RESUMEN

Natural products encompass a diverse range of compounds with high impact applications in consumer care, agriculture and most notably, therapeutics. However, despite the expansive chemical repertoire indicated in genomic information of microbes, only a small subset can be obtained under laboratory conditions. To increase accessible chemical space and realize Nature's full chemical potential, a multi-pronged genetic- and cultivation-based strategy has been employed to activate and upregulate natural product biosyntheses in native and heterologous strains. This data descriptor documents a characterized collection of 2,138 liquid chromatography-tandem mass spectrometry (LC/MS-MS) spectra of fermentation extracts from 54 native actinobacterial strains collected from soil and marine environments in Singapore, and their 459 activated mutants in 3 to 5 media. A total of 743 unique metabolites have been identified, with the activated mutants demonstrating an approximately 2-fold expansion in accessible chemical space over wild type strains. Interrogating this expanded chemical diversity with cheminformatic tools can provide direction for the discovery of novel natural products with desirable functional activity.

Asunto(s)

Actinobacteria , Mutación , Espectrometría de Masas en Tándem , Actinobacteria/genética , Actinobacteria/metabolismo , Cromatografía Liquida , Productos Biológicos/metabolismo , Productos Biológicos/química , Singapur , Microbiología del Suelo

RESUMEN

AIMS: Type 2 diabetes mellitus (T2DM) is related to an increased risk of postoperative cognitive dysfunction (POCD), which may be caused by neuronal hyperexcitability. Astrocyte glutamate transporter 1 (GLT-1) plays a crucial role in regulating neuron excitability. We investigated if T2DM would magnify the increased neuronal excitability induced by anesthesia/surgery (A/S) and lead to POCD in young adult mice, and if so, determined whether these effects were associated with GLT-1 expression. METHODS: T2DM model was induced by high fat diet (HFD) and injecting STZ. Then, we evaluated the spatial learning and memory of T2DM mice after A/S with the novel object recognition test (NORT) and object location test (OLT). Western blotting and immunofluorescence were used to analyze the expression levels of GLT-1 and neuronal excitability. Oxidative stress reaction and neuronal apoptosis were detected with SOD2 expression, MMP level, and Tunel staining. Hippocampal functional synaptic plasticity was assessed with long-term potentiation (LTP). In the intervention study, we overexpressed hippocampal astrocyte GLT-1 in GFAP-Cre mice. Besides, AAV-Camkllα-hM4Di-mCherry was injected to inhibit neuronal hyperexcitability in CA1 region. RESULTS: Our study found T2DM but not A/S reduced GLT-1 expression in hippocampal astrocytes. Interestingly, GLT-1 deficiency alone couldn't lead to cognitive decline, but the downregulation of GLT-1 in T2DM mice obviously enhanced increased hippocampal glutamatergic neuron excitability induced by A/S. The hyperexcitability caused neuronal apoptosis and cognitive impairment. Overexpression of GLT-1 rescued postoperative cognitive dysfunction, glutamatergic neuron hyperexcitability, oxidative stress reaction, and apoptosis in hippocampus. Moreover, chemogenetic inhibition of hippocampal glutamatergic neurons reduced oxidative stress and apoptosis and alleviated postoperative cognitive dysfunction. CONCLUSIONS: These findings suggest that the adult mice with type 2 diabetes are at an increased risk of developing POCD, perhaps due to the downregulation of GLT-1 in hippocampal astrocytes, which enhances increased glutamatergic neuron excitability induced by A/S and leads to oxidative stress reaction, and neuronal apoptosis.

