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1.
Cell ; 184(15): 3899-3914.e16, 2021 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-34237254

RESUMEN

The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.


Asunto(s)
Microbioma Gastrointestinal , Infecciones por VIH/inmunología , Infecciones por VIH/microbiología , Terapia Antirretroviral Altamente Activa , Biodiversidad , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Quimiocinas/sangre , Estudios de Cohortes , Glucólisis , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Humanos , Inflamación/genética , Inflamación/patología , Mitocondrias/metabolismo , Monocitos/metabolismo , Ácidos Nucleicos/sangre , Análisis de Componente Principal , Serratia/fisiología , Células TH1/inmunología , Células Th2/inmunología , Transcripción Genética , Uganda , Carga Viral/inmunología
2.
Cell ; 183(1): 185-196.e14, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-33007262

RESUMEN

Several HIV-1 and SIV vaccine candidates have shown partial protection against viral challenges in rhesus macaques. However, the protective efficacy of vaccine-elicited polyclonal antibodies has not previously been demonstrated in adoptive transfer studies in nonhuman primates. In this study, we show that passive transfer of purified antibodies from vaccinated macaques can protect naive animals against SIVmac251 challenges. We vaccinated 30 rhesus macaques with Ad26-SIV Env/Gag/Pol and SIV Env gp140 protein vaccines and assessed the induction of antibody responses and a putative protective signature. This signature included multiple antibody functions and correlated with upregulation of interferon pathways in vaccinated animals. Adoptive transfer of purified immunoglobulin G (IgG) from the vaccinated animals with the most robust protective signatures provided partial protection against SIVmac251 challenges in naive recipient rhesus macaques. These data demonstrate the protective efficacy of purified vaccine-elicited antiviral antibodies in this model, even in the absence of virus neutralization.


Asunto(s)
Inmunización Pasiva/métodos , Vacunas contra el SIDAS/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunas contra el SIDA/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Formación de Anticuerpos/inmunología , Productos del Gen env/inmunología , Productos del Gen gag/inmunología , Productos del Gen pol/inmunología , VIH-1/inmunología , Inmunoglobulina G/inmunología , Macaca mulatta/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología
3.
Nat Immunol ; 22(10): 1294-1305, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34556879

RESUMEN

Development of effective human immunodeficiency virus 1 (HIV-1) vaccines requires synergy between innate and adaptive immune cells. Here we show that induction of the transcription factor CREB1 and its target genes by the recombinant canarypox vector ALVAC + Alum augments immunogenicity in non-human primates (NHPs) and predicts reduced HIV-1 acquisition in the RV144 trial. These target genes include those encoding cytokines/chemokines associated with heightened protection from simian immunodeficiency virus challenge in NHPs. Expression of CREB1 target genes probably results from direct cGAMP (STING agonist)-modulated p-CREB1 activity that drives the recruitment of CD4+ T cells and B cells to the site of antigen presentation. Importantly, unlike NHPs immunized with ALVAC + Alum, those immunized with ALVAC + MF59, the regimen in the HVTN702 trial that showed no protection from HIV infection, exhibited significantly reduced CREB1 target gene expression. Our integrated systems biology approach has validated CREB1 as a critical driver of vaccine efficacy and highlights that adjuvants that trigger CREB1 signaling may be critical for efficacious HIV-1 vaccines.


Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Inmunogenicidad Vacunal/inmunología , Vacunas Virales/inmunología , Vacunas contra el SIDA/inmunología , Adyuvantes Inmunológicos/farmacología , Animales , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Expresión Génica/inmunología , Vectores Genéticos/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/virología , Humanos , Inmunización/métodos , Primates/inmunología , Primates/virología , Vacunación/métodos
4.
Immunity ; 56(5): 1132-1147.e6, 2023 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-37030290

RESUMEN

HIV infection persists during antiretroviral therapy (ART) due to a reservoir of latently infected cells that harbor replication-competent virus and evade immunity. Previous ex vivo studies suggested that CD8+ T cells from people with HIV may suppress HIV expression via non-cytolytic mechanisms, but the mechanisms responsible for this effect remain unclear. Here, we used a primary cell-based in vitro latency model and demonstrated that co-culture of autologous activated CD8+ T cells with HIV-infected memory CD4+ T cells promoted specific changes in metabolic and/or signaling pathways resulting in increased CD4+ T cell survival, quiescence, and stemness. Collectively, these pathways negatively regulated HIV expression and ultimately promoted the establishment of latency. As shown previously, we observed that macrophages, but not B cells, promoted latency in CD4+ T cells. The identification of CD8-specific mechanisms of pro-latency activity may favor the development of approaches to eliminate the viral reservoir in people with HIV.


