RESUMEN

Herein, a visible-light-promoted radical cascade cyclization of heterocyclic ketene aminals (HKAs) and thiocyanates was developed to access functionalized fused 2-iminothiazolines. This novel cascade reaction can be realized under only visible-light irradiation without the help of external photocatalysts, oxidants, and additives. These multicomponent cascade reactions demonstrate excellent selectivity for the Z-isomers and ensure the formation of the products only in their isomeric form. Preliminary mechanism investigations demonstrated that HKAs and thiocyanates can form electron donor-acceptor complexes for harvesting the energy of visible light to activate substrates and generate reactive radicals. This protocol can be used for synthesizing various natural-like products such as fused 2-iminothiazolines. This approach demonstrates multiple advantages such as commercially available substrates, convenient operation, environmentally friendly, mild conditions, and an efficient multicomponent reaction (2A + B).

RESUMEN

BACKGROUND: Critically ill patients in the intensive care unit (ICU) often experience dysglycaemia. However, studies investigating the link between acute kidney injury (AKI) and dysglycaemia, especially in those with and without diabetes mellitus (DM), are limited. METHODS: We used the Medical Information Mart for Intensive Care IV database to investigate the association between AKI within 7 days of admission and subsequent dysglycaemia. The primary outcome was the occurrence of dysglycaemia (both hypoglycemia and hyperglycemia) after 7 days of ICU admission. Logistic regression analyzed the relationship between AKI and dysglycaemia, while a Cox proportional hazards model estimated the long-term mortality risk linked to the AKI combined with dysglycaemia. RESULTS: A cohort of 20,008 critically ill patients were included. The AKI group demonstrated a higher prevalence of dysglycaemia, compared to the non-AKI group. AKI patients had an increased risk of dysglycaemia (adjusted odds ratio [aOR] 1.53, 95% confidence interval [CI] 1.41-1.65), hypoglycemia (aOR 1.56, 95% CI 1.41-1.73), and hyperglycemia (aOR 1.53, 95% CI 1.41-1.66). In subgroup analysis, compared to DM patients, AKI showed higher risk of dysglycaemia in non-DM patients (aOR: 1.93 vs. 1.33, Pint<0.01). Additionally, the AKI with dysglycaemia group exhibited a higher risk of long-term mortality compared to the non-AKI without dysglycaemia group. Dysglycaemia also mediated the relationship between AKI and long-term mortality. CONCLUSION: AKI was associated with a higher risk of dysglycaemia, especially in non-DM patients, and the combination of AKI and dysglycaemia was linked to higher long-term mortality. Further research is needed to develop optimal glycemic control strategies for AKI patients.

Asunto(s)

Lesión Renal Aguda , Enfermedad Crítica , Hiperglucemia , Hipoglucemia , Unidades de Cuidados Intensivos , Humanos , Lesión Renal Aguda/sangre , Lesión Renal Aguda/mortalidad , Lesión Renal Aguda/etiología , Lesión Renal Aguda/epidemiología , Masculino , Estudios Retrospectivos , Femenino , Enfermedad Crítica/mortalidad , Persona de Mediana Edad , Anciano , Hiperglucemia/complicaciones , Hiperglucemia/sangre , Hiperglucemia/epidemiología , Hipoglucemia/complicaciones , Hipoglucemia/sangre , Hipoglucemia/epidemiología , Hipoglucemia/mortalidad , Unidades de Cuidados Intensivos/estadística & datos numéricos , Diabetes Mellitus/epidemiología , Factores de Riesgo , Modelos Logísticos , Modelos de Riesgos Proporcionales , Glucemia/análisis , Prevalencia

