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Public health studies indicate that artificial light is a high-risk factor for metabolic disorders. However, the neural mechanism underlying metabolic modulation by light remains elusive. Here, we found that light can acutely decrease glucose tolerance (GT) in mice by activation of intrinsically photosensitive retinal ganglion cells (ipRGCs) innervating the hypothalamic supraoptic nucleus (SON). Vasopressin neurons in the SON project to the paraventricular nucleus, then to the GABAergic neurons in the solitary tract nucleus, and eventually to brown adipose tissue (BAT). Light activation of this neural circuit directly blocks adaptive thermogenesis in BAT, thereby decreasing GT. In humans, light also modulates GT at the temperature where BAT is active. Thus, our work unveils a retina-SON-BAT axis that mediates the effect of light on glucose metabolism, which may explain the connection between artificial light and metabolic dysregulation, suggesting a potential prevention and treatment strategy for managing glucose metabolic disorders.
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Tejido Adiposo Pardo , Hipotálamo , Ratones , Animales , Humanos , Tejido Adiposo Pardo/metabolismo , Hipotálamo/metabolismo , Termogénesis/fisiología , Retina , Células Ganglionares de la Retina , Glucosa/metabolismoRESUMEN
Aberrant energy status contributes to multiple metabolic diseases, including obesity, diabetes, and cancer, but the underlying mechanism remains elusive. Here, we report that ketogenic-diet-induced changes in energy status enhance the efficacy of anti-CTLA-4 immunotherapy by decreasing PD-L1 protein levels and increasing expression of type-I interferon (IFN) and antigen presentation genes. Mechanistically, energy deprivation activates AMP-activated protein kinase (AMPK), which in turn, phosphorylates PD-L1 on Ser283, thereby disrupting its interaction with CMTM4 and subsequently triggering PD-L1 degradation. In addition, AMPK phosphorylates EZH2, which disrupts PRC2 function, leading to enhanced IFNs and antigen presentation gene expression. Through these mechanisms, AMPK agonists or ketogenic diets enhance the efficacy of anti-CTLA-4 immunotherapy and improve the overall survival rate in syngeneic mouse tumor models. Our findings reveal a pivotal role for AMPK in regulating the immune response to immune-checkpoint blockade and advocate for combining ketogenic diets or AMPK agonists with anti-CTLA4 immunotherapy to combat cancer.
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Proteínas Quinasas Activadas por AMP/genética , Antígeno B7-H1/genética , Neoplasias de la Mama/genética , Antígeno CTLA-4/genética , Neoplasias Colorrectales/genética , Inhibidores de Puntos de Control Inmunológico , Proteínas Quinasas Activadas por AMP/inmunología , Aloinjertos , Animales , Anticuerpos Neutralizantes/farmacología , Antineoplásicos/farmacología , Antígeno B7-H1/inmunología , Compuestos de Bifenilo/farmacología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Línea Celular Tumoral , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/terapia , Dieta Cetogénica/métodos , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/genética , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia/métodos , Proteínas con Dominio MARVEL/genética , Proteínas con Dominio MARVEL/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Pironas/farmacología , Transducción de Señal , Análisis de Supervivencia , Tiofenos/farmacologíaRESUMEN
Synaptic plasticity induced by cocaine and other drugs underlies addiction. Here we elucidate molecular events at synapses that cause this plasticity and the resulting behavioral response to cocaine in mice. In response to D1-dopamine-receptor signaling that is induced by drug administration, the glutamate-receptor protein metabotropic glutamate receptor 5 (mGluR5) is phosphorylated by microtubule-associated protein kinase (MAPK), which we show potentiates Pin1-mediated prolyl-isomerization of mGluR5 in instances where the product of an activity-dependent gene, Homer1a, is present to enable Pin1-mGluR5 interaction. These biochemical events potentiate N-methyl-D-aspartate receptor (NMDAR)-mediated currents that underlie synaptic plasticity and cocaine-evoked motor sensitization as tested in mice with relevant mutations. The findings elucidate how a coincidence of signals from the nucleus and the synapse can render mGluR5 accessible to activation with consequences for drug-induced dopamine responses and point to depotentiation at corticostriatal synapses as a possible therapeutic target for treating addiction.