Asunto(s)
Infecciones por VIH , Humanos , Linfocitos T CD8-positivos , Latencia del Virus , Linfocitos T CD4-Positivos , Replicación Viral
5.
Plant Physiol ; 196(2): 1460-1474, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-38820143

RESUMEN

ELONGATED HYPOCOTYL 5 (HY5) is a major light-associated transcription factor involved in plant growth and development. In Arabidopsis (Arabidopsis thaliana), the role of HY5 is very well defined in regulating primary root growth and lateral root formation; however, information regarding its role in root hair development is still lacking, and little is known about the genetic pathways regulating this process. In this study, we investigated the role of HY5 and its associated components in root hair development. Detailed analysis of root hair phenotype in wild-type and light signaling mutants under light and dark conditions revealed the importance of light-dependent HY5-mediated root hair initiation. Altered auxin levels in the root apex of the hy5 mutant and interaction of HY5 with promoters of root hair developmental genes were responsible for differential expression of root hair developmental genes and phenotype in the hy5 mutant. The partial complementation of root hair in the hy5 mutant after external supplementation of auxin and regaining of root hair in PIN-FORMED 2 and PIN-FORMED 2 mutants after grafting suggested that the auxin-mediated root hair development pathway requires HY5. Furthermore, miR397b overexpression (miR397bOX) and CRISPR/Cas9-based mutants (miR397bCR) indicated miR397b targets genes encoding reduced residual arabinose (RRA1/RRA2), which in turn regulate root hair growth. The regulation of the miR397b-(RRA1/RRA2) module by HY5 demonstrated its indirect role by targeting root hair cell wall genes. Together, this study demonstrated that HY5 controls root hair development by integrating auxin signaling and other miRNA-mediated pathways.


Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Regulación de la Expresión Génica de las Plantas , Ácidos Indolacéticos , MicroARNs , Raíces de Plantas , Arabidopsis/genética , Arabidopsis/crecimiento & desarrollo , Arabidopsis/efectos de los fármacos , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Ácidos Indolacéticos/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/genética , Raíces de Plantas/metabolismo , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Mutación/genética , Fenotipo
6.
FASEB J ; 38(18): e70067, 2024 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-39320982

RESUMEN

Abdominal aortic aneurysm (AAA) formation is a chronic vascular pathology characterized by inflammation, leukocyte infiltration, and vascular remodeling. The aim of this study was to delineate the protective role of Resolvin D2 (RvD2), a bioactive isoform of specialized pro-resolving lipid mediators, via G-protein-coupled receptor 18 (GPR18) receptor signaling in attenuating AAAs. Importantly, RvD2 and GPR18 levels were significantly decreased in aortic tissue of AAA patients compared with controls. Furthermore, using an established murine model of AAA in C57BL/6 (WT) mice, we observed that treatment with RvD2 significantly attenuated aortic diameter, pro-inflammatory cytokine production, immune cell infiltration (neutrophils and macrophages), elastic fiber disruption, and increased smooth muscle cell α-actin expression as well as increased TGF-ß2 and IL-10 expressions compared to untreated mice. Moreover, the RvD2-mediated protection from vascular remodeling and AAA formation was blocked when mice were previously treated with siRNA for GPR18 signifying the importance of RvD2/GPR18 signaling in vascular inflammation. Mechanistically, RvD2-mediated protection significantly enhanced infiltration and activation of monocytic myeloid-derived suppressor cells (M-MDSCs) by increasing TGF-ß2 and IL-10 secretions in a GPR18-dependent manner to attenuate aortic inflammation and vascular remodeling. Collectively, this study demonstrates that RvD2 treatment induces an expansion of myeloid-lineage committed progenitors, such as M-MDSCs, activates GPR18-dependent signaling to enhance TGF-ß2 and IL-10 secretion, and mitigates SMC activation that contributes to resolution of aortic inflammation and remodeling during AAA formation.