RESUMEN

Maize phenotypes are plastic, determined by the complex interplay of genetics and environmental variables. Uncovering the genes responsible and understanding how their effects change across a large geographic region are challenging. In this study, we conducted systematic analysis to identify environmental indices that strongly influence 19 traits (including flowering time, plant architecture, and yield component traits) measured in the maize nested association mapping (NAM) population grown in 11 environments. Identified environmental indices based on day length, temperature, moisture, and combinations of these are biologically meaningful. Next, we leveraged a total of more than 20 million SNP and SV markers derived from recent de novo sequencing of the NAM founders for trait prediction and dissection. When combined with identified environmental indices, genomic prediction enables accurate performance predictions. Genome-wide association studies (GWASs) detected genetic loci associated with the plastic response to the identified environmental indices for all examined traits. By systematically uncovering the major environmental and genomic factors underlying phenotypic plasticity in a wide variety of traits and depositing our results as a track on the MaizeGDB genome browser, we provide a community resource as well as a comprehensive analytical framework to facilitate continuing complex trait dissection and prediction in maize and other crops. Our findings also provide a conceptual framework for the genetic architecture of phenotypic plasticity by accommodating two alternative models, regulatory gene model and allelic sensitivity model, as special cases of a continuum.

RESUMEN

Migraine is highly prevalent and debilitating. The persistent headaches in this condition are thought to arise from the activation and sensitization of the trigeminovascular pathway. Both clinical and animal model studies have suggested that neuroimmune interactions contribute to the pathophysiology of migraine headache. In this review, we first summarize the findings from human studies implicating the dysregulation of the immune system in migraine, including genetic analyses, measurement of circulatory factors, and neuroimaging data. We next discuss recent advances from rodent studies aimed at elucidating the neuroimmune interactions that manifest at various levels of the trigeminovascular pathway and lead to the recruitment of innate and adaptive immune cells as well as immunocompetent glial cells. These cells reciprocally modulate neuronal activity via multiple pro- and anti-inflammatory mediators, thereby regulating peripheral and central sensitization. Throughout the discussions, we highlight the potential clinical and translational implications of the findings.

RESUMEN

OBJECTIVES: The study aimed to investigate the relationship between blood pressure (BP) levels and mortality among critically ill older adults in the intensive care unit (ICU), establish optimal BP target for this population, and assess the mediating effect of severe malnutrition on BP-related mortality. METHODS: Data were extracted from the Medical Information Mart for Intensive Care IV version 2.2 database, focusing on critically ill patients aged 80 years and older. The analysis included various BP parameters, such as systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP). RESULTS: The study cohort comprised 14,660 critically ill patients, of whom 1558 (10.6 %) experienced ICU mortality and 2493 (17.0 %) experienced in-hospital mortality. Lower BP levels (SBP ≤ 112 mmHg; DBP ≤ 53 mmHg; MAP ≤65 mmHg), were associated with an increased risk of both ICU and in-hospital mortality. Notably, only reduced SBP levels were linked to a higher risk of 1-year mortality, with an adjusted hazard ratio 1.13 (95 % confidence interval 1.05 to 1.23). Additionally, severe malnutrition was identified as a mediator in the relationship between low BP levels and ICU mortality, with BP levels positively correlated with prognostic nutritional indexes. CONCLUSION: Among critically ill older adults, lower BP levels are significantly associated with higher risks of ICU and in-hospital mortality, while reduced SBP levels are linked to 1-year mortality. These findings emphasize the importance of assessing nutritional status in older ICU patients with low BP levels to potentially mitigate mortality risk.

RESUMEN

The side population (SP) cells are identified through Hoechst 33342 staining and analyzed using flow cytometry (FCM). The Hoechst SP method is utilized for the isolation of stem cells based on the dye efflux properties of ATP-binding cassette (ABC) transporters. The method was initially employed for the identification and isolation of hematopoietic stem cells (HSCs), but it has now evolved to primarily focus on the identification and isolation of cancer stem cells (CSCs). The traditional detection method of FCM uses a 355 nm laser to excite the dye to detect SP cells. Through this study, we have successfully identified alternative approaches for dye excitation that can effectively replace the detection of SP cells using a 355 nm laser. This is achieved through the utilization of high-power 375 nm or 405 nm lasers. This allows us to exercise enhanced selectivity in the detection of SP cells rather than being solely limited to the 355 nm laser flow cytometry.