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Trastornos Relacionados con Cocaína/fisiopatología , Cocaína/metabolismo , Dopamina/metabolismo , Isomerasa de Peptidilprolil/metabolismo , Secuencia de Aminoácidos , Animales , Encéfalo/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Embrión de Mamíferos/metabolismo , Proteínas de Andamiaje Homer , Potenciación a Largo Plazo , Ratones , Datos de Secuencia Molecular , Peptidilprolil Isomerasa de Interacción con NIMA , Fosforilación , Receptores AMPA/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Ácido Kaínico/química , Receptores de Ácido Kaínico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismoRESUMEN
Classical Swine Fever (CSF), caused by the Classical Swine Fever Virus (CSFV), inflicts significant economic losses on the global pig industry. A key factor in the challenge of eradicating this virus is its ability to evade the host's innate immune response, leading to persistent infections. In our study, we elucidate the molecular mechanism through which CSFV exploits m6A modifications to circumvent host immune surveillance, thus facilitating its proliferation. We initially discovered that m6A modifications were elevated both in vivo and in vitro upon CSFV infection, particularly noting an increase in the expression of the methyltransferase METTL14. CSFV non-structural protein 5B was found to hijack HRD1, the E3 ubiquitin ligase for METTL14, preventing METTL14 degradation. MeRIP-seq analysis further revealed that METTL14 specifically targeted and methylated TLRs, notably TLR4. METTL14-mediated regulation of TLR4 degradation, facilitated by YTHDF2, led to the accelerated mRNA decay of TLR4. Consequently, TLR4-mediated NF-κB signaling, a crucial component of the innate immune response, is suppressed by CSFV. Collectively, these data effectively highlight the viral evasion tactics, shedding light on potential antiviral strategies targeting METTL14 to curb CSFV infection.
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Adenina , Virus de la Fiebre Porcina Clásica , Peste Porcina Clásica , Animales , Virus de la Fiebre Porcina Clásica/genética , Inmunidad Innata , Porcinos , Receptor Toll-Like 4RESUMEN
We have created a mouse genetic model that mimics a human mutation of Shank3 that deletes the C terminus and is associated with autism. Expressed as a single copy [Shank3(+/ΔC) mice], Shank3ΔC protein interacts with the wild-type (WT) gene product and results in >90% reduction of Shank3 at synapses. This "gain-of-function" phenotype is linked to increased polyubiquitination of WT Shank3 and its redistribution into proteasomes. Similarly, the NR1 subunit of the NMDA receptor is reduced at synapses with increased polyubiquitination. Assays of postsynaptic density proteins, spine morphology, and synapse number are unchanged in Shank3(+/ΔC) mice, but the amplitude of NMDAR responses is reduced together with reduced NMDAR-dependent LTP and LTD. Reciprocally, mGluR-dependent LTD is markedly enhanced. Shank3(+/ΔC) mice show behavioral deficits suggestive of autism and reduced NMDA receptor function. These studies reveal a mechanism distinct from haploinsufficiency by which mutations of Shank3 can evoke an autism-like disorder.
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Trastorno Autístico/genética , Proteínas Portadoras/metabolismo , Modelos Animales de Enfermedad , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Trastorno Autístico/metabolismo , Trastorno Autístico/fisiopatología , Proteínas Portadoras/genética , Hipocampo/metabolismo , Humanos , Relaciones Interpersonales , Potenciación a Largo Plazo , Depresión Sináptica a Largo Plazo , Ratones , Proteínas de Microfilamentos , Proteínas del Tejido Nervioso , Receptores de Glutamato Metabotrópico/metabolismo , Sinapsis/metabolismo , UbiquitinaciónRESUMEN
Upstream open reading frames (uORFs) are known to negatively affect translation of the downstream ORF. The regulatory proteins involved in relieving this inhibition are however poorly characterized. In response to cellular stress, eIF2α phosphorylation leads to an inhibition of global protein synthesis, while translation of specific factors such as CHOP is induced. We analyzed a 105-nt inhibitory uORF in the transcript of human CHOP (huORFchop ) and found that overexpression of the zebrafish or human ENDOU poly(U)-endoribonuclease (Endouc or ENDOU-1, respectively) increases CHOP mRNA translation also in the absence of stress. We also found that Endouc/ENDOU-1 binds and cleaves the huORFchop transcript at position 80G-81U, which induces CHOP translation independently of phosphorylated eIF2α. However, both ENDOU and phospho-eIF2α are nonetheless required for maximal translation of CHOP mRNA. Increased levels of ENDOU shift a huORFchop reporter as well as endogenous CHOP transcripts from the monosome to polysome fraction, indicating an increase in translation. Furthermore, we found that the uncapped truncated huORFchop -69-105-nt transcript contains an internal ribosome entry site (IRES), facilitating translation of the cleaved transcript. Therefore, we propose a model where ENDOU-mediated transcript cleavage positively regulates CHOP translation resulting in increased CHOP protein levels upon stress. Specifically, CHOP transcript cleavage changes the configuration of huORFchop thereby releasing its inhibition and allowing the stalled ribosomes to resume translation of the downstream ORF.