Asunto(s)
Aneurisma de la Aorta Abdominal , Ácidos Docosahexaenoicos , Ratones Endogámicos C57BL , Células Supresoras de Origen Mieloide , Receptores Acoplados a Proteínas G , Transducción de Señal , Animales , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/prevención & control , Aneurisma de la Aorta Abdominal/tratamiento farmacológico , Receptores Acoplados a Proteínas G/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , Ácidos Docosahexaenoicos/farmacología , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/efectos de los fármacos , Humanos , Masculino , Remodelación Vascular/efectos de los fármacos , Monocitos/metabolismo , Monocitos/efectos de los fármacos , Interleucina-10/metabolismo , Factor de Crecimiento Transformador beta2/metabolismo
7.
J Am Chem Soc ; 2024 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-39417990

RESUMEN

Singlet fission (SF) and triplet-triplet annihilation upconversion (TTA-UC) nominally enable the interconversion of higher-energy singlet states with two lower-energy triplet states and vice versa, with both processes having envisaged application for enhanced solar power devices. The mechanism of SF/TTA-UC involves a complex array of different multiexcitonic triplet-pair states that are coupled by the exchange interaction to varying extents. In this work a family of bounded intramolecular SF materials, based upon the chromophore 1,6-diphenyl-1,3,5-hexatriene, were designed and synthesized. Their SF behavior was characterized using fluorescence lifetime, transient absorption, and magnetic field dependence studies. The capacity for the formation of weakly exchange-coupled triplet pairs, and subsequent spin-evolution, is shown to be strongly dependent upon the combined factors of oligomer size and geometry. By contextualizing these results with the wider SF literature, we present a general schematic model for SF/TTA-UC of greater completeness than portrayed elsewhere.

8.
J Am Chem Soc ; 146(42): 28985-28993, 2024 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-39380134

RESUMEN

Singlet fission (SF), which involves the conversion of a singlet excited state into two triplet excitons, holds great potential to boost the efficiency of photovoltaics. However, losses due to triplet-triplet annihilation hamper the efficient harvesting of SF-generated triplet excitons, which limits an effective implementation in solar energy conversion schemes. A fundamental understanding of the underlying structure-property relationships is thus crucial to define design principles for cutting-edge SF materials, yet it remains elusive. Herein, we harness helical supramolecular polymers decorated with pentacene side groups to elucidate intermolecular SF dynamics in solution and promote the formation of long-lived mobile triplets. By leveraging the hydrogen bonding-driven assembly of benzene-1,3,5-tricarboxamide (BTA) cores into one-dimensional scaffolds, we direct the organization of appended pentacene motifs into long-range ordered helical frameworks. Dynamic interactions between weakly coupled SF pendants mediate singlet conversion within hundreds of picoseconds, affording triplet quantum yields well above 100%. Moreover, analysis of triplet dynamics with a Monte Carlo simulation model reveals that triplet diffusion along the supramolecular fibers is favored over annihilation, resulting in independent triplets exhibiting considerably slow decay on the time scale of tens of microseconds. The molecular packing within the assembly is tuned by subtle changes in monomer design to increase the rate and efficiency of SF while ensuring exceptionally long-lived mobile triplets, allowing to maintain triplet quantum yields exceeding 100% for at least 100 ns. This work opens new opportunities to exploit self-assembled supramolecular polymers as functional templates to achieve long-lived SF-generated triplets.