Asunto(s)

Bencimidazoles , Citometría de Flujo , Células de Población Lateral , Citometría de Flujo/métodos , Bencimidazoles/química , Células de Población Lateral/citología , Células de Población Lateral/metabolismo , Humanos , Colorantes Fluorescentes/química , Animales , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismo

RESUMEN

Skeletal muscle quality and yield are important production traits in livestock, and improving skeletal muscle quality while increasing its yield is an important goal of economic breeding. The proliferation and differentiation process of sheep myoblasts directly affects the growth and development of their muscles, thereby affecting the yield of mutton. Myomesin 3 (Myom3), as a functional gene related to muscle growth, currently lacks research on its function in myoblasts. This study aims to investigate the effect of the Myom3 gene on the proliferation and differentiation of sheep myoblasts and its potential molecular mechanisms. The results showed that inhibitor of Myom3 in the proliferation phase of myoblasts resulted in significant downregulation of the proliferation marker gene paired box 7 (Pax7) and myogenic regulatory factors (MRFs; Myf5, Myod1, Myog, P < 0.01), a significant decrease in the EdU-positive cell rate (P < 0.05), and a significant increase in the cell apoptosis rate (P < 0.01), which inhibited the proliferation of myoblasts and promoted their apoptosis. During the differentiation phase of myoblasts, the inhibitor of Myom3 resulted in significant downregulation of the Pax7 gene, upregulation of MRFs (Myod1, Myog, P < 0.05), and a significant increase in fusion index (P < 0.05), promoting the differentiation of myoblasts. Further transcriptome sequencing revealed that differentially expressed genes in the Myom3 interference group were mainly enriched in the MAPK signaling pathway, TNF signaling pathway, and IL-17 signaling pathway. In summary, the inhibitor of Myom3 inhibits myoblast proliferation and promotes myoblast differentiation. Therefore, Myom3 has a potential regulatory effect on the growth and development of sheep muscles, and in-depth functional research can be used for molecular breeding practices in sheep.

RESUMEN

AIMS: The relationship between sarcopenia and cognitive impairment in older adults remains contentious. This study investigates this association and examines the long-term prognosis for individuals with both conditions. METHODS: Utilizing data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014, this study focuses on the correlation between sarcopenia and cognitive impairment, as well as the extended prognosis for individuals managing these conditions. RESULTS: The study cohort comprised 2890 participants, with 648 (22.4 %) diagnosed with sarcopenia. Multivariable logistic regression analysis identified a significant association between sarcopenia and an increased risk of cognitive impairment (adjusted odds ratio [aOR]: 1.68, 95 % confidence interval [CI]: 1.30-2.17). Over a median follow-up period of 48 months, 200 individuals (6.9 %) succumbed to cardiovascular and cerebrovascular diseases (CCVDs), including hypertension, congestive heart failure, coronary artery disease, and stroke, as well as Alzheimer's disease (AD). Participants had comorbid conditions such as CCVDs and diabetes mellitus. Kaplan-Meier survival analysis and the Cox proportional hazards model indicated that individuals with both sarcopenia and cognitive impairment had the highest mortality risk from CCVDs and AD (adjusted hazard ratio [aHR]: 2.73, 95 % CI: 1.48-5.02). Individuals with sarcopenia and comorbidities exhibited a higher mortality risk from CCVDs or AD compared to those without sarcopenia but with comorbidities (aHR: 2.71, 95 % CI: 1.37-5.37). CONCLUSION: Sarcopenia is independently associated with cognitive impairment. Older adults with both sarcopenia and cognitive impairment or concurrent comorbidities face increased mortality risks from CCVDs or AD compared to their healthy counterparts.

RESUMEN

Recent regional investigations in the United States have revealed a thought-provoking perspective: household electricity consumption may act as an inferior commodity, displaying a negative correlation with wealth. This finding challenges the outcomes of various other econometric analyses and underscores the importance of scrutinizing power consumption patterns across different regional service areas. While it is commonly believed that home electricity usage decreases as income rises, this may not always hold true universally. This study focuses on power usage in Seattle, Washington households, a prominent urban economy in the Pacific Northwest. Employing dynamic error correction modeling techniques, the research demonstrates statistically significant fluctuations in domestic power usage attributed to variations in actual value, actual revenue, and cold weather. In the immediate future, energy for homes in this urban economy resembles any other commodity. However, investing in electricity for homes in Seattle may not be advisable in the long run. Home power usage in Seattle declines with each percentage point increase in actual per capita income over 1.2 %. This finding highlights the need for careful consideration and strategic planning in energy management policies for urban economies like Seattle.