Asunto(s)

Astrocitos , Diabetes Mellitus Tipo 2 , Regulación hacia Abajo , Transportador 2 de Aminoácidos Excitadores , Hipocampo , Ratones Endogámicos C57BL , Complicaciones Cognitivas Postoperatorias , Animales , Transportador 2 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores/biosíntesis , Transportador 2 de Aminoácidos Excitadores/genética , Astrocitos/metabolismo , Complicaciones Cognitivas Postoperatorias/etiología , Complicaciones Cognitivas Postoperatorias/metabolismo , Hipocampo/metabolismo , Ratones , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones Transgénicos

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This study unveils the "green" metal-organic framework (MOF) structuring mechanism by decoding proton transfer in water during ZIF-8 synthesis. Combining in situ small- to wide-angle X-ray scattering, multiscale simulations, and quantum calculations, we reveal that the ZIF-8 early-stage nucleation and crystallization process in aqueous solution unfolds in three distinct stages. In stage I, imidazole ligands replace water in zinc-water cages, triggering an "acidity flip" that promotes proton transfer. This leads to the assembly of structures from single zinc ions to 3D amorphous cluster nuclei. In stage II, amorphous nuclei undergo a critical transformation, evolving into crystalline nuclei and subsequently forming mesoscale-ordered structures and crystallites. The process proceeds until the amorphous precursors are completely consumed, with the transformation kinetics governed by an energy barrier that determines the rate-limiting step. In stage III, stable crystallite nanoparticles form in solution, characterized by a temperature-dependent thermal equilibrium of molecular interactions at the crystal-solution interface. Beyond these core advancements, we explore the influence of encapsulated pepsin and nonencapsulated lysozyme on ZIF-8 formation, finding that their amino acid proton transfer capacity and concentration influence the resulting biomolecule-MOF composite's shape and encapsulation efficiency. The findings contribute to understanding the molecular mechanisms behind biomimetic mineralization and have potential implications for engineering proteins within amorphous MOF nuclei as protein embryo growth sites.

RESUMEN

The aberrant fibrillization of huntingtin exon 1 (Httex1) characterized by an expanded polyglutamine (polyQ) tract is a defining feature of Huntington's disease, a neurodegenerative disorder. Recent investigations underscore the involvement of a small EDRK-rich factor 1a (SERF1a) in promoting Httex1 fibrillization through interactions with its N terminus. By establishing an integrated approach with size-exclusion-column-based small- and wide-angle X-ray scattering (SEC-SWAXS), NMR, and molecular simulations using Rosetta, the analysis here reveals a tight binding of two NT17 fragments of Httex1 (comprising the initial 17 amino acids at the N terminus) to the N-terminal region of SERF1a. In contrast, examination of the complex structure of SERF1a with a coiled NT17-polyQ peptide (33 amino acids in total) indicates sparse contacts of the NT17 and polyQ segments with the N-terminal side of SERF1a. Furthermore, the integrated SEC-SWAXS and molecular-simulation analysis suggests that the coiled NT17 segment can transform into a helical conformation when associated with a polyQ segment exhibiting high helical content. Intriguingly, NT17-polyQ peptides with enhanced secondary structures display diminished interactions with SERF1a. This insight into the conformation-dependent binding of NT17 provides clues to a catalytic association mechanism underlying SERF1a's facilitation of Httext1 fibrillization.

Asunto(s)

Proteína Huntingtina , Péptidos , Proteína Huntingtina/genética , Proteína Huntingtina/química , Proteína Huntingtina/metabolismo , Péptidos/química , Péptidos/metabolismo , Péptidos/genética , Humanos , Exones/genética , Unión Proteica , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Simulación de Dinámica Molecular , Espectroscopía de Resonancia Magnética , Difracción de Rayos X

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The inherent ambiguity in reconstructed images from coherent diffraction imaging (CDI) poses an intrinsic challenge, as images derived from the same dataset under varying initial conditions often display inconsistencies. This study introduces a method that employs the Noise2Noise approach combined with neural networks to effectively mitigate these ambiguities. We applied this methodology to hundreds of ambiguous reconstructed images retrieved from a single diffraction pattern using a conventional retrieval algorithm. Our results demonstrate that ambiguous features in these reconstructions are effectively treated as inter-reconstruction noise and are significantly reduced. The post-Noise2Noise treated images closely approximate the average and singular value decomposition analysis of various reconstructions, providing consistent and reliable reconstructions.

