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The hedonic value of salt fundamentally changes depending on the internal state. High concentrations of salt induce innate aversion under sated states, whereas such aversive stimuli transform into appetitive ones under sodium depletion. Neural mechanisms underlying this state-dependent salt valence switch are poorly understood. Using transcriptomics state-to-cell-type mapping and neural manipulations, we show that positive and negative valences of salt are controlled by anatomically distinct neural circuits in the mammalian brain. The hindbrain interoceptive circuit regulates sodium-specific appetitive drive , whereas behavioral tolerance of aversive salts is encoded by a dedicated class of neurons in the forebrain lamina terminalis (LT) expressing prostaglandin E2 (PGE2) receptor, Ptger3. We show that these LT neurons regulate salt tolerance by selectively modulating aversive taste sensitivity, partly through a PGE2-Ptger3 axis. These results reveal the bimodal regulation of appetitive and tolerance signals toward salt, which together dictate the amount of sodium consumption under different internal states.
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Vías Nerviosas , Sodio , Gusto , Animales , Vías Nerviosas/fisiología , Gusto/fisiología , Ratones , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: WHO recommends that electronic medication monitors, a form of digital adherence technology, be used as a complement to directly observed treatment (DOT) for tuberculosis, as DOT is inconvenient and costly. However, existing evidence about the effectiveness of these monitors is inconclusive. Therefore, we evaluated the effectiveness of a comprehensive package based on electronic medication monitors among patients with tuberculosis in Tibet Autonomous Region (hereafter Tibet), China. METHODS: This multicentre, randomised controlled trial recruited patients from six counties in Shigatse, Tibet. Eligible participants had drug-susceptible tuberculosis and were aged 15 years or older when starting standard tuberculosis treatment. Tuberculosis doctors recruited patients from the public tuberculosis dispensary in each county and the study statistician randomly assigned them to the intervention or control group based on the predetermined randomised allocation sequence. Intervention patients received an electronic medication monitor box. The box included audio medication-adherence reminders and recorded box-opening data, which were transmitted to a cloud-based server and were accessible to health-care providers to allow remote adherence monitoring. A linked smartphone app enabled text, audio, and video communication between patients and health-care providers. Patients were also provided with a free data plan. Patients selected a treatment supporter (often a family member) who was trained to support patients with using the electronic medication monitor and app. Patients in the control group received usual care plus a deactivated electronic medication monitor, which only recorded and transmitted box-opening data that was not made available to health-care providers. The control group also had no access to the app or trained treatment supporters. The primary outcome was a binary indicator of poor monthly adherence, defined as missing 20% or more of planned doses in the treatment month, measured using electronic medication monitor opening data, and verified by counting used medication blister packages during consultations. We recorded other secondary treatment outcomes based on national tuberculosis reporting data. We analysed the primary outcome based on the intention-to-treat population. This trial is registered at ISRCTN, 52132803. FINDINGS: Between Nov 17, 2018, and April 5, 2021, 278 patients were enrolled into the study. 143 patients were randomly assigned to the intervention group and 135 patients to the control group. Follow-up ended when the final patient completed treatment on Oct 4, 2021. In the intervention group, 87 (10%) of the 854 treatment months showed poor adherence compared with 290 (37%) of the 795 months in the control group. The corresponding adjusted risk difference for the intervention versus control was -29·2 percentage points (95% CI -35·3 to -22·2; p<0·0001). Five of the six secondary treatment outcomes also showed clear improvements, including treatment success, which was found for 133 (94%) of the 142 individuals in the intervention arm and 98 (73%) of the 134 individuals in the control arm, with an adjusted risk difference of 21 percentage points (95% CI 12·4-29·4); p<0·0001. INTERPRETATION: The interventions were effective at improving tuberculosis treatment adherence and outcomes, and the trial suggests that a comprehensive package involving electronic medication monitors might positively affect tuberculosis programmes in high-burden and low-resource settings. FUNDING: TB REACH.