RESUMEN

Yeasts are pivotal brewing microbes that are associated with the flavor and quality of Chinese baijiu, yet research on dominant yeasts in strong-flavor baijiu brewing remains limited. In this study, Saccharomyces cerevisiae, Pichia kudriavzevii, and Kazachstania bulderi were identified as predominated yeasts in strong-flavor baijiu. Each strain showed distinct characteristics in ethanol resistance, thermal tolerance, and lactic acid tolerance, severally. S. cerevisiae FJ1-2 excelled in ethanol and ethyl ester production, P. kudriavzevii FJ1-1 in ethyl acetate, and K. bulderi FJ1-3 in lactic acid generation. Subsequently, the reinforced Fuqu of each yeast were severally prepared for application in baijiu brewing to verify their functions. Results revealed that the relative abundance of fortified yeast in each group rose. Pichia, Kazachstania, and Saccharomyces emerged as the core microbe for each group, respectively, by co-occurrence network analysis, influencing the microbiota to regulate flavor substances. In short, P. kudriavzevii FJ1-1 enhanced ethyl acetate. K. bulderi FJ1-3 improved ethyl caproate production and decreased levels of ethyl acetate and higher alcohols by modulating yeast community between Pichia and Saccharomyces. This is a systematic endeavor to study the functions of yeasts of strong-flavor baijiu, providing a solid basis for improving baijiu quality.

RESUMEN

Biofilm formation of Klebsiella pneumoniae can protect bacteria from antibiotics and is difficult to eradicate. Thus, the influence of subinhibitory concentrations of antibiotics on bacteria is becoming increasingly important. Our study showed that subminimum inhibitory concentrations (sub-MICs) of tetracycline antibiotics can increase biofilm formation in minocycline-resistant Klebsiella pneumoniae clinical strains. However, in the bacterial adhesion and invasion experiments, the adhesion and invasion ability decreased and the survival rate of Galleria mellonella increased. Under sub-MICs of tetracycline antibiotics treatment, abnormal stretching of bacteria was observed by scanning electron microscopy. Treatment with sub-MICs of tetracyclines leads to increased surface hydrophobicity and eDNA content and decreased outer membrane permeability. The expression levels of the fimA, luxS, qseB, and qseC genes decreased, the expression level of mrkA increased, and the expression level of acrA was inconsistent under different tetracycline antibiotics treatments. Together, our results suggested that the increase in Klebsiella pneumoniae biofilm formation caused by sub-MICs of tetracycline antibiotics may occur by affecting bacterial physical and chemical properties and associated genes expression.

Asunto(s)

Antibacterianos , Biopelículas , Klebsiella pneumoniae , Pruebas de Sensibilidad Microbiana , Biopelículas/efectos de los fármacos , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/genética , Antibacterianos/farmacología , Minociclina/farmacología , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/tratamiento farmacológico , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Animales , Tetraciclina/farmacología , Adhesión Bacteriana/efectos de los fármacos , Farmacorresistencia Bacteriana/efectos de los fármacos , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Mariposas Nocturnas/efectos de los fármacos , Mariposas Nocturnas/microbiología , Humanos , Interacciones Hidrofóbicas e Hidrofílicas

RESUMEN

At present, electrochemical CO2 reduction has been developed towards industrial current density, but the high faradaic efficiency at wide potential range or large current density is still an arduous task. Therefore, in this work, the highly exposed Ni single atoms (NiNCR-0.72) was synthesized through simple metal organic frameworks (MOFs)-derived method with SiO2 protection strategy. The obtained catalyst keeps CO faradaic efficiency (FECO) above 91 % under the wide potential range, and achieves a high FECO of 96.0 % and large CO partial current density of -206.8 mA cm-2 at -0.7 V in flow cell. The experimental results and theoretical calculation disclose that NiNCR-0.72 possesses the robust structure with rich mesopore and more highly exposed Ni-N active sites under SiO2 protection, which could facilitate CO2 transportation, lower energy barrier of CO2 reduction, and raise difficulty of hydrogen evolution reaction. The protection strategy is instructive to the synthesis of other MOFs-derived metal single atoms.