9.
Nat Mater ; 22(8): 977-984, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37308547

RESUMEN

Photoinduced spin-charge interconversion in semiconductors with spin-orbit coupling could provide a route to optically addressable spintronics without the use of external magnetic fields. However, in structurally disordered polycrystalline semiconductors, which are being widely explored for device applications, the presence and role of spin-associated charge currents remains unclear. Here, using femtosecond circular-polarization-resolved pump-probe microscopy on polycrystalline halide perovskite thin films, we observe the photoinduced ultrafast formation of spin domains on the micrometre scale formed through lateral spin currents. Micrometre-scale variations in the intensity of optical second-harmonic generation and vertical piezoresponse suggest that the spin-domain formation is driven by the presence of strong local inversion symmetry breaking via structural disorder. We propose that this leads to spatially varying Rashba-like spin textures that drive spin-momentum-locked currents, leading to local spin accumulation. Ultrafast spin-domain formation in polycrystalline halide perovskite films provides an optically addressable platform for nanoscale spin-device physics.

10.
Blood ; 140(17): 1858-1874, 2022 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-35789258

RESUMEN

The discovery of humans with monogenic disorders has a rich history of generating new insights into biology. Here we report the first human identified with complete deficiency of nuclear factor of activated T cells 1 (NFAT1). NFAT1, encoded by NFATC2, mediates calcium-calcineurin signals that drive cell activation, proliferation, and survival. The patient is homozygous for a damaging germline NFATC2 variant (c.2023_2026delTACC; p.Tyr675Thrfs∗18) and presented with joint contractures, osteochondromas, and recurrent B-cell lymphoma. Absence of NFAT1 protein in chondrocytes caused enrichment in prosurvival and inflammatory genes. Systematic single-cell-omic analyses in PBMCs revealed an environment that promotes lymphomagenesis with accumulation of naïve B cells (enriched for oncogenic signatures MYC and JAK1), exhausted CD4+ T cells, impaired T follicular helper cells, and aberrant CD8+ T cells. This work highlights the pleiotropic role of human NFAT1, will empower the diagnosis of additional patients with NFAT1 deficiency, and further defines the detrimental effects associated with long-term use of calcineurin inhibitors.


Asunto(s)
Contractura , Leucemia de Células B , Osteocondroma , Humanos , Calcineurina/genética , Leucemia de Células B/genética , Leucemia de Células B/metabolismo , Recurrencia Local de Neoplasia , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Linfoma de Células B/genética , Linfoma de Células B/metabolismo
11.
Br J Dermatol ; 191(3): 428-436, 2024 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-38736216

RESUMEN

BACKGROUND: Autofluorescence (AF)-Raman microspectroscopy is a technology that can detect residual basal cell carcinoma (BCC) on the resection margin of fresh, surgically excised tissue specimens. The technology does not require tissue fixation, staining, labelling or sectioning, and provides quantitative diagnosis maps of the surgical margins in 30 min. OBJECTIVES: To determine the accuracy of the AF-Raman instrument in detecting incomplete BCC excisions during Mohs micrographic surgery (MMS), using histology as the reference standard. METHODS: Skin layers from 130 patients undergoing MMS at the Nottingham University Hospitals NHS Trust (September 2022-July 2023) were investigated with the AF-Raman instrument. The layers were measured when fresh, immediately after excision. The AF-Raman results and the intraoperative assessment by Mohs surgeons were compared with a postoperative consensus-derived reference produced by three dermatopathologists. The sensitivity, specificity, and positive and negative predictive values were calculated. The study was registered with ClinicalTrials.gov (NCT03482622). RESULTS: AF-Raman analysis was successfully completed for 125 of 130 layers and, on average, covered 91% of the specimen surface area, with the lowest surface area covered being 87% for the eyelid and the highest being 94% for forehead specimens. The AF-Raman instrument identified positive margins in 24 of 36 BCC-positive cases [67% sensitivity, 95% confidence interval (CI) 49-82] and negative margins in 65 of 89 BCC-negative cases (73% specificity, 95% CI 63-82). Only one of 12 false-negative cases was caused by misclassification by the AF-Raman algorithm. The other 11 false-negatives cases were a result of no valid Raman signal being recorded at the location of the residual BCC due to either occlusion by blood or poor contact between tissue and the cassette window. The intraoperative diagnosis by Mohs surgeons identified positive margins in 31 of 36 BCC-positive cases (86% sensitivity, 95% CI 70-95) and negative margins in 79 of 89 BCC-negative cases (89% specificity, 95% CI 81-95). CONCLUSIONS: The AF-Raman instrument has the potential to provide intraoperative microscopic assessment of surgical margins in BCC surgery. Further improvements are required for tissue processing, to ensure complete coverage of the surgical specimens.