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Tuberculosis , Humanos , Tibet , Tuberculosis/tratamiento farmacológico , Resultado del Tratamiento , Cumplimiento de la Medicación , ChinaRESUMEN
Regulation of glucose transport, which is central for control of whole-body metabolism, is determined by the amount of GLUT4 glucose transporter (also known as SLC2A4) in the plasma membrane (PM) of fat and muscle cells. Physiologic signals [such as activated insulin receptor or AMP-activated protein kinase (AMPK)] increase PM GLUT4. Here, we show that the distribution of GLUT4 between the PM and interior of human muscle cells is dynamically maintained, and that AMPK promotes PM redistribution of GLUT4 by regulating exocytosis and endocytosis. Stimulation of exocytosis by AMPK is mediated by Rab10 and the Rab GTPase-activating protein TBC1D4. APEX2 proximity mapping reveals that GLUT4 traverses both PM-proximal and PM-distal compartments in unstimulated muscle cells, further supporting retention of GLUT4 by a constitutive retrieval mechanism. AMPK-stimulated translocation involves GLUT4 redistribution among the same compartments traversed in unstimulated cells, with a significant recruitment of GLUT4 from the Golgi and trans-Golgi network compartments. Our comprehensive proximal protein mapping provides an integrated, high-density, whole-cell accounting of the localization of GLUT4 at a resolution of â¼20â nm that serves as a structural framework for understanding the molecular mechanisms regulating GLUT4 trafficking downstream of different signaling inputs in a physiologically relevant cell type.
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Transportador de Glucosa de Tipo 4 , Células Musculares , Proteoma , Humanos , Proteínas Quinasas Activadas por AMP , Membrana Celular , Músculos , Transportador de Glucosa de Tipo 4/metabolismoRESUMEN
Omics data from clinical samples are the predominant source of target discovery and drug development. Typically, hundreds or thousands of differentially expressed genes or proteins can be identified from omics data. This scale of possibilities is overwhelming for target discovery and validation using biochemical or cellular experiments. Most of these proteins and genes have no corresponding drugs or even active compounds. Moreover, a proportion of them may have been previously reported as being relevant to the disease of interest. To facilitate translational drug discovery from omics data, we have developed a new classification tool named Omics and Text driven Translational Medicine (OTTM). This tool can markedly narrow the range of proteins or genes that merit further validation via drug availability assessment and literature mining. For the 4489 candidate proteins identified in our previous proteomics study, OTTM recommended 40 FDA-approved or clinical trial drugs. Of these, 15 are available commercially and were tested on hepatocellular carcinoma Hep-G2 cells. Two drugs-tafenoquine succinate (an FDA-approved antimalarial drug targeting CYC1) and branaplam (a Phase 3 clinical drug targeting SMN1 for the treatment of spinal muscular atrophy)-showed potent inhibitory activity against Hep-G2 cell viability, suggesting that CYC1 and SMN1 may be potential therapeutic target proteins for hepatocellular carcinoma. In summary, OTTM is an efficient classification tool that can accelerate the discovery of effective drugs and targets using thousands of candidate proteins identified from omics data. The online and local versions of OTTM are available at http://otter-simm.com/ottm.html.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Ciencia Traslacional Biomédica , Proteómica , Descubrimiento de DrogasRESUMEN
We describe evidence for dissociable roles of the medial and lateral orbitofrontal cortex (OFC) in major depressive disorder (MDD) from structure, functional activation, functional connectivity, metabolism, and neurochemical systems. The reward-related medial orbitofrontal cortex has lower connectivity and less reward sensitivity in MDD associated with anhedonia symptoms; and the non-reward related lateral OFC has higher functional connectivity and more sensitivity to non-reward/aversive stimuli in MDD associated with negative bias symptoms. Importantly, we propose that conventional antidepressants act to normalize the hyperactive lateral (but not medial) OFC to reduce negative bias in MDD; while other treatments are needed to operate on the medial OFC to reduce anhedonia, with emerging evidence suggesting that ketamine may act in this way. The orbitofrontal cortex is the key cortical region in emotion and reward, and the current review presents much new evidence about the different ways that the medial and lateral OFC are involved in MDD.