RESUMEN

CD4+ T cells are central mediators of protective immunity to blood-stage malaria, particularly for their capacity in orchestrating germinal center reaction and generating parasite-specific high-affinity antibodies. T follicular helper (Tfh) cells are predominant CD4+ effector T cell subset implicated in these processes, yet the factors and detailed mechanisms that assist Tfh cell development and function during Plasmodium infection are largely undefined. Here we provide evidence that receptor for activated C kinase 1 (RACK1), an adaptor protein of various intracellular signals, is not only important for CD4+ T cell expansion as previously implied but also plays a prominent role in Tfh cell differentiation and function during blood-stage Plasmodium yoelii 17XNL infection. Consequently, RACK1 in CD4+ T cells contributes significantly to germinal center formation, parasite-specific IgG production, and host resistance to the infection. Mechanistic exploration detects specific interaction of RACK1 with STAT3 in P. yoelii 17XNL-responsive CD4+ T cells, ablation of RACK1 leads to defective STAT3 phosphorylation, accompanied by substantially lower amount of STAT3 protein in CD4+ T cells, whereas retroviral overexpression of RACK1 or STAT3 in RACK1-deficient CD4+ T cells greatly restores STAT3 activity and Bcl-6 expression under the Tfh polarization condition. Further analyses suggest RACK1 positively regulates STAT3 stability by inhibiting the ubiquitin-proteasomal degradation process, thus promoting optimal STAT3 activity and Bcl-6 induction during Tfh cell differentiation. These findings uncover a novel mechanism by which RACK1 participates in posttranslational regulation of STAT3, Tfh cell differentiation, and subsequent development of anti-Plasmodium humoral immunity.

Asunto(s)

Diferenciación Celular , Malaria , Plasmodium yoelii , Receptores de Cinasa C Activada , Factor de Transcripción STAT3 , Células T Auxiliares Foliculares , Animales , Receptores de Cinasa C Activada/metabolismo , Factor de Transcripción STAT3/metabolismo , Malaria/inmunología , Malaria/parasitología , Ratones , Plasmodium yoelii/inmunología , Células T Auxiliares Foliculares/inmunología , Células T Auxiliares Foliculares/metabolismo , Ratones Endogámicos C57BL , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Ratones Noqueados , Centro Germinal/inmunología

RESUMEN

Guide Black-Fur sheep (GD) is a breed of Tibetan sheep (Ovis aries) that lives in the Qinghai-Tibetan plateau region at an altitude of over 4,000 m. However, a lack of genomic information has made it difficult to understand the high-altitude adaptation of these sheep. We sequenced and assembled the GD reference genome using PacBio, Hi-C, and Illumina sequencing technologies. The final assembled genome size was 2.73 Gb, with a contig N50 of 20.30 Mb and a scaffold N50 of 107.63 Mb. The genome is predicted to contain 20,759 protein-coding genes, of which 98.42 have functional annotations. Repeat elements account for approximately 52.2% of the genomic landscape. The completeness of the GD genome assembly is highlighted by a BUSCO score of 93.1%. This high-quality genome assembly provides a critical resource for future molecular breeding and genetic improvement of Tibetan sheep.

Asunto(s)

Genoma , Oveja Doméstica , Animales , Altitud , Cromosomas , Ovinos/genética , Oveja Doméstica/genética , Tibet

RESUMEN

The resin of Ferula sinkiangensis has been traditionally utilized for treating gastrointestinal disorders, inflammation, tumors, various cancers, and alopecia areata. The primary bioactive constituents, sesquiterpene coumarins, have demonstrated notable therapeutic potential against neuroinflammation. In this study, a structure-guided fractionation method was used to isolate nine novel sesquiterpene coumarins from the resin of F. sinkiangensis. These compounds were characterized and structurally elucidated using comprehensive physicochemical and spectroscopic techniques, including calculated electronic circular dichroism (ECD). Anti-neuroinflammatory assays revealed that compounds 2, 3, and 6 significantly inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated BV2 microglial cells, with IC50 values ranging from 1.63 to 12.25 µmol·L-1.