RESUMEN

Vortioxetine is a novel multimodal antidepressant, but its precise efficacy and dose-response relationship for treating different symptoms in major depressive disorder (MDD) is still unclear. This umbrella review aims to assess the effectiveness, tolerability, and dose-response relationship of vortioxetine across a comprehensive range of clinical features in adults with MDD, including cognition, depression, anxiety, quality of life, and side effects. We meticulously searched eight electronic databases and included systematic reviews (SRs) and meta-analyses (MAs) of vortioxetine. The methodological quality of each included SR was independently assessed using the AMSTAR2 tool. To evaluate the credibility of the evidence, we utilized the GRADE framework and the Ioannidis criteria. In total, 35 SRs with 278 MAs met the inclusion criteria and based on these studies we performed 56 MAs of interest. While vortioxetine has been consistently shown to have positive effects on various domains, the evidence regarding cognitive performance and depression symptoms is notably robust compared to placebo, despite of relatively overall low quality of evidence. Finally, a dose-response relationship was observed across all categories within the treatment range of 5-20 mg/d and a dosage of vortioxetine 20 mg/d is recommended for adult MDD patients to achieve full functional recovery.

Asunto(s)

Antidepresivos , Trastorno Depresivo Mayor , Relación Dosis-Respuesta a Droga , Vortioxetina , Vortioxetina/farmacología , Vortioxetina/administración & dosificación , Humanos , Trastorno Depresivo Mayor/tratamiento farmacológico , Antidepresivos/farmacología , Antidepresivos/administración & dosificación , Calidad de Vida

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BACKGROUND: Acute kidney injury (AKI) is a common and serious complication after cardiac surgery that significantly affects patient outcomes. Given the limited treatment options available, identifying modifiable risk factors is critical. Frailty and obesity, two heterogeneous physiological states, have significant implications for identifying and preventing AKI. Our study investigated the interplay among frailty, body composition, and AKI risk after cardiac surgery to inform patient management strategies. MATERIAL AND METHODS: This retrospective cohort study included three international cohorts. Primary analysis was conducted in adult patients who underwent cardiac surgery between 2014 and 2019 at Wuhan XX Hospital, China. We tested the generalizability of our findings with data from two independent international cohorts, the Medical Information Mart for Intensive Care IV (MIMIC-IV) and the eICU Collaborative Research Database. Frailty was assessed using a clinical lab-based frailty index (FI-LAB), while total body fat percentage (BF%) was calculated based on a formula accounting for BMI, sex, and age. Logistic regression models were used to analyze the associations between frailty, body fat, and AKI, adjusting for pertinent covariates. RESULTS: A total of 8785 patients across three international cohorts were included in the study. In the primary analysis of 3,569 patients from Wuhan XX Hospital, moderate and severe frailty were associated with an increased AKI risk after cardiac surgery. Moreover, a nonlinear relationship was observed between body fat percentage and AKI risk. When stratified by the degree of frailty, lower body fat correlated with a decreased incidence of AKI. Extended analyses using the MIMIC-IV and eICU cohorts (n=3,951 and n=1,265, respectively) validated these findings and demonstrated that a lower total BF% was associated with decreased AKI incidence. Moderation analysis revealed that the effect of frailty on AKI risk was moderated by the body fat percentage. Sensitivity analyses demonstrated results consistent with the main analyses. CONCLUSION: Higher degrees of frailty were associated with an elevated risk of AKI following cardiac surgery, and total BF% moderated this relationship. This research underscores the significance of integrating frailty and body fat assessments into routine cardiovascular care to identify high-risk patients for AKI and implement personalized interventions to improve patient outcomes.