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Anhedonia , Trastorno Depresivo Mayor , Corteza Prefrontal , Humanos , Anhedonia/fisiología , Antidepresivos/uso terapéutico , Antidepresivos/farmacología , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/tratamiento farmacológico , Emociones/fisiología , Ketamina/uso terapéutico , Ketamina/farmacología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiopatología , RecompensaRESUMEN
Hydrothermal process is an emerging technology that contributes to sustainable production of biomass-derived chemicals, fuels, and materials. This technology uses hot compressed water to convert various biomass feedstocks including recalcitrant organic compounds in biowastes into desired solid, liquid, and gaseous products. In recent years, considerable progress has been made in the hydrothermal conversion of lignocellulosic as well as nonlignocellulosic biomass to value-added products and bioenergy to fulfill the principles of circular economy. However, it is important to assess hydrothermal processes in terms of their capabilities and limitations from different sustainability aspects so that further advances can be made toward improvement of their technical maturity and commercialization potential. The key aims of this comprehensive review are to (a) explain the inherent properties of biomass feedstocks and physio-chemical characteristics of their bioproducts, (b) elucidate related transformation pathways, (c) clarify the role of hydrothermal process for biomass conversion, (d) evaluate the capability of hydrothermal treatment coupled with other technologies for producing novel chemicals, fuels and materials, (e) explore different sustainability assessments of hydrothermal processes for potential large-scale applications, and (f) offer our perspectives to facilitate the transition from a primarily petro-based to an alternative biobased society in the context of changing climate.
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Alzheimer's disease is neurodegenerative and characterized by progressive cognitive impairment. Synaptic dysfunction appears in the early stage of Alzheimer's disease and is significantly correlated with cognitive impairment. However, the specific regulatory mechanism remains unclear. Here, we found the transcription factor Maf1 to be upregulated in Alzheimer's disease and determined that conditional knockout of Maf1 in a transgenic mouse model of Alzheimer's disease restored learning and memory function; the downregulation of Maf1 reduced the intraneuronal calcium concentration and restored neuronal synaptic morphology. We also demonstrated that Maf1 regulated the expression of NMDAR1 by binding to the promoter region of Grin1, further regulating calcium homeostasis and synaptic remodelling in neurons. Our results clarify the important role and mechanism of the Maf1-NMDAR1 signalling pathway in stabilizing synaptic structure, neuronal function and behaviour during Alzheimer's disease pathogenesis. This therefore serves as a potential diagnostic and therapeutic target for the early stage of Alzheimer's disease.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Ratones Transgénicos , Anciano , Animales , Femenino , Humanos , Masculino , Ratones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Espinas Dendríticas/metabolismo , Espinas Dendríticas/patología , Modelos Animales de Enfermedad , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Proteínas Represoras/genética , Proteínas Represoras/metabolismoRESUMEN
Ovarian cancer is a gynecological tumor with extremely high mortality and poor prognosis. Exosomes derived from tumor cells contain abundant proteins that may influence tumor metastasis. The purpose of our study was to explore the proteomic profile of serum exosomes from epithelial ovarian cancer (EOC) patients and to find potential diagnostic markers for EOC. We obtained purified exosomes from serum using ultracentrifugation. Migration assay was used to evaluate the effects of exosomes on the migration of EOC cells. Proteomic profile of serum exosomes was analyzed by liquid chromatogram-tandem mass spectrometry. The levels of low-density lipoprotein receptor-related protein 1 (LRP1) in serum and serum exosomes were determined by enzyme-linked immunosorbent assay. Western blot and Immunohistochemistry were used to determine the level of LRP1 in tissues. Moreover, we performed small-interfering RNA-mediated knockdown of LRP1 in EOC cells to obtain SI-LRP1-Exos and SI-NC-Exos. The detailed mechanisms by which exosomal LRP1 affected the migration of EOC cells in vitro and in vivo were also explored. We found that serum exosomes from EOC patients contributed to the migration of EOC cells. The level of serum exosomal LRP1 of EOC patients was significantly upregulated compared with that of healthy volunteers, which was consistent with the result of enzyme-linked immunosorbent assay. We found that exosomal LRP1 regulated the expression of MMP2 and MMP9 through ERK signaling pathway and affected the migration of EOC cells in vitro and in vivo. Therefore, we propose that exosomal LRP1 contributes to the migration of EOC and may act as an important diagnostic and prognostic biomarker of EOC.