Asunto(s)

Antiinflamatorios , Cumarinas , Ferula , Microglía , Óxido Nítrico , Sesquiterpenos , Ferula/química , Cumarinas/farmacología , Cumarinas/aislamiento & purificación , Cumarinas/química , Sesquiterpenos/farmacología , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Microglía/efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Estructura Molecular , Animales , Ratones , Línea Celular , Lipopolisacáridos/farmacología , Resinas de Plantas/química , Extractos Vegetales/farmacología , Extractos Vegetales/química

RESUMEN

Introduction: The escalating prevalence of bacterial resistance, particularly multidrug-resistant bacteria like Acinetobacter baumannii, has become a significant global public health concern. The CRISPR-Cas system, a crucial defense mechanism in bacteria against foreign genetic elements, provides a competitive advantage. Type I-Fb and Type I-Fa are two subtypes of CRISPR-Cas systems that were found in A. baumannii, and the I-Fb CRISPR-Cas system regulates antibiotic resistance in A. baumannii. However, it is noteworthy that a majority of clinical isolates of A. baumannii lack or have incomplete CRISPR-Cas systems and most of them are multidrug-resistant. In light of this, our study aimed to examine the impact of antibiotic pressure on the fitness cost of the I-Fb CRISPR-Cas system in A. baumannii. Methods and Results: In the study, we conducted in vitro competition experiments to investigate the influence of sub-minimum inhibitory concentration (sub-MIC) on the CRISPR-Cas systems' fitness cost in A. baumannii. We found that the fitness cost of the CRISPR-Cas system was increased under sub-MIC conditions. The expression of CRISPR-Cas-related genes was decreased, while the conjugation frequency was increased in AB43 under sub-MIC conditions. Through metabolomic analysis, we identified that sub-MIC conditions primarily affected energy metabolism pathways. In particular, we observed increased carbon metabolism, nitrogen metabolism, and intracellular ATP. Notably, the CRISPR-Cas system demonstrated resistance to the efflux pump-mediated resistance. Furthermore, the expression of efflux pump-related genes was increased under sub-MIC conditions. Conclusion: Our findings suggest that the I-Fb CRISPR-Cas system confers a significant competitive advantage in A. baumanni. However, under sub-MIC conditions, its function and the ability to inhibit the energy required for efflux pumps are reduced, resulting in an increased fitness cost and loss of competitive advantage.

RESUMEN

This study aims to compare the accuracy of genomic estimated breeding values (GEBV) estimated using a genomic best linear unbiased prediction (GBLUP) method and GEBV estimates incorporating prior marker information from a genome-wide association study (GWAS) for the weaning weight trait in highland Merino sheep. The objective is to provide theoretical and technical support for improving the accuracy of genomic selection. The study used a population of 1007 highland Merino ewes, with the weaning weight at 3 months as the target trait. The population was randomly divided into two groups. The first group was used for GWAS analysis to identify significant markers, and the top 5%, top 10%, top 15%, and top 20% markers were selected as prior marker information. The second group was used to estimate genetic parameters and compare the accuracy of GEBV predictions using different prior marker information. The accuracy was obtained using a five-fold cross-validation. Finally, both groups were subjected to cross-validation. The study's findings revealed that the heritability of the weaning weight trait, as calculated using the GBLUP model, ranged from 0.122 to 0.394, with corresponding prediction accuracies falling between 0.075 and 0.228. By incorporating prior marker information from GWAS, the heritability was enhanced to a range of 0.125 to 0.407. The inclusion of the top 5% to top 20% significant SNPs from GWAS results as prior information into GS showed potential for improving the accuracy of predicting genomic breeding value.