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ARN Mensajero/genética , Factor de Transcripción CHOP/genética , Endorribonucleasas Específicas de Uridilato/metabolismo , Animales , Células HEK293 , Células HeLa , Humanos , Motivos de Nucleótidos , Sistemas de Lectura Abierta/genética , Biosíntesis de Proteínas , ARN Mensajero/química , ARN Mensajero/metabolismo , Ribosomas/metabolismo , Factor de Transcripción CHOP/metabolismo , Pez CebraRESUMEN
Sepsis arises from an uncontrolled inflammatory response triggered by infection or stress, accompanied by alteration in cellular energy metabolism, and a strong correlation exists between these factors. Alpha-ketoglutarate (α-KG), an intermediate product of the TCA cycle, has the potential to modulate the inflammatory response and is considered a crucial link between energy metabolism and inflammation. The scavenger receptor (SR-A5), a significant pattern recognition receptor, assumes a vital function in anti-inflammatory reactions. In the current investigation, we have successfully illustrated the ability of α-KG to mitigate inflammatory factors in the serum of septic mice and ameliorate tissue damage. Additionally, α-KG has been shown to modulate metabolic reprogramming and macrophage polarization. Moreover, our findings indicate that the regulatory influence of α-KG on sepsis is mediated through SR-A5. We also elucidated the mechanism by which α-KG regulates SR-A5 expression and found that α-KG reduced the N6-methyladenosine level of macrophages by up-regulating the m6A demethylase ALKBH5. α-KG plays a crucial role in inhibiting inflammation by regulating SR-A5 expression through m6A demethylation during sepsis. The outcomes of this research provide valuable insights into the relationship between energy metabolism and inflammation regulation, as well as the underlying molecular regulatory mechanism.
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The role of mesenchymal-stem-cell-derived exosomes (MSCs-Exo) in the regulation of macrophage polarization has been recognized in several diseases. There is emerging evidence that MSCs-Exo partially prevent the progression of diabetic nephropathy (DN). This study aimed to investigate whether exosomes secreted by MSCs pre-treated with a diabetic environment (Exo-pre) have a more pronounced protective effect against DN by regulating the balance of macrophages. Exo-pre and Exo-Con were isolated from the culture medium of UC-MSCs pre-treated with a diabetic mimic environment and natural UC-MSCs, respectively. Exo-pre and Exo-Con were injected into the tail veins of db/db mice three times a week for 6 weeks. Serum creatinine and serum urea nitrogen levels, the urinary protein/creatinine ratio, and histological staining were used to determine renal function and morphology. Macrophage phenotypes were analyzed by immunofluorescence, western blotting, and quantitative reverse transcription polymerase chain reaction. In vitro, lipopolysaccharide-induced M1 macrophages were incubated separately with Exo-Con and Exo-pre. We performed microRNA (miRNA) sequencing to identify candidate miRNAs and predict their target genes. An miRNA inhibitor was used to confirm the role of miRNAs in macrophage modulation. Exo-pre were more potent than Exo-Con at alleviating DN. Exo-pre administration significantly reduced the number of M1 macrophages and increased the number of M2 macrophages in the kidney compared to Exo-Con administration. Parallel outcomes were observed in the co-culture experiments. Moreover, miR-486-5p was distinctly expressed in Exo-Con and Exo-pre groups, and it played an important role in macrophage polarization by targeting PIK3R1 through the PI3K/Akt pathway. Reducing miR-486-5p levels in Exo-pre abolished macrophage polarization modulation. Exo-pre administration exhibited a superior effect on DN by remodeling the macrophage balance by shuttling miR-486-5p, which targets PIK3R1.