RESUMEN

Transmetalation represents an appealing strategy toward fabricating and tuning functional metal-organic polymers and frameworks for diverse applications. In particular, building two-dimensional metal-organic and organometallic networks affords versatile nanoarchitectures of potential interest for nanodevices and quantum technology. The controlled replacement of embedded metal centers holds promise for exploring versatile material varieties by serial modification and different functionalization. Herein, we introduce a protocol for the modification of a single-layer carbon-metal-based organometallic network via transmetalation. By integrating external Cu atoms into the alkynyl-Ag organometallic network constructed with 1,3,5-triethynylbenzene precursors, we successfully realized in situ its highly regular alkynyl-Cu counterpart on the Ag(111) surface. While maintaining a similar lattice periodicity and pore morphology to the original alkynyl-Ag sheet, the Cu-based network exhibits increased thermal stability, guaranteeing improved robustness for practical implementation.

RESUMEN

BACKGROUND: ChatGPT is a novel and online large-scale language model used as a source providing up-to-date and useful health-related knowledges to patients and clinicians. However, its performance on Helicobacter pylori infection-related questions remain unknown. This study aimed to evaluate the accuracy of ChatGPT's responses on H. pylori-related questions compared with that of gastroenterologists during the same period. METHODS: Twenty-five H. pylori-related questions from five domains: Indication, Diagnostics, Treatment, Gastric cancer and prevention, and Gut Microbiota were selected based on the Maastricht VI Consensus report. Each question was tested three times with ChatGPT3.5 and ChatGPT4. Two independent H. pylori experts assessed the responses from ChatGPT, with discrepancies resolved by a third reviewer. Simultaneously, a nationwide survey with the same questions was conducted among 1279 gastroenterologists and 154 medical students. The accuracy of responses from ChatGPT3.5 and ChatGPT4 was compared with that of gastroenterologists. RESULTS: Overall, both ChatGPT3.5 and ChatGPT4 demonstrated high accuracy, with median accuracy rates of 92% for each of the three responses, surpassing the accuracy of nationwide gastroenterologists (median: 80%) and equivalent to that of senior gastroenterologists. Compared with ChatGPT3.5, ChatGPT4 provided more concise responses with the same accuracy. ChatGPT3.5 performed well in the Indication, Treatment, and Gut Microbiota domains, whereas ChatGPT4 excelled in Diagnostics, Gastric cancer and prevention, and Gut Microbiota domains. CONCLUSION: ChatGPT exhibited high accuracy and reproducibility in addressing H. pylori-related questions except the decision for H. pylori treatment, performing at the level of senior gastroenterologists and could serve as an auxiliary information tool for assisting patients and clinicians.

Asunto(s)

Infecciones por Helicobacter , Helicobacter pylori , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/microbiología , Humanos , Helicobacter pylori/efectos de los fármacos , Encuestas y Cuestionarios , Masculino , Femenino , Adulto , Persona de Mediana Edad

RESUMEN

AIM: To identify latent profiles of narrative competence in nursing students and examine the association between the potential competence profiles and professional identity from a person-centred perspective. BACKGROUND: According to the Ring theory of personhood, nursing students can develop their professional identities from individual, relational and social aspects through interaction with patients, as well as listening to, understanding and responding to patients' disease narratives. However, few studies have examined the relationship between narrative competence and professional identity through the quantitative method. DESIGN: A cross-sectional analytic study. METHODS: A total of 472 nursing students responded to the survey between March and May 2023. The Professional Identity Questionnaire for Nurse Students and the Narrative Competence Scale were given to participants. Latent profile analysis was conducted to identify narrative competence profiles. The Bolck-Croon-Hagenaars method was used to analyse whether these latent profiles for narrative competence affected nursing students' general, individual, interpersonal and social professional identities. RESULTS: Latent profiles were identified as "low narrative competence" (12.1 %), "relatively low narrative competence" (39.9 %), "moderate narrative competence" (40.1 %) and "high narrative competence" (7.9 %). The profiles only show level differences rather than combinations of competence areas. These profiles had varying effects on the nursing students' general professional identities, as well as their individual, relational and social professional identities. CONCLUSION: This study highlights the significance of providing tailored guidance and support to nursing students, taking into account their unique narrative competency profile, to promote the formation of professional identity from individual, relational and social aspects. Nursing educators should effectively distinguish nursing students with inadequate narrative competence and value patients' disease narratives to promote narrative competence and professional identity.