RESUMEN

OBJECTIVE: Despite the high prevalence, mild traumatic brain injury (mTBI)-induced chronic headache and cognitive deficits are poorly understood and lack effective treatments. Low-dose interleukin-2 (LD-IL-2) treatment soon after mTBI or overexpressing IL-2 in brain astrocytes prior to injury protects mice from developing post-traumatic headache (PTH)-related behaviors and cognitive decline. The present study addresses a clinically relevant knowledge gap: whether LD-IL-2 treatment long after the initial injury is still effective for chronic PTH and cognitive deficits. METHODS: mTBI was induced by a noninvasive closed-head weight drop method. LD-IL-2 was administered 4-6 weeks post-mTBI to assess its effects on chronic PTH-related facial mechanical hypersensitivity as well as mTBI-induced impairment in novel object recognition and object location tests. Endogenous regulatory T (Treg) cells were depleted to investigate the mechanism of action of LD-IL-2. RESULTS: Delayed LD-IL-2 treatment abolished chronic PTH-related behaviors. It also completely reversed mTBI-induced cognitive impairment in both male and female mice. Treg cell depletion not only prolonged PTH-related behaviors but also abolished the effects of LD-IL-2. Interestingly, LD-IL-2 treatment significantly increased the number of Treg cells in dura but not in brain tissues. INTERPRETATION: These results suggest that the beneficial effects of LD-IL-2 treatment are mediated through the expansion of meningeal Treg cells. Collectively, our study identifies Treg as a cellular target and LD-IL-2 as a promising therapy for both chronic PTH and mTBI-induced cognitive impairment for both males and females, with a wide therapeutic time window and the potential of reducing polypharmacy in mTBI treatment. ANN NEUROL 2024;96:508-525.

Asunto(s)

Conmoción Encefálica , Disfunción Cognitiva , Modelos Animales de Enfermedad , Interleucina-2 , Animales , Ratones , Masculino , Femenino , Disfunción Cognitiva/etiología , Disfunción Cognitiva/tratamiento farmacológico , Conmoción Encefálica/complicaciones , Conmoción Encefálica/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Ratones Endogámicos C57BL , Cefalea Postraumática/etiología , Cefalea Postraumática/tratamiento farmacológico , Dolor/etiología , Dolor/tratamiento farmacológico

RESUMEN

The slow-developing neurological disorder Alzheimer's disease (AD) has no recognized etiology. A bioinformatics investigation verified copper metabolism indicators for AD development. GEO contributed AD-related datasets GSE1297 and GSE5281. Differential expression analysis and WGCNA confirmed biomarker candidate genes. Each immune cell type in AD and control samples was scored using single sample gene set enrichment analysis. Receiver Operating Characteristic (ROC) analysis, short Time-series Expression Miner (STEM) grouping, and expression analysis between control and AD samples discovered copper metabolism indicators that impacted AD progression. We test clinical samples and cellular function to ensure study correctness. Biomarker-targeting miRNAs and lncRNAs were predicted by starBase. Trust website anticipated biomarker-targeting transcription factors. In the end, Cytoscape constructed the TF/miRNA-mRNA and lncRNA-miRNA networks. The DGIdb database predicted biomarker-targeted drugs. We identified 57 differentially expressed copper metabolism-related genes (DE-CMRGs). Next, fourteen copper metabolism indicators impacting AD progression were identified: CCK, ATP6V1E1, SYT1, LDHA, PAM, HPRT1, SCG5, ATP6V1D, GOT1, NFKBIA, SPHK1, MITF, BRCA1, and CD38. A TF/miRNA-mRNA regulation network was then established with two miRNAs (hsa-miR-34a-5p and 34c-5p), six TFs (NFKB1, RELA, MYC, HIF1A, JUN, and SP1), and four biomarkers. The DGIdb database contained 171 drugs targeting ten copper metabolism-relevant biomarkers (BRCA1, MITF, NFKBIA, CD38, CCK2, HPRT1, SPHK1, LDHA, SCG5, and SYT1). Copper metabolism biomarkers CCK, ATP6V1E1, SYT1, LDHA, PAM, HPRT1, SCG5, ATP6V1D, GOT1, NFKBIA, SPHK1, MITF, BRCA1, and CD38 alter AD progression, laying the groundwork for disease pathophysiology and novel AD diagnostic and treatment.

Asunto(s)

Enfermedad de Alzheimer , Biomarcadores , Cobre , Factor de Transcripción Asociado a Microftalmía