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Nefropatías Diabéticas , Exosomas , Macrófagos , Células Madre Mesenquimatosas , MicroARNs , Cordón Umbilical , Exosomas/metabolismo , Animales , Células Madre Mesenquimatosas/metabolismo , Nefropatías Diabéticas/metabolismo , Ratones , Macrófagos/metabolismo , MicroARNs/metabolismo , MicroARNs/genética , Cordón Umbilical/citología , Cordón Umbilical/metabolismo , Masculino , Ratones Endogámicos C57BL , Activación de MacrófagosRESUMEN
Human brain microvascular endothelial cells (HBMVECs) and microglia play critical roles in regulating cerebral homeostasis during ischemic stroke. However, the role of HBMVECs-derived exosomes in microglia polarization after stroke remains unknown. We isolated exosomes (Exos) from oxygen glucose deprivation (OGD)-exposed HBMVECs, before added them into microglia. Microglia polarization markers were tested using RT-qPCR or flow cytometry. Inflammatory cytokines were measured with ELISA. Endothelial cell damage was assessed by cell viability, apoptosis, apoptosis-related proteins, oxidative stress, and angiogenic activity using CCK-8, flow cytometry, western blot, ELISA, and endothelial tube formation assay, respectively. We also established middle cerebral artery occlusion (MCAO) mice model to examine the function of circ_0000495 on stroke in vivo. Our study found that HBMVECs-Exos reduced M2 markers (IL-10, CD163, and CD206), increased M1 markers (TNF-α, IL-1ß, and IL-12), CD86-positive cells, and inflammatory cytokines (TNF-α and IL-1ß), indicating the promotion of microglial M1-polarization. Microglial M1-polarization induced by HBMVECs-Exos reduced viability and promoted apoptosis and oxidative stress, revealing the aggravation of endothelial cell damage. However, circ_0000495 silencing inhibited HBMVECs-Exos-induced alterations. Mechanistically, circ_0000495 adsorbed miR-579-3p to upregulate toll-like receptor 4 (TLR4) in microglia; miR-579-3p suppressed HBMVECs-Exos-induced alterations via declining TLR4; furthermore, Yin Yang 1 (YY1) transcriptionally activated circ_0000495 in HBMVECs. Importantly, circ_0000495 aggravated ischemic brain injury in vivo via activating TLR4/nuclear factor-κB (NF-κB) pathway. Collectively, OGD-treated HBMVECs-Exos transmitted circ_0000495 to regulate miR-579-3p/TLR4/NF-κB axis in microglia, thereby facilitating microglial M1-polarization and endothelial cell damage.
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Exosomas , MicroARNs , Accidente Cerebrovascular , Animales , Ratones , Humanos , Células Endoteliales , Microglía , Receptor Toll-Like 4/genética , FN-kappa B , Factor de Necrosis Tumoral alfa , Encéfalo , Hipoxia , Oxígeno , Citocinas , MicroARNs/genéticaRESUMEN
Covering: 2017.01 to 2023.11Natural products biosynthesized by myxobacteria are appealing due to their sophisticated chemical skeletons, remarkable biological activities, and intriguing biosynthetic enzymology. This review aims to systematically summarize the advances in the discovery methods, new structures, and bioactivities of myxobacterial NPs reported in the period of 2017-2023. In addition, the peculiar biosynthetic pathways of several structural families are also highlighted.
