expression of flavonoid biosynthetic genes by directly targeting both shared and distinct sets of biosynthetic gene promoters. Together, our results indicate that TCP13 promotes the SAS-like response by directly targeting a subset of shade-responsive genes without activating the PIF-auxin signaling pathway.
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Proteínas de Arabidopsis , Arabidopsis , Fitocromo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Flavonoides/metabolismo , Regulação da Expressão Gênica de Plantas , Hipocótilo/genética , Hipocótilo/metabolismo , Ácidos Indolacéticos/metabolismo , Luz , Fitocromo/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The aim of this study was to evaluate the safety and efficacy of digital therapeutic application of Sleep Index-Based Treatment for Insomnia (dSIBT-I) and compare them with those of digital application of Cognitive Behavioural Therapy for Insomnia (dCBT-I). This randomised prospective pilot study was conducted at the Asan Medical Center. A total of 50 patients with insomnia were recruited between December 2022 and January 2023 and randomly allocated to the dSIBT-I or dCBT-I group. The study was carried out for one month. The primary outcome was the significant reduction in Insomnia Severity Index score at Week 4 compared to baseline, while the secondary outcome was proportion of participants whose Insomnia Severity Index scores were reduced to <15 at Week 4. We performed linear mixed model and generalised estimating equation analyses. Both dSIBT-I and dCBT-I groups showed significant improvements in Insomnia Severity Index scores at Week 4. There was no significant difference between two groups in terms of Insomnia Severity Index scores at Week 4 (group × time effect, F = 1.07, p = 0.382) and proportion of participants whose Insomnia Severity Index scores were reduced to <15 at Week 4 (group × time effects, F = 1.80, p = 0.615). However, at Week 2, the dSIBT-I group showed better results than the dCBT-I group in terms of both Insomnia Severity Index scores (p = 0.044) and proportion of participants whose Insomnia Severity Index scores were reduced to <15 (82.6% vs. 48.0%, p = 0.017). No treatment-emergent adverse events were reported in either group. The dSIBT-I is a safe and effective therapy for insomnia, with rapid treatment effects.
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Distúrbios do Início e da Manutenção do Sono , Humanos , Distúrbios do Início e da Manutenção do Sono/terapia , Projetos Piloto , Resultado do Tratamento , Estudos Prospectivos , SonoRESUMO
BACKGROUND/AIMS: Helicobacter pylori (H. pylori) infections can recur as either recrudescence or reinfection. At a time when the decline in the eradication rate is becoming evident, increases in the rate of recurrence are concerning. In addition, there are no guidelines for selecting an eradication regimen for H. pylori recurrence. MATERIALS AND METHODS: A total of 996 H. pylori-infected patients treated with proton-pump inhibitor-based triple eradication therapy between 2017 and 2022 were enrolled in the study, and successful eradication therapies were confirmed by the 13 C-urea breath test. When retested within 1 year after successful eradication, analysis related to recrudescence was performed, and when retested after 1 year, analysis related to reinfection was performed. We reviewed the medical records and treatment outcomes of patients with H. pylori reinfection after successful eradication. RESULTS: The recrudescence rate was 3.9% (9/228), and the reinfection rate was 3.7% (36/970 person-year). The frequency of reinfection reached 5.9% per person-year within the first 24 months and 2.0%-2.4% per person-year thereafter. In multivariate factor analysis, reinfection was significantly higher in patients with non-ulcer dyspepsia (p < 0.01). At first-line therapy for reinfection, the eradication rate of standard triple therapy (STT) was 50.0% (16/32). The eradication rate of second-line bismuth quadruple therapy was 81.3% (13/16), and levofloxacin-based rescue therapy was 66.7% (2/3). CONCLUSION: Re-treatment of patients with H. pylori reinfection with STT had limited efficacy. Prospective research is needed to determine whether patients with non-ulcer dyspepsia are vulnerable to reinfection.
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Dispepsia , Gastrite , Infecções por Helicobacter , Helicobacter pylori , Humanos , Infecções por Helicobacter/tratamento farmacológico , Antibacterianos/uso terapêutico , Dispepsia/tratamento farmacológico , Reinfecção/tratamento farmacológico , Estudos Prospectivos , Gastrite/tratamento farmacológico , Recidiva , República da Coreia/epidemiologia , Quimioterapia Combinada , Testes RespiratóriosRESUMO
Combined liver-kidney transplantation (CLKT) is a surgical procedure that involves transplanting both liver and kidney organs. There are two types of CLKT: simultaneous liver-kidney transplantation (smLKT) and sequential LKT (sqLKT). CLKT accounts for a small percentage of liver transplantations (LTs), particularly in pediatric cases. Nevertheless, the procedure has demonstrated excellent outcomes, with high survival rates and lower rejection rates. The main indications for CLKT in pediatric patients differ somewhat from that in adults, in which end-stage kidney disease after LT is the major indication. In children, congenital diseases are common reason for performing CLKT; the examples of such diseases include autosomal recessive polycystic kidney disease with congenital hepatic fibrosis which equally affects both organs, and primary hyperoxaluria type 1, a primary liver disease leading kidney failure. The decision between smLKT or sqLKT depends on the dominant organ failure, the specific pathophysiology, and available organ sources. However, there remain significant surgical and societal challenges surrounding CLKT. Innovations in pharmacology and genetic engineering have decreased the necessity for CLKT in early-diagnosed cases without portal hypertension or kidney replacement therapy. Nonetheless, these advancements are not universally accessible. Therefore, decision-making algorithms should be crafted, considering region-specific organ allocation systems and prevailing medical environments.