Basal cell carcinoma (BCC) is one of the most common human cancers, occurring mostly on the face and neck. Most BCCs are treated by cutting them out under local anaesthetic. This is routinely done in a hospital by a dermatologist or plastic surgeon. Surgery aims to remove all the cancer leaving the smallest scar possible, but it is often difficult to know how much normal skin to remove. Results from the laboratory often take 1 to 2 weeks to show if the cancer is clear. A technique called 'Mohs' (micrographic surgery) is recommended for these 'high-risk' BCCs. Mohs surgery removes thin layers of skin and investigates them under a microscope while the patient is still in the hospital. This is repeated until all the layers are clear of cancer. Because of the patchy availability of Mohs surgery, many patients with high-risk BCCs are treated by traditional methods that may not be as good as Mohs. We have developed an instrument that scans layers of skin and can quickly detect BCC. The instrument allows surgeons to check each removed skin layer for cancer cells to decide if more layers need to be removed. In this study, the instrument was tested on skin tissue layers from 130 patients who had Mohs surgery at the Nottingham Treatment Centre. The results showed that the instrument can measure skin layers in approximately 30 minutes and identify BCC with a similar accuracy to a Mohs surgeon, but only when the skin layers are prepared properly. With future improvements, the technology might be used to guide Mohs surgery or help surgeons in centres that do not have access to Mohs surgery.


Asunto(s)
Carcinoma Basocelular , Márgenes de Escisión , Cirugía de Mohs , Neoplasias Cutáneas , Femenino , Humanos , Masculino , Carcinoma Basocelular/cirugía , Carcinoma Basocelular/patología , Carcinoma Basocelular/diagnóstico , Neoplasia Residual/patología , Imagen Óptica/métodos , Imagen Óptica/normas , Sensibilidad y Especificidad , Piel/patología , Neoplasias Cutáneas/cirugía , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/diagnóstico , Espectrometría Raman/métodos
12.
Clin Transplant ; 38(9): e15448, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39229679

RESUMEN

INTRODUCTION: Simultaneous pancreas-kidney transplantation (SPK) is the preferred treatment for individuals with type-1 diabetes and end-stage renal disease. However, a limited supply of "Ideal Pancreas Donors" contributed to a growing disparity between available organs and recipients. Even though SPK outcomes from pediatric donors match those from adult donors, unclear guidelines on minimum age and weight criteria for extra small pediatric pancreas donors lead to hesitancy among several transplant centers to utilize these grafts due to concerns about inadequate islet mass, technical challenges, and increased risk of allograft thrombosis. METHODS: This report details the successful outcomes of SPK transplantations performed at the study center between December 2021 and January 2024, using four extra small pediatric brain-dead donors (ESPDs). Each donor was aged ≤5 years and weighed <20 kg. RESULTS: All SPK recipients achieved immediate posttransplant euglycemia without requiring insulin. None of the recipients experienced graft pancreatitis, graft thrombosis, allograft rejection, or required re-exploration. During a 5-27-month follow-up period, all ESPD recipients maintained optimal graft function, as evidenced by normal glucose tolerance tests and HbA1c (4.9%-5.2%), with 100% graft and patient survival. CONCLUSION: This report examines the usage of ESPDs in SPK transplantation, highlighting their potential to expand the donor pool and reduce wait times in areas with scarce deceased organ donations, thereby increasing the number of available organs for transplantation with acceptable outcomes. Revising donor selection guidelines to reflect the diverse risk-benefit profiles of waitlisted individuals is crucial to addressing geographical disparities and reducing organ discard rates.