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Productos Biológicos , Myxococcales , Productos Biológicos/metabolismo , Productos Biológicos/química , Myxococcales/metabolismo , Myxococcales/química , Estructura Molecular , Vías Biosintéticas , Descubrimiento de DrogasRESUMEN
Baculoviruses are highly host specific, and their host range is usually restricted to a single or a few closely related insect species, except for few virus species, e.g. Alphabaculovirus aucalifonicae and Alphabaculovirus mabrassicae. In this study, two new alphabaculovirus isolates were isolated from the larvae of Mamestra brassicae and Mythimna separata, which were named as Mamestra brassicae multiple nucleopolyhedrovirus isolate QD (MbMNPV-QD) and Mythimna separata multiple nucleopolyhedrovirus isolate Hb (MyseMNPV-Hb), respectively. The Kimura two-parameter values based on the concatenated 38 core genes of baculovirus revealed that MbMNPV (isolates QD/CHb1/K1/CTa), MyseMNPV-Hb, Helicoverpa armigera multiple nucleopolyhedrovirus (HearMNPV) and Mamestra configurata nucleopolyhedrovirus B (MacoNPV-B) were different isolates of a same virus species. A phylogenetic tree of baculoviruses and nudiviruses constructed from their 20 homologous gene sequences, and that of their isolated hosts constructed from 13 protein-coding genes of the insect mitochondrial genomes, were used to analyse the coevolution of baculoviruses with their isolated hosts. The results showed that M. brassicae was the most likely ancestral host of these virus isolates, included MbMNPV isolates, MyseMNPV-Hb, HearMNPV, and MacoNPV-B. Therefore, we concluded that these virus isolates belong to the existing virus species - Alphabaculovirus mabrassicae with M. brassicae as their ancestral host.
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Mariposas Nocturnas , Nucleopoliedrovirus , Animales , Nucleopoliedrovirus/genética , Filogenia , Larva , Baculoviridae , Especificidad del Huésped , InsectosRESUMEN
BACKGROUND: Biologic therapies in the context of IBD and pregnancy lead to improved maternal and fetal outcomes. Placental transfer results in detectable drug concentrations in infants. Rotavirus infection results in diarrheal related hospitalizations, however, the live oral vaccine is not currently recommended in biologic exposed infants. AIMS: To assess the effect of maternal biologic therapies on the infant immune system and safety of live rotavirus vaccination in biologic-exposed infants. METHODS: Biologic-exposed infants underwent standardized clinical assessments, drug concentration, and immune function testing (complete blood count, differential, immunoglobulin levels, extended B-cell and T-cell subset enumeration, Recent Thymic Emigrants, regulatory T-cell numbers, mitogen stimulation assays, and review of T-cell Receptor Excision Circles in the newborn screen). Rotavirus vaccine-specific adverse effects following immunizations up to 42 days post the last dose of the vaccine series were recorded. RESULTS: There were 57 infants born to 52 mothers with IBD exposed to infliximab (n=21), adalimumab (n=19), vedolizumab (n=10), and ustekinumab (n=7) in the third trimester. Median 39 (IQR 38-39) weeks at delivery. Immunologic assessments validated for age were normal in all infants despite median infliximab concentrations of 6.1 ug/mL (range 0.4-28.8), adalimumab 1.7 ug/mL (range 0.7-7.9), ustekinumab 0.6 ug/mL (range 0-1.1) and undetectable for vedolizumab at 10.7 weeks (IQR 9.4-12.4) of age. The live oral rotavirus vaccine series was provided to 50 infants with the first dose given at a median of 13 weeks of age. No adverse effects following immunization were reported. CONCLUSION: Immune function testing was normal and administration of live rotavirus vaccination appeared low-risk in biologic-exposed infants irrespective of circulating drug levels.
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Immune thrombocytopenia (ITP) is an autoimmune disease caused by the loss of immune tolerance to platelet autoantigens, resulting in reduced platelet production and increased platelet destruction. Impaired megakaryocyte differentiation and maturation is a key factor in the pathogenesis and treatment of ITP. Sarcandra glabra, a plant of the Chloranthaceae family, is commonly used in clinical practice to treat ITP, and daucosterol (Dau) is one of its active ingredients. However, whether Dau can treat ITP and the key mechanism of its effect are still unclear. In this study, we found that Dau could effectively promote the differentiation and maturation of megakaryocytes and the formation of polyploidy in the megakaryocyte differentiation disorder model constructed by co-culturing Dami and HS-5 cells. In vivo experiments showed that Dau could not only increase the number of polyploidized megakaryocytes in the ITP rat model, but also promote the recovery of platelet count. In addition, through network pharmacology analysis, we speculated that the JAK2-STAT3 signaling pathway might be involved in the process of Dau promoting megakaryocyte differentiation. Western blot results showed that Dau inhibited the expression of P-JAK2 and P-STAT3. In summary, these results provide a basis for further studying the pharmacological mechanism of Dau in treating ITP.