Asunto(s)

Narración , Identificación Social , Estudiantes de Enfermería , Humanos , Estudios Transversales , Estudiantes de Enfermería/psicología , Femenino , Encuestas y Cuestionarios , Masculino , Adulto , Bachillerato en Enfermería , Competencia Profesional , Personeidad , Adulto Joven

RESUMEN

Intracerebral hemorrhage (ICH) is a prevalent hemorrhagic cerebrovascular emergency. Alleviating neurological damage in the early stages of ICH is critical for enhancing patient prognosis and survival rate. A novel form of cell death called ferroptosis is intimately linked to hemorrhage-induced brain tissue injury. Although studies have demonstrated the significant preventive impact of bovine serum albumin-stabilized selenium nanoparticles (BSA-SeNPs) against disorders connected to the neurological system, the neuroprotective effect on the hemorrhage stroke and the mechanism remain unknown. Therefore, based on the favorable biocompatibility of BSA-SeNPs, h-ICH (hippocampus-intracerebral hemorrhage) model was constructed to perform BSA-SeNPs therapy. As expected, these BSA-SeNPs could effectively improve the cognitive deficits and ameliorate the damage of hippocampal neuron. Furthermore, BSA-SeNPs reverse the morphology of mitochondria and enhanced the mitochondrial function, evidenced by mitochondrial respiration function (OCR) and mitochondrial membrane potential (MMP). Mechanistically, BSA-SeNPs could efficiently activate the Nrf2 to enhance the expression of antioxidant GPX4 at mRNA and protein levels, and further inhibit lipid peroxidation production in erastin-induced ferroptotic damages. Taken together, this study not only sheds light on the clinical application of BSA-SeNPs, but also provides its newly theoretical support for the strategy of the intervention and treatment of neurological impairment following ICH.

Asunto(s)

Hemorragia Cerebral , Ferroptosis , Factor 2 Relacionado con NF-E2 , Nanopartículas , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Selenio , Animales , Humanos , Masculino , Ratones , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/metabolismo , Modelos Animales de Enfermedad , Ferroptosis/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Nanopartículas/química , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/administración & dosificación , Factor 2 Relacionado con NF-E2/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Selenio/química , Selenio/farmacología , Albúmina Sérica Bovina/química

RESUMEN

The transformation of organoboron compounds plays an important role in synthetic chemistry, and recent advancements in boron-migration reactions have garnered considerable attention. Here, we report an unprecedented 1,2-boron migrative acylation upon photocatalysis-facilitated N-heterocyclic carbene catalysis. The design of a redox-active boronic ester substrate, serving as an excellent ß-boron radical precursor, is the linchpin to the success of this chemistry. With the established protocol, a wide spectrum of ß-boryl ketones has been rapidly synthesized, which could further undergo various C─B bond transformations to give multifunctionalized products. The robustness of this catalytic strategy is underscored by its successful application in late-stage modification of drug-derived molecules and natural products. Preliminary mechanistic investigations, including several control experiments, photochemistry measurements, and computational studies, shed light on the catalytic radical reaction mechanism.