Asunto(s)
Diabetes Mellitus Tipo 1 , Supervivencia de Injerto , Fallo Renal Crónico , Trasplante de Riñón , Trasplante de Páncreas , Donantes de Tejidos , Obtención de Tejidos y Órganos , Humanos , Trasplante de Páncreas/métodos , Donantes de Tejidos/provisión & distribución , Masculino , Femenino , Obtención de Tejidos y Órganos/métodos , Diabetes Mellitus Tipo 1/cirugía , Diabetes Mellitus Tipo 1/complicaciones , Pronóstico , Preescolar , Niño , Estudios de Seguimiento , Fallo Renal Crónico/cirugía , Adulto , Estudios Retrospectivos , Selección de Donante/normas , Adolescente
13.
Org Biomol Chem ; 22(36): 7354-7372, 2024 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-38973505

RESUMEN

Substituted tetrahydrofuran derivatives were designed and synthesized to serve as the P2 ligand for a series of potent HIV-1 protease inhibitors. Both enantiomers of the tetrahydrofuran derivatives were synthesized stereoselectivity in optically active forms using lipase-PS catalyzed enzymatic resolution as the key step. These tetrahydrofuran derivatives are designed to promote hydrogen bonding and van der Waals interactions with the backbone atoms in the S2 subsite of the HIV-1 protease active site. Several inhibitors displayed very potent HIV-1 protease inhibitory activity. A high-resolution X-ray crystal structure of an inhibitor-bound HIV-1 protease provided important insight into the ligand binding site interactions in the active site.


Asunto(s)
Diseño de Fármacos , Furanos , Inhibidores de la Proteasa del VIH , Proteasa del VIH , VIH-1 , Modelos Moleculares , Furanos/química , Furanos/farmacología , Furanos/síntesis química , Inhibidores de la Proteasa del VIH/farmacología , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/química , Cristalografía por Rayos X , Proteasa del VIH/metabolismo , Proteasa del VIH/química , VIH-1/enzimología , VIH-1/efectos de los fármacos , Relación Estructura-Actividad , Humanos , Estructura Molecular , Dominio Catalítico , Estereoisomerismo
14.
Crit Care ; 28(1): 18, 2024 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-38212826

RESUMEN

BACKGROUND: Sepsis and trauma are known to disrupt gut bacterial microbiome communities, but the impacts and perturbations in the fungal (mycobiome) community after severe infection or injury, particularly in patients experiencing chronic critical illness (CCI), remain unstudied. METHODS: We assess persistence of the gut mycobiome perturbation (dysbiosis) in patients experiencing CCI following sepsis or trauma for up to two-to-three weeks after intensive care unit hospitalization. RESULTS: We show that the dysbiotic mycobiome arrays shift toward a pathobiome state, which is more susceptible to infection, in CCI patients compared to age-matched healthy subjects. The fungal community in CCI patients is largely dominated by Candida spp; while, the commensal fungal species are depleted. Additionally, these myco-pathobiome arrays correlate with alterations in micro-ecological niche involving specific gut bacteria and gut-blood metabolites. CONCLUSIONS: The findings reveal the persistence of mycobiome dysbiosis in both sepsis and trauma settings, even up to two weeks post-sepsis and trauma, highlighting the need to assess and address the increased risk of fungal infections in CCI patients.


Asunto(s)
Microbioma Gastrointestinal , Micobioma , Sepsis , Humanos , Disbiosis/complicaciones , Disbiosis/microbiología , Candida , Bacterias , Sepsis/complicaciones , Hongos
15.
J Nanobiotechnology ; 22(1): 323, 2024 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-38849931