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Diferenciación Celular , Janus Quinasa 2 , Megacariocitos , Púrpura Trombocitopénica Idiopática , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Humanos , Masculino , Ratas , Diferenciación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Janus Quinasa 2/metabolismo , Megacariocitos/metabolismo , Megacariocitos/efectos de los fármacos , Megacariocitos/citología , Púrpura Trombocitopénica Idiopática/metabolismo , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/patología , Transducción de Señal/efectos de los fármacos , Sitoesteroles/farmacología , Factor de Transcripción STAT3/metabolismoRESUMEN
Breast cancer (BC) is a multifaceted disease characterized by distinct molecular subtypes and varying responses to treatment. In BC, the phosphatidylinositol 3-kinase (PI3K) pathway has emerged as a crucial contributor to the development, advancement, and resistance to treatment. This review article explores the implications of the PI3K pathway in predictive, preventive, and personalized medicine for BC. It emphasizes the identification of predictive biomarkers, such as PIK3CA mutations, and the utility of molecular profiling in guiding treatment decisions. The review also discusses the potential of targeting the PI3K pathway for preventive strategies and the customization of therapy based on tumor stage, molecular subtypes, and genetic alterations. Overcoming resistance to PI3K inhibitors and exploring combination therapies are addressed as important considerations. While this field holds promise in improving patient outcomes, further research and clinical trials are needed to validate these approaches and translate them into clinical practice.
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Neoplasias de la Mama , Fosfatidilinositol 3-Quinasa , Humanos , Femenino , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Mama/patología , Medicina de Precisión , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Mutación/genética , Fosfatidilinositol 3-Quinasa Clase I , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
As the important molecular machinery for membrane protein sorting in eukaryotic cells, the endosomal sorting and transport complexes (ESCRT-0/I/II/III and VPS4) usually participate in various replication stages of enveloped viruses, such as endocytosis and budding. The main subunit of ESCRT-I, Tsg101, has been previously revealed to play a role in the entry and replication of classical swine fever virus (CSFV). However, the effect of the whole ESCRT machinery during CSFV infection has not yet been well defined. Here, we systematically determine the effects of subunits of ESCRT on entry, replication, and budding of CSFV by genetic analysis. We show that EAP20 (VPS25) (ESCRT-II), CHMP4B and CHMP7 (ESCRT-III) regulate CSFV entry and assist vesicles in transporting CSFV from Clathrin, early endosomes, late endosomes to lysosomes. Importantly, we first demonstrate that HRS (ESCRT-0), VPS28 (ESCRT-I), VPS25 (ESCRT-II) and adaptor protein ALIX play important roles in the formation of virus replication complexes (VRC) together with CHMP2B/4B/7 (ESCRT-III), and VPS4A. Further analyses reveal these subunits interact with CSFV nonstructural proteins (NS) and locate in the endoplasmic reticulum, but not Golgi, suggesting the role of ESCRT in regulating VRC assembly. In addition, we demonstrate that VPS4A is close to lipid droplets (LDs), indicating the importance of lipid metabolism in the formation of VRC and nucleic acid production. Altogether, we draw a new picture of cellular ESCRT machinery in CSFV entry and VRC formation, which could provide alternative strategies for preventing and controlling the diseases caused by CSFV or other Pestivirus.
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Virus de la Fiebre Porcina Clásica/metabolismo , Peste Porcina Clásica/virología , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , ARN/metabolismo , Proteínas no Estructurales Virales/metabolismo , Animales , Línea Celular , Virus de la Fiebre Porcina Clásica/genética , Clatrina/metabolismo , Retículo Endoplásmico/metabolismo , Interacciones Microbiota-Huesped , Porcinos , Vesículas Transportadoras , Internalización del Virus , Replicación ViralRESUMEN
Mode-pairing quantum key distribution (MP-QKD) holds great promise for the practical implementation of QKD in the near future. It combines the security advantages of measurement device independence while still being capable of breaking the Pirandola-Laurenza-Ottaviani-Banchi bound without the need for highly demanding phase-locking and phase-tracking technologies for deployment. In this work, we explore optimization strategies for MP-QKD in a wavelength-division multiplexing scenario. The simulation results reveal that incorporation of multiple wavelengths not only leads to a direct increase in key rate but also enhances the pairing efficiency by employing our novel pairing strategies among different wavelengths. As a result, our work provides a new avenue for the future application and development of MP-QKD.