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Exosomas , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario , Exosomas/metabolismo , Proteómica , Neoplasias Ováricas/patología , Transducción de Señal , Línea Celular Tumoral , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismoRESUMEN
Lithium-ion batteries (LIBs) are widely used as power storage systems in electronic devices and electric vehicles (EVs). Recycling of spent LIBs is of utmost importance from various perspectives including recovery of valuable metals (mostly Co and Li) and mitigation of environmental pollution. Recycling methods such as direct recycling, pyrometallurgy, hydrometallurgy, bio-hydrometallurgy (bioleaching) and electrometallurgy are generally used to resynthesise LIBs. These methods have their own benefits and drawbacks. This manuscript provides a critical review of recent advances in the recycling of spent LIBs, including the development of recycling processes, identification of the products obtained from recycling, and the effects of recycling methods on environmental burdens. Insights into chemical reactions, thermodynamics, kinetics, and the influence of operating parameters of each recycling technology are provided. The sustainability of recycling technologies (e.g., life cycle assessment and life cycle cost analysis) is critically evaluated. Finally, the existing challenges and future prospects are presented for further development of sustainable, highly efficient, and environmentally benign recycling of spent LIBs to contribute to the circular economy.
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The copper chaperone for Sod1 (Ccs) is a metallochaperone that plays a multifaceted role in the maturation of Cu,Zn superoxide dismutase (Sod1). The Ccs mutation R163W was identified in an infant with fatal neurological abnormalities. Based on a comprehensive structural and functional analysis, we developed the first data-driven model for R163W-related pathogenic phenotypes. The work here confirms previous findings that the substitution of arginine with tryptophan at this site, which is located adjacent to a conserved Zn binding site, creates an unstable Zn-deficient protein that loses its ability to efficiently activate Sod1. Intriguingly, R163W Ccs can reduce copper (i.e., Cu(II) â Cu(I)) bound in its Sod1-like domain (D2), and this novel redox event is accompanied by disulfide bond formation. The loss of Zn binding, along with the unusual ability to bind copper in D2, diverts R163W Ccs toward aggregation. The remarkably high affinity of D2 Cu(I) binding converts R163W from a Cu chaperone to a Cu scavenger that accelerates Sod1 deactivation (i.e., an Anti-chaperone). Overall, these findings present a first-of-its-kind molecular mechanism for Ccs dysfunction that leads to pathogenesis in humans.
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Schistosomiasis is a parasitic disease characterized by liver fibrosis, a process driven by the activation of hepatic stellate cells (HSCs) and subsequent collagen production. Previous studies from our laboratory have demonstrated the ability of Schistosoma japonicum protein P40 (SjP40) to inhibit HSCs activation and exert an antifibrotic effect. In this study, we aimed to elucidate the molecular mechanism underlying the inhibitory effect of recombinant SjP40 (rSjP40) on HSCs activation. Using a cell model in which rSjP40 inhibited LX-2 cell activation, we performed RNA-seq analyses and identified ATF3 as the most significantly altered gene. Further investigation revealed that rSjP40 inhibited HSCs activation partly by suppressing ATF3 activation. Knockdown of ATF3 in mouse liver significantly alleviated S. japonicum-induced liver fibrosis. Moreover, our results indicate that ATF3 is a direct target of microRNA-494-3p, a microRNA associated with anti-liver fibrosis effects. rSjP40 was found to downregulate ATF3 expression by upregulating microRNA-494-3p in LX-2 cells. This downregulation led to the inhibition of the expression of liver fibrosis proteins α-SMA and COL1A1, ultimately alleviating liver fibrosis caused by S. japonicum.