RESUMEN

Objective: This study aimed to evaluate the feasibility of a hybrid Glubran-supported single-Proglide technique for large bore femoral access closure during percutaneous access endovascular aneurysm repair (EVAR). Methods: A retrospective cohort study was performed for all percutaneous EVARs at our center from January 2023 to June 2023. All patients received the hybrid Glubran-supported single-Proglide technique involving a mixture of surgical glue and Lipiodol injection after single suture placement for femoral access closure. Technical success was defined as achieving complete hemostasis without a bailout strategy. Vascular complications and bleeding were defined by Valve Academic Research Consortium-3 (VARC-3) criteria. Vascular access changes and 30-day mortality were recorded. Results: The technique success rate for the entire study population was 100% (55 femoral access in 37 patients; median age: 72; 78% males). The mean sheath size was 20.4 ± 2.3F. The mean manual compression time was 3.5 ± 1.4 min, the mean hemostasis time was 9.0 ± 2.5 min, and the mean procedural time was 103.9 ± 34.7 min. One patient (1.6%) developed an access site infection and recovered conservatively. No VARC-3 vascular complications and access changes were observed. No 30-day mortality happened. Conclusions: The hybrid Glubran-supported single-Proglide technique is feasible for large bore access closure during EVAR and may be a viable alternative; however, larger prospective studies are required to confirm its efficacy.

RESUMEN

Endogenous opioid antinociception is a self-regulatory mechanism that reduces chronic pain, but its underlying circuit mechanism remains largely unknown. Here, we showed that endogenous opioid antinociception required the activation of mu-opioid receptors (MORs) in GABAergic neurons of the central amygdala nucleus (CEA) in a persistent-hyperalgesia mouse model. Pharmacogenetic suppression of these CEAMOR neurons, which mimics the effect of MOR activation, alleviated the persistent hyperalgesia. Furthermore, single-neuron projection analysis revealed multiple projectome-based subtypes of CEAMOR neurons, each innervating distinct target brain regions. We found that the suppression of axon branches projecting to the parabrachial nucleus (PB) of one subtype of CEAMOR neurons alleviated persistent hyperalgesia, indicating a subtype- and axonal-branch-specific mechanism of action. Further electrophysiological analysis revealed that suppression of a distinct CEA-PB disinhibitory circuit controlled endogenous opioid antinociception. Thus, this study identified the central neural circuit that underlies endogenous opioid antinociception, providing new insight into the endogenous pain modulatory mechanisms.

RESUMEN

BACKGROUND: Fear of childbirth is a common concern in pregnant women and their spouses due to the unpredictability of the process and outcome of a delivery, which results in adverse effects on mental health, birth outcomes and family intimacy. However, there is a lack of studies that explore the influencing factors of fear of childbirth among expectant couples from a dyadic perspective. The aim of this study is to explore the correlation of dyadic coping, resilience and fear of childbirth in pregnant couples and to construct an actor-partner interdependence model to verify dyadic effects. METHODS: This cross-sectional survey included 420 couples and was conducted between November 2022 and March 2023 in the obstetric department at two hospitals in China. Convenience sampling and an actor-partner interdependence model was used. FINDINGS: The prevalence of fear of childbirth among pregnant women and their spouses is 37.4 % and 33.1 %, respectively. Women's resilience and dyadic coping had a partner effect on spouses' fear of childbirth, in addition to an actor effect on their own fear of childbirth. Spouses' resilience and dyadic coping had only actor effects on themselves, and no partner effect was found on the pregnant women. CONCLUSION: Women's fear of childbirth was positively associated with spouses' fear of childbirth. Interventions for fear of childbirth should include improving resilience and enhancing dyadic stress support and coping. This study provides empirical evidence for future clinical research and interventions on the psychological status of pregnant women and their partners during pregnancy.

Asunto(s)

Adaptación Psicológica , Miedo , Parto , Resiliencia Psicológica , Humanos , Femenino , Adulto , Embarazo , Estudios Transversales , Miedo/psicología , China , Parto/psicología , Encuestas y Cuestionarios , Masculino , Esposos/psicología , Mujeres Embarazadas/psicología