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Non-structural carbohydrates (NSCs) are building blocks for biomass and fuel metabolic processes. However, it remains unclear how tropical forests mobilize, export, and transport NSCs to cope with extreme droughts. We combined drought manipulation and ecosystem 13CO2 pulse-labeling in an enclosed rainforest at Biosphere 2, assessed changes in NSCs, and traced newly assimilated carbohydrates in plant species with diverse hydraulic traits and canopy positions. We show that drought caused a depletion of leaf starch reserves and slowed export and transport of newly assimilated carbohydrates below ground. Drought effects were more pronounced in conservative canopy trees with limited supply of new photosynthates and relatively constant water status than in those with continual photosynthetic supply and deteriorated water status. We provide experimental evidence that local utilization, export, and transport of newly assimilated carbon are closely coupled with plant water use in canopy trees. We highlight that these processes are critical for understanding and predicting tree resistance and ecosystem fluxes in tropical forest under drought.
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Carbono , Bosque Lluvioso , Carbono/metabolismo , Ecosistema , Sequías , Agua/metabolismo , Árboles/metabolismo , Carbohidratos , Hojas de la Planta/metabolismoRESUMEN
BACKGROUND: Early intervention and diagnosis of Metabolic Syndrome (MetS) are crucial for preventing adult cardiovascular disease. However, the optimal indicator for identifying MetS in adolescent remains controversial. METHODS: In total,1408 Chinese adolescents and 3550 American adolescents aged 12-17 years were included. MetS was defined according to the modified version for adolescents based on Adult Treatment Panel III (NCEP-ATP III) criteria. Areas under the curve (AUC) and corresponding 95% confidence interval (95% CI) of 8 anthropometric/metabolic indexes, such as waist circumference (WC), body mass index (BMI), a body shape index (ABSI), waist triglyceride index (WTI), were calculated to illustrate their ability to differentiate MetS. Sensitivity analysis using the other MetS criteria was performed. RESULTS: Under the modified NCEP-ATP III criteria, WTI had the best discriminating ability in overall adolescents, with AUC of 0.922 (95% CI: 0.900-0.945) in Chinese and 0.959 (95% CI: 0.949-0.969) in American. In contrast, ABSI had the lowest AUCs. Results of sensitivity analysis were generally consistent for the whole Chinese and American population, with the AUC for WC being the highest under some criteria, but it was not statistically different from that of WTI. CONCLUSIONS: WTI had relatively high discriminatory power for MetS detection in Chinese and American adolescents, but the performance of ABSI was poor. IMPACT: While many studies have compared the discriminatory power of some anthropometric indicators for MetS, there are few focused on pediatrics. The current study is the first to compare the discriminating ability of anthropometric/metabolic indicators (WC, BMI, TMI, ABSI, WHtR, VAI, WTI, and TyG) for MetS in adolescents. WTI remains the optimal indicator in screening for MetS in adolescents. WC was also a simple and reliable indicator when screening for MetS in adolescents, but the performance of ABSI was poor. This study provides a theoretical basis for the early identification of MetS in adolescents by adopting effective indicators.
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The development of natural products for potential new drugs faces obstacles such as unknown mechanisms, poor solubility, and limited bioavailability, which limit the broadened applicability of natural products. Therefore, there is a need for advanced pharmaceutical formulations of active compounds or natural products. In recent years, novel nano-drug delivery systems (NDDS) for natural products, including nanosuspensions, nanoliposomes, micelle, microemulsions/self-microemulsions, nanocapsules, and solid lipid nanoparticles, have been developed to improve solubility, bioavailability, and tissue distribution as well as for prolonged retention and enhanced permeation. Here, we updated the NDDS delivery systems used for natural products with the potential enhancement in therapeutic efficiency observed with nano-delivery systems.
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Productos Biológicos , Sistemas de Liberación de Medicamentos , Sistema de Administración de Fármacos con Nanopartículas , Disponibilidad BiológicaRESUMEN
A Lewis acid-catalyzed intramolecular Hosomi-Sakurai reaction of o-(allylsilyl)benzaldehyde/ketone has been developed. The reaction proceeds through simultaneous C-Si bond cleavage and C-C bond reconstruction. This protocol provides a rapid approach for the synthesis of allyl-substituted benzoxasiloles under mild conditions.