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Factor de Transcripción Activador 3 , Proteínas del Helminto , Células Estrelladas Hepáticas , Cirrosis Hepática , MicroARNs , Schistosoma japonicum , Esquistosomiasis Japónica , Animales , Factor de Transcripción Activador 3/metabolismo , Factor de Transcripción Activador 3/genética , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/parasitología , Esquistosomiasis Japónica/parasitología , Esquistosomiasis Japónica/metabolismo , Esquistosomiasis Japónica/genética , Cirrosis Hepática/parasitología , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Cirrosis Hepática/metabolismo , Ratones , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Proteínas del Helminto/genética , Proteínas del Helminto/metabolismo , Actinas/metabolismo , Actinas/genética , Línea Celular , Regulación de la Expresión Génica , Hígado/metabolismo , Hígado/parasitología , Hígado/patología , Modelos Animales de Enfermedad , Antígenos HelmínticosRESUMEN
The central histaminergic system has a pivotal role in emotional regulation and psychiatric disorders, including anxiety, depression and schizophrenia. However, the effect of histamine on neuronal activity of the centrolateral amygdala (CeL), an essential node for fear and anxiety processing, remains unknown. Here, using immunostaining and whole-cell patch clamp recording combined with optogenetic manipulation of histaminergic terminals in CeL slices prepared from histidine decarboxylase (HDC)-Cre rats, we show that histamine selectively suppresses excitatory synaptic transmissions, including glutamatergic transmission from the basolateral amygdala, on both PKC-δ- and SOM-positive CeL neurons. The histamine-induced effect is mediated by H3 receptors expressed on VGLUT1-/VGLUT2-positive presynaptic terminals in CeL. Furthermore, optoactivation of histaminergic afferent terminals from the hypothalamic tuberomammillary nucleus (TMN) also significantly suppresses glutamatergic transmissions in CeL via H3 receptors. Histamine neither modulates inhibitory synaptic transmission by presynaptic H3 receptors nor directly excites CeL neurons by postsynaptic H1, H2 or H4 receptors. These results suggest that histaminergic afferent inputs and presynaptic H3 heteroreceptors may hold a critical position in balancing excitatory and inhibitory synaptic transmissions in CeL by selective modulation of glutamatergic drive, which may not only account for the pathophysiology of psychiatric disorders but also provide potential psychotherapeutic targets. KEY POINTS: Histamine selectively suppresses the excitatory, rather than inhibitory, synaptic transmissions on both PKC-δ- and SOM-positive neurons in the centrolateral amygdala (CeL). H3 receptors expressed on VGLUT1- or VGLUT2-positive afferent terminals mediate the suppression of histamine on glutamatergic synaptic transmission in CeL. Optogenetic activation of hypothalamic tuberomammillary nucleus (TMN)-CeL histaminergic projections inhibits glutamatergic transmission in CeL via H3 receptors.
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Biological functions of the highly conserved ubiquitin-like protein 5 (UBL5) are not well understood. In Caenorhabditis elegans, UBL5 is induced under mitochondrial stress to mount the mitochondrial unfolded protein response (UPR). However, the role of UBL5 in the more prevalent endoplasmic reticulum (ER) stress-UPR in the mammalian system is unknown. In the present work, we demonstrated that UBL5 was an ER stress-responsive protein, undergoing rapid depletion in mammalian cells and livers of mice. The ER stress-induced UBL5 depletion was mediated by proteasome-dependent yet ubiquitin-independent proteolysis. Activation of the protein kinase R-like ER kinase arm of the UPR was essential and sufficient for inducing UBL5 degradation. RNA-Seq analysis of UBL5-regulated transcriptome revealed that multiple death pathways were activated in UBL5-silenced cells. In agreement with this, UBL5 knockdown induced severe apoptosis in culture and suppressed tumorigenicity of cancer cells in vivo. Furthermore, overexpression of UBL5 protected specifically against ER stress-induced apoptosis. These results identify UBL5 as a physiologically relevant survival regulator that is proteolytically depleted by the UPR-protein kinase R-like ER kinase pathway, linking ER stress to cell death.