RESUMEN

AIM: To investigate the morphological characteristics of retinal vessels in patients with different severity of diabetic retinopathy (DR) and in patients with or without diabetic macular edema (DME). METHODS: The 239 eyes of DR patients and 100 eyes of healthy individuals were recruited for the study. The severity of DR patients was graded as mild, moderate and severe non-proliferative diabetic retinopathy (NPDR) according to the international clinical diabetic retinopathy (ICDR) disease severity scale classification, and retinal vascular morphology was quantitatively analyzed in ultra-wide field images using RU-net and transfer learning methods. The presence of DME was determined by optical coherence tomography (OCT), and differences in vascular morphological characteristics were compared between patients with and without DME. RESULTS: Retinal vessel segmentation using RU-net and transfer learning system had an accuracy of 99% and a Dice metric of 0.76. Compared with the healthy group, the DR group had smaller vessel angles (33.68±3.01 vs 37.78±1.60), smaller fractal dimension (Df) values (1.33±0.05 vs 1.41±0.03), less vessel density (1.12±0.44 vs 2.09±0.36) and fewer vascular branches (206.1±88.8 vs 396.5±91.3), all P<0.001. As the severity of DR increased, Df values decreased, P=0.031. No significant difference between the DME and non-DME groups were observed in vascular morphological characteristics. CONCLUSION: In this study, an artificial intelligence retinal vessel segmentation system is used with 99% accuracy, thus providing with relatively satisfactory performance in the evaluation of quantitative vascular morphology. DR patients have a tendency of vascular occlusion and dropout. The presence of DME does not compromise the integral retinal vascular pattern.

RESUMEN

Phospholipase D (PLD) lipid-signaling enzyme superfamily has been widely implicated in various human malignancies, but its role and underlying mechanism remain unclear in nasopharyngeal carcinoma (NPC). Here, we analyze the expressions of 6 PLD family members between 87 NPC and 10 control samples through transcriptome analysis. Our findings reveal a notable upregulation of PLD1 in both NPC tumors and cell lines, correlating with worse disease-free and overall survival in NPC patients. Functional assays further elucidate PLD1's oncogenic role, demonstrating its pivotal promotion of critical tumorigenic processes such as cell proliferation and migration in vitro, as well as tumor growth in vivo. Notably, our study uncovers a positive feedback loop between PLD1 and the NF-κB signaling pathway to render NPC progression. Specifically, PLD1 enhances NF-κB activity by facilitating the phosphorylation and nuclear translocation of RELA (p65), which in turn binds to the promoter of PLD1, augmenting its expression. Moreover, RELA overexpression markedly rescues the inhibitory effects in PLD1-depleted NPC cells. Importantly, the application of the PLD1 inhibitor, VU0155069, substantially inhibits NPC tumorigenesis in a patient-derived xenograft (PDX) model. Together, our findings identify PLD1/NF-κB signaling as a positive feedback loop with promising therapeutic and prognostic potential in NPC.

RESUMEN

Peptidoglycan (PG) sacculi surround the cytoplasmic membrane, maintaining cell integrity by withstanding internal turgor pressure. During cell growth, PG endopeptidases cleave the crosslinks of the fully closed sacculi, allowing for the incorporation of new glycan strands and expansion of the peptidoglycan mesh. Outer-membrane-anchored NlpI associates with hydrolases and synthases near PG synthesis complexes, facilitating spatially close PG hydrolysis. Here, we present the structure of adaptor NlpI in complex with the endopeptidase MepS, revealing atomic details of how NlpI recruits multiple MepS molecules and subsequently influences PG expansion. NlpI binding elicits a disorder-to-order transition in the intrinsically disordered N-terminal of MepS, concomitantly promoting the dimerization of monomeric MepS. This results in the alignment of two asymmetric MepS dimers respectively located on the two opposite sides of the dimerization interface of NlpI, thus enhancing MepS activity in PG hydrolysis. Notably, the protein level of MepS is primarily modulated by the tail-specific protease Prc, which is known to interact with NlpI. The structure of the Prc-NlpI-MepS complex demonstrates that NlpI brings together MepS and Prc, leading to the efficient MepS degradation by Prc. Collectively, our results provide structural insights into the NlpI-enabled avidity effect of cellular endopeptidases and NlpI-directed MepS degradation by Prc.