RESUMEN

BACKGROUND: The non-toxic self-crosslinked hydrogel films designed from biocompatible materials allow for controlled drug release and have gathered remarkable attention from healthcare professionals as wound dressing materials. Thus, in the current study the chitosan (CS) film is infused with oil-in-water Pickering emulsion (PE) loaded with bioactive compound quercetin (Qu) and stabilized by dialdehyde cellulose nanocrystal-silver nanoparticles (DCNC-AgNPs). The DCNC-AgNPs play a dual role in stabilizing PE and are involved in the self-crosslinking with CS films. Also, this film could combine the advantage of the controlled release and synergistic wound-healing effect of Qu and AgNPs. RESULTS: The DCNC-AgNPs were synthesized using sodium periodate oxidation of CNC. The DCNC-AgNPs were used to stabilize oil-in-water PE loaded with Qu in its oil phase by high speed homogenization. Stable PEs were prepared by 20% v/v oil: water ratio with maximum encapsulation of Qu in the oil phase. The Qu-loaded PE was then added to CS solution (50% v/v) to prepare self-crosslinked films (CS-PE-Qu). After grafting CS films with PE, the surface and cross-sectional SEM images show an inter-penetrated network within the matrix between DCNC and CS due to the formation of a Schiff base bond between the reactive aldehyde groups of DCNC-AgNPs and amino groups of CS. Further, the addition of glycerol influenced the extensibility, swelling ratio, and drug release of the films. The fabricated CS-PE-Qu films were analyzed for their wound healing and tissue regeneration potential using cell scratch assay and full-thickness excisional skin wound model in mice. The as-fabricated CS-PE-Qu films showed great biocompatibility, increased HaCat cell migration, and promoted collagen synthesis in HDFa cells. In addition, the CS-PE-Qu films exhibited non-hemolysis and improved wound closure rate in mice compared to CS, CS-Qu, and CS-blank PE. The H&E staining of the wounded skin tissue indicated the wounded tissue regeneration in CS-PE-Qu films treated mice. CONCLUSION: Results obtained here confirm the wound healing benefits of CS-PE-Qu films and project them as promising biocompatible material and well suited for full-thickness wound healing in clinical applications.


Asunto(s)
Quitosano , Emulsiones , Hidrogeles , Nanopartículas del Metal , Quercetina , Plata , Piel , Cicatrización de Heridas , Quercetina/química , Quercetina/farmacología , Cicatrización de Heridas/efectos de los fármacos , Quitosano/química , Animales , Emulsiones/química , Ratones , Humanos , Piel/efectos de los fármacos , Piel/lesiones , Nanopartículas del Metal/química , Plata/química , Hidrogeles/química , Materiales Biocompatibles/química , Vendajes , Liberación de Fármacos , Sistemas de Liberación de Medicamentos/métodos , Celulosa/química , Masculino , Regeneración/efectos de los fármacos , Células HaCaT , Oxidación-Reducción , Metilgalactósidos
16.
Tetrahedron Lett ; 1402024 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-38586565

RESUMEN

We describe a stereoselective synthesis of an optically active (1R, 3aS, 5R, 6S, 7aR)-octahydro-1,6-epoxy-isobenzo-furan-5-ol derivative. This stereochemically defined heterocycle serves as a high-affinity ligand for a variety of HIV-1 protease inhibitors. The key synthetic steps involve a highly enantioselective enzymatic desymmetrization of meso-1,2(dihydroxymethyl)cyclohex-4-ene and conversion of the resulting optically active alcohol to a methoxy hexahydroisobenzofuran derivative. A substrate controlled stereoselective dihydroxylation afforded syn-1,2-diols. Oxidation of diol provided the substituted 1,2-diketone and L-Selectride reduction provided the corresponding inverted syn-1,2-diols. Acid catalyzed cyclization furnished the ligand alcohol in optically active form.

17.
Biochem Genet ; 2024 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-39311992

RESUMEN

Picrorhiza kurroa is a valuable medicinal herb of Himalayan region, containing two major pharmacological iridoid glycosides: Picroside-I and Picroside-II, in addition to several other secondary metabolites. The metabolic diversity of P. kurroa may stem from the evolutionary processes attributed to pathway genes family expansion via gene duplication or splicing giving rise to paralogues which are further controlled by regulatory components. Occurrence of multiple pathway gene paralogues coupled with which TFs associate with paralogues in different genetic backgrounds (populations) in tissue-specific manner are still unresolved. Here, we unravelled possible correlations between TFs and gene paralogues across a range of P. kurroa accessions which might be contributing to differential contents of Picroside-I and Picroside-II in different tissues/organs. Characterization of shoots, roots, and stolons of eighty-five accessions of P. kurroa revealed significant variations for Picroside-I and Picroside-II contents. Comparative transcriptome analysis of shoot-derived transcriptome (PKSS), and root-derived transcriptome (PKSR) followed by their expression analysis in different P. kurroa accessions revealed TFs; PkWRKY71, PkWRKY12, PkNAC25, and PkMyb46 possibly regulate different gene paralogues. Genes encoding these putative TFs and pathway gene paralogues were further used to generate a robust co-expression network, thereby, uncovering their coordinated behaviour in association with Picroside-I and Picroside-II contents in shoots and roots, respectively. The outcome has provided potential leads, which through further functional validation can provide suitable targets, either for pathway engineering or as gene markers for selection of genetically superior populations of P. kurroa.