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Muerte Celular , Estrés del Retículo Endoplásmico , Ubiquitinas , eIF-2 Quinasa , Animales , Ratones , Apoptosis , eIF-2 Quinasa/metabolismo , Ubiquitinas/genética , Ubiquitinas/metabolismo , Respuesta de Proteína DesplegadaRESUMEN
The cross-regulation of immunity and metabolism is currently a research hotspot in life sciences and immunology. Metabolic immunology plays an important role in cutting-edge fields such as metabolic regulatory mechanisms in immune cell development and function, and metabolic targets and immune-related disease pathways. Protein post-translational modification (PTM) is a key epigenetic mechanism that regulates various biological processes and highlights metabolite functions. Currently, more than 400 PTM types have been identified to affect the functions of several proteins. Among these, metabolic PTMs, particularly various newly identified histone or non-histone acylation modifications, can effectively regulate various functions, processes and diseases of the immune system, as well as immune-related diseases. Thus, drugs aimed at targeted acylation modification can have substantial therapeutic potential in regulating immunity, indicating a new direction for further clinical translational research. This review summarises the characteristics and functions of seven novel lysine acylation modifications, including succinylation, S-palmitoylation, lactylation, crotonylation, 2-hydroxyisobutyrylation, ß-hydroxybutyrylation and malonylation, and their association with immunity, thereby providing valuable references for the diagnosis and treatment of immune disorders associated with new acylation modifications.
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Procesamiento Proteico-Postraduccional , Humanos , Acilación , Animales , Inmunidad , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/metabolismo , Lisina/metabolismoRESUMEN
Transition metal-catalyzed reductive cross-couplings to build C-C/Si bonds have been developed, but the reductive cross-coupling to create the C(sp2)-B bond has not been explored. Herein, we describe a nickel-catalyzed reductive cross-coupling between aryl halides and bromoboranes to construct a C(sp2)-B bond. This protocol offers a convenient approach for the synthesis of a wide range of aryl boronate esters, using readily available starting materials. Mechanistic studies indicate that the key to the success of the reaction is the activation of the B-Br bond of bromoboranes with a Lewis base such as 2-MeO-py. The activation ensures that bromoboranes will react with the active nickel(I) catalyst prior to aryl halides, which is different from the sequence of the general nickel-catalyzed reductive C(sp2)-C/Si cross-coupling, where the oxidative addition of an aryl halide proceeds first. Notably, this approach minimizes the production of undesired homocoupling byproduct without the requirement of excessive quantities of either substrate.
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Vulvovaginal candidiasis (VVC) is a common condition among women. Fluconazole remains the dominant treatment option for VVC. Oteseconazole is a highly selective inhibitor of fungal CYP51. This randomized, double-blinded, phase 3 trial was conducted to evaluate the efficacy and safety of oteseconazole compared with fluconazole in treating severe VVC. Female subjects presenting with vulvovaginal signs and symptoms score of ≥7 and positive Candida infection determined by potassium hydroxide test or Gram staining were randomly assigned to receive oteseconazole (600 mg on D1 and 450 mg on D2) or fluconazole (150 mg on D1 and D4) in a 1:1 ratio. The primary endpoint was the proportion of subjects achieving therapeutic cure [defined as achieving both clinical cure (absence of signs and symptoms of VVC) and mycological cure (negative culture of Candida species)] at D28. A total of 322 subjects were randomized and 321 subjects were treated. At D28, a statistically significantly higher proportion of subjects achieved therapeutic cure in the oteseconazole group than in the fluconazole group (66.88% vs 45.91%; P = 0.0002). Oteseconazole treatment resulted in an increased proportion of subjects achieving mycological cure (82.50% vs 59.12%; P < 0.0001) and clinical cure (71.25% vs 55.97%; P = 0.0046) compared with fluconazole. The incidence of treatment-emergent adverse events was similar between the two groups. No subjects discontinued study treatment or withdrew study due to adverse events. Oteseconazole showed statistically significant and clinically meaningful superiority over fluconazole for the treatment of severe VVC and was generally tolerated.