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Hipertensão Portal , Nefropatias , Transplante de Rim , Falência Hepática , Transplante de Fígado , Adulto , Criança , Humanos , Transplante de Rim/métodos , Transplante de Fígado/métodos , Resultado do Tratamento , Falência Hepática/cirurgia , RimRESUMO
Chirality is an essential geometric property unifying small molecules, biological macromolecules, inorganic nanomaterials, biological microparticles, and many other chemical structures. Numerous chirality measures have attempted to quantify this geometric property of mirror asymmetry and to correlate these measures with physical and chemical properties. However, their utility has been widely limited because these correlations have been largely notional. Furthermore, chirality measures also require prohibitively demanding computations, especially for chiral structures comprised of thousands of atoms. Acknowledging the fundamental problems with quantification of mirror asymmetry, including the ambiguity of sign-variable pseudoscalar chirality measures, we revisit this subject because of the significance of quantifying chirality for quantitative biomimetics and describing the chirality of nanoscale materials that display chirality continuum and scale-dependent mirror asymmetry. We apply the concept of torsion within the framework of differential geometry to the graph theoretical representation of chiral molecules and nanostructures to address some of the fundamental problems and practical limitations of other chirality measures. Chiral gold clusters and other chiral structures are used as models to elaborate a graph-theoretical chirality (GTC) measure, demonstrating its applicability to chiral materials with different degrees of chirality at different scales. For specific cases, we show that GTC provides an adequate description of both the sign and magnitude of mirror asymmetry. The direct correlations with macroscopic properties, such as chiroptical spectra, are enhanced by using the hybrid chirality measures combining parameters from discrete mathematics and physics. Taking molecular helices as an example, we established a direct relation between GTC and optical activity, indicating that this chirality measure can be applied to chiral metamaterials and complex chiral constructs.
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INTRODUCTION: This study aimed to explore whether the Discrepancy between the desired time in Bed and the desired total Sleep Time (DBST) index influences insomnia severity in the older adult population and examined the potential role of psychological inflexibility in this association. METHODS: An online survey study was conducted for older individuals aged ≥ 65 via a survey company between January and February 2023. A total of 300 responses and data without personally identifiable information were delivered to the researchers. The survey questionnaires include the DBST, Glasgow Sleep Effort Scale (GSES), Insomnia Severity Index (ISI), Dysfunctional Beliefs about Sleep-2 items (DBS-2), and Acceptance and Action Questionnaire-II (AAQ-II). RESULTS: The analysis included 295 older adult participants. The DBST index was significantly correlated with all questionnaires. Linear regression revealed the DBST index was predicted only by the ISI (ß = 0.26, p = 0.003). Mediation analysis showed that the GSES (Z = 2.92, p = 0.003) and DBS-2 (Z = 2.17, p = 0.030) mediated the effect of the DBST index on the ISI, while the AAQ-II did not. Path analysis showed that the DBST could be directly predicted by the ISI (Z = 2.94, p = 0.003), GSES (Z = 2.75, p = 0.006), and DBS2 (Z = 2.71, p = 0.007) but not by the AAQ-II itself. However, the AAQ-II exerted a significant indirect effect on the ISI through the DBS-2 (Z = 2.21, p = 0.027) and GSES (z = 2.24, p = 0.025). CONCLUSIONS: Our study showed that preoccupation and dysfunctional beliefs about sleep may mediate the relationship between the DBST index and insomnia severity in the older adult population. We opine that psychological inflexibility might play a significant role in insomnia severity via preoccupation with and dysfunctional beliefs about sleep.
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The reintegration of former members of violent extremist groups is a pressing policy challenge. Governments and policymakers often have to change minds among reticent populations and shift perceived community norms in order to pave the way for peaceful reintegration. How can they do so on a mass scale? Previous research shows that messages from trusted authorities can be effective in creating attitude change and shifting perceptions of social norms. In this study, we test whether messages from religious leaders-trusted authorities in many communities worldwide-can change minds and shift norms around an issue related to conflict resolution: the reintegration of former members of violent extremist groups. Our study takes place in Maiduguri, Nigeria, the birthplace of the violent extremist group Boko Haram. Participants were randomly assigned to listen to either a placebo radio message or to a treatment message from a religious leader emphasizing the importance of forgiveness, announcing the leader's forgiveness of repentant fighters, and calling on followers to forgive. Participants were then asked about their attitudes, intended behaviors, and perceptions of social norms surrounding the reintegration of an ex-Boko Haram fighter. The religious leader message significantly increased support for reintegration and willingness to interact with the ex-fighter in social, political, and economic life (8 to 10 percentage points). It also shifted people's beliefs that others in their community were more supportive of reintegration (6 to 10 percentage points). Our findings suggest that trusted authorities such as religious leaders can be effective messengers for promoting peace.