Asunto(s)

Endopeptidasas , Lipoproteínas , Peptidoglicano , Peptidoglicano/metabolismo , Endopeptidasas/metabolismo , Endopeptidasas/química , Lipoproteínas/metabolismo , Lipoproteínas/química , Unión Proteica , Multimerización de Proteína , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química , Modelos Moleculares , Cristalografía por Rayos X , Hidrólisis , Escherichia coli/metabolismo

RESUMEN

Drought stress has a significant impact on the quality and quantity of lake water. Understanding this impact is crucial for preventing water security risks and pollution recovery. However, there is a lack of systemic understanding of how drought affects water quality and quantity, and how they change in multiple dimensions. This manuscript established a synthesized methodology with the principles to judge the applicability and three steps of application to detect the change in water quality and water level under severe drought in Xingyun Lake, China. Results show that (1) The water level and water quality of Xingyun Lake have a synchronous and evident response to drought during 2009-2014. The rainfall during 2008-2015 declined by 22.9 % to normal, and the inundated area and lake water depth in 2012 decreased by 10.50 % from 2002 to 1.38 m to the average depth, respectively. The pollution index climbed above 1.21 after 2008, fluctuating around 1.42. (2) Under drought, the water quality indicators significantly changed in the terms of the overall feature, trend, eigenvalue, and morphological characteristics. The water quality indicators of Set2008-2015 are significantly different from set2000-2007 and not in the groups of set1994-2000. The morphological characteristics of water quality indicators in set2008-2015 differs significantly from that in set2000-2007 shown by the minimum, maximum, median, quartiles, and extreme values. (3) Although NH3-N showed no significant change, the water quality deteriorated in the physical, chemical, and biological aspects. The TP, IMN, and BOD5 changed more evidently than DO and NH3-N. (4) Water quality grade and indicator concentration deteriorated significantly and sharply under severe drought and are threatened deeply by TP and TN. The synthesized methodology is scientifically constructed and canbe employed in the characteristics cognition of water quality and water level to severe drought in and out of this research. And the intervention time and various regulating measures for pollution degradation and water quality recovery canbe constructed based on the multi-dimensional analysis of water quality change under drought evolution.

RESUMEN

The infiltration of CD8 + T cells in the tumor microenvironment is associated with better survival and immunotherapy response. However, their roles in gastric cancer have not been explored so far. In here, the profiles of GC gene expression were collected from The Cancer Genome Atlas database. Single-cell transcriptomic data originated from GSE134520. Cell clustering, annotation, and CD8 + T-cell differential genes were from the TISCH database. We determined 896 CD8 + T-cell differential genes by scRNA-seq analysis. After integrating immune-related genes, 174 overlapping genes were obtained and a novel risk model was subsequently built. The performance of CD8 + T-cell-associated gene signature was assessed in the training and external validation sets. The gene signature showed independent risk factors of overall survival for GC. A quantitative nomogram was built to enhance the clinical efficacy of this signature. Furthermore, low-risk individuals showed higher mutation status, higher immune checkpoint expression, low Tumour Immune Dysfunction and Exclusion (TIDE) scores, and higher IPS-PD-1 combined IPS-CTLA4 scores, indicating a greater response to immunotherapy. In addition, analysis of IMvigor210 immunotherapy cohort demonstrated that low-risk individuals had a favorable response to prognosis and immunotherapy. In conclusion, we generated a CD8 + T-cell-related signature that can serve as a promising tool for personalized prognosis prediction and guiding decisions regarding immunotherapy in GC patients.

Asunto(s)

Linfocitos T CD8-positivos , Análisis de la Célula Individual , Neoplasias Gástricas , Microambiente Tumoral , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/diagnóstico , Linfocitos T CD8-positivos/inmunología , Pronóstico , Análisis de la Célula Individual/métodos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Transcriptoma , Análisis de Secuencia de ARN/métodos , Biomarcadores de Tumor/genética , Masculino , Femenino , Perfilación de la Expresión Génica , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Nomogramas , Regulación Neoplásica de la Expresión Génica , Inmunoterapia/métodos