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Candidiasis Vulvovaginal , Fluconazol , Femenino , Humanos , Fluconazol/farmacología , Candidiasis Vulvovaginal/tratamiento farmacológico , Candidiasis Vulvovaginal/microbiología , Antifúngicos/efectos adversos , Candida , Administración Oral , Candida albicansRESUMEN
The endoplasmic reticulum (ER) is a complex and dynamic organelle that initiates unfolded protein response (UPR) and endoplasmic reticulum stress (ER Stress) in response to the accumulation of unfolded or misfolded proteins within its lumen. Autophagy is a paramount intracellular degradation system that facilitates the transportation of proteins, cytoplasmic components, and organelles to lysosomes for degradation and recycling. Preeclampsia (PE) and intrauterine growth retardation (IUGR) are two common complications of pregnancy associated with abnormal trophoblast differentiation and placental dysfunctions and have a major impact on fetal development and maternal health. The intricate interplay between ER Stress, and autophagy and their impact on pregnancy outcomes, through mediating trophoblast differentiation and placental development, has been highlighted in various reports. Autophagy controls trophoblast regulation through a variety of gene expressions and signalling pathways while excessive ER Stress triggers downstream apoptotic signalling, culminating in trophoblast apoptosis. This comprehensive review delves into the intricacies of placental development and explores the underlying mechanisms of PE and IUGR. In addition, this review will elucidate the molecular mechanisms of ER Stress and autophagy, both individually and in their interplay, in mediating placental development and trophoblast differentiation, particularly highlighting their roles in PE and IUGR development. This research seeks to the interplay between ER Stress and impaired autophagy in the placental trophoderm, offering novel insights into their contribution to pregnancy complications.
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Nonstructural protein 13 (nsp13), the helicase of SARS-CoV-2, has been shown to possess multiple functions that are essential for viral replication, and is considered an attractive target for the development of novel antivirals. We were initially interested in the interplay between nsp13 and interferon (IFN) signaling, and found that nsp13 inhibited reporter signal in an IFN-ß promoter assay. Surprisingly, the ectopic expression of different components of the RIG-I/MDA5 pathway, which were used to stimulate IFN-ß promoter, was also mitigated by nsp13. However, endogenous expression of these genes was not affected by nsp13. Interestingly, nsp13 restricted the expression of foreign genes originating from plasmid transfection, but failed to inhibit them after chromosome integration. These data, together with results from a runoff transcription assay and RNA sequencing, suggested a specific inhibition of episomal but not chromosomal gene transcription by nsp13. By using different truncated and mutant forms of nsp13, we demonstrated that its NTPase and helicase activities contributed to the inhibition of episomal DNA transcription, and that this restriction required direct interaction with episomal DNA. Based on these findings, we developed an economical and convenient high-throughput drug screening method targeting nsp13. We evaluated the inhibitory effects of various compounds on nsp13 by the expression of reporter gene plasmid after co-transfection with nsp13. In conclusion, we found that nsp13 can specifically inhibit episomal DNA transcription and developed a high-throughput drug screening method targeting nsp13 to facilitate the development of new antiviral drugs. IMPORTANCE To combat COVID-19, we need to understand SARS-CoV-2 and develop effective antiviral drugs. In our study, we serendipitously found that SARS-CoV-2 nsp13 could suppress episomal DNA transcription without affecting chromosomal DNA. Detailed characterization revealed that nsp13 suppresses episomal gene expression through its NTPase and helicase functions following DNA binding. Furthermore, we developed a high-throughput drug screening system targeting SARS-CoV-2 nsp13. Compared to traditional SARS-CoV-2 drug screening methods, our system is more economical and convenient, facilitating the development of more potent and selective nsp13 inhibitors and enabling the discovery of new antiviral therapies.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Nucleósido-Trifosfatasa/genética , ARN Helicasas/metabolismo , Proteínas no Estructurales Virales/metabolismo , ADN Helicasas/genética , ADN Helicasas/metabolismo , Antivirales/farmacología , ADN , Plásmidos/genéticaRESUMEN