18.
J Perinat Med ; 2024 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-39275942

RESUMEN

OBJECTIVES: Complementary and Alternative Medicine (CAM) is a group of diverse medical and healthcare systems, practices, and products that are not generally considered part of conventional medicine. Pregnant women are vulnerable to adverse effects of medicines, especially during the first trimester. Though it is advised to avoid unnecessary intake of medicine during pregnancy, CAM use is widespread. METHODS: A cross-sectional questionnaire-based study was conducted on 120 pregnant women attending the antenatal clinic of a tertiary-care teaching hospital in Udaipur district of Southern Rajasthan, India. Women of age 18 years and above were surveyed between July 2022 to December 2023 by convenient sampling strategy and data were entered in a pretested and pre-validated questionnaire. The data were analyzed using descriptive statistics, the Chi-square test was applied to compare CAM use among different demographic categories and a p-value less than 0.05 was considered statistically significant. RESULTS: Out of 120 participants, 58 (48.33 %) were using CAM therapy. Out of 58 users, 44 (75.86 %) were using herbal & traditional medicines. Twenty (34.48 %) were using CAM for a healthy baby, 18 (31.03 %) for easy delivery and 17 (29.31 %) for boosting immunity. Forty (68.96 %) participants started CAM on the advice of a relative/friend. Fifty six (46.67 %) participants believe that CAM therapy cannot cause adverse effects on the in utero child, while 32 (26.67 %) believe that CAM and modern medicines don't interact. CONCLUSIONS: CAM use among pregnant women is substantial. There is a need to raise awareness among the healthcare professionals and pregnant women regarding possible adverse effects and drug-drug interactions with CAM use.

19.
J Am Chem Soc ; 145(4): 2499-2510, 2023 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-36683341

RESUMEN

Intramolecular singlet fission (iSF) facilitates single-molecule exciton multiplication, converting an excited singlet state to a pair of triplet states within a single molecule. A critical parameter in determining the feasibility of SF-enhanced photovoltaic designs is the triplet energy; many existing iSF materials have triplet energies too low for efficient transfer to silicon via a photon multiplier scheme. In this work, a series of six novel dimers based upon the high-triplet-energy, SF-active chromophore, 1,6-diphenyl-1,3,5-hexatriene (DPH) [E(T1) ∼ 1.5 eV], were designed, synthesized, and characterized. Transient absorption spectroscopy and fluorescence lifetime studies reveal that five of the dimers display iSF activity, with time constants for singlet fission varying between 7 ± 2 ps and 2.2 ± 0.2 ns and a high triplet yield of 163 ± 63% in the best-performing dimer. A strong dependence of the rate of fission on the coupling geometry is demonstrated. For optimized iSF behavior, close spatial proximity and minimal through-bond communication are found to be crucial for balancing the rate of SF against the reverse recombination process.

20.
Emerg Infect Dis ; 29(11): 2406-2408, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37877682

RESUMEN

Scedosporium aurianticum infection developed in 2 recipients of kidney transplants in India, acquired from the same deceased near-drowning donor. Given the substantial risk for death associated with Scedosporium infection among solid-organ transplant recipients, safety protocols for organ transplantation from nearly drowned donors should be thoroughly revaluated and refined.


Asunto(s)
Trasplante de Riñón , Ahogamiento Inminente , Trasplante de Órganos , Humanos , Trasplante de Riñón/efectos adversos , Donantes de Tejidos
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