As the most abundant RNA modification, N6-methyladenosine (m6A) plays an important role in various RNA activities including gene expression and translation. With the rapid application of MeRIP-seq technology, samples of multiple groups, such as the involved multiple viral/ bacterial infection or distinct cell differentiation stages, are extracted from same experimental unit. However, our current knowledge about how the dynamic m6A regulating gene expression and the role in certain biological processes (e.g. immune response in this complex context) is largely elusive due to lack of effective tools. To address this issue, we proposed a Bayesian hierarchical mixture model (called m6Aexpress-BHM) to predict m6A regulation of gene expression (m6A-reg-exp) in multiple groups of MeRIP-seq experiment with limited samples. Comprehensive evaluations of m6Aexpress-BHM on the simulated data demonstrate its high predicting precision and robustness. Applying m6Aexpress-BHM on three real-world datasets (i.e. Flaviviridae infection, infected time-points of bacteria and differentiation stages of dendritic cells), we predicted more m6A-reg-exp genes with positive regulatory mode that significantly participate in innate immune or adaptive immune pathways, revealing the underlying mechanism of the regulatory function of m6A during immune response. In addition, we also found that m6A may influence the expression of PD-1/PD-L1 via regulating its interacted genes. These results demonstrate the power of m6Aexpress-BHM, helping us understand the m6A regulatory function in immune system.
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Adenosina , ARN , Adenosina/genética , Adenosina/metabolismo , Teorema de Bayes , Regulación de la Expresión Génica , Metilación , ARN/genéticaRESUMEN
Multiple primary tumor (MPT) is a special and rare cancer type, defined as more than two primary tumors presenting at the diagnosis in a single patient. The molecular characteristics and tumorigenesis of MPT remain unclear due to insufficient approaches. Here, we present MPTevol, a practical computational framework for comprehensively exploring the MPT from multiregion sequencing (MRS) experiments. To verify the utility of MPTevol, we performed whole-exome MRS for 33 samples of a rare patient with triple-primary tumors and three metastatic sites and systematically investigated clonal dynamics and metastatic routines. MPTevol assists in comparing genomic profiles across samples, detecting clonal evolutionary history and metastatic routines and quantifying the metastatic history. All triple-primary tumors were independent origins and their genomic characteristics were consistent with corresponding sporadic tumors, strongly supporting their independent tumorigenesis. We further showed two independent early monoclonal seeding events for the metastases in the ovary and uterus. We revealed that two ovarian metastases were disseminated from the same subclone of the primary tumor through undergoing whole-genome doubling processes, suggesting metastases-to-metastases seeding occurred when tumors had similar microenvironments. Surprisingly, according to the metastasis timing model of MPTevol, we found that primary tumors of about 0.058-0.124 cm diameter have been disseminating to distant organs, which is much earlier than conventional clinical views. We developed MPT-specialized analysis framework MPTevol and demonstrated its utility in explicitly resolving clonal evolutionary history and metastatic seeding routines with a rare MPT case. MPTevol is implemented in R and is available at https://github.com/qingjian1991/MPTevol under the GPL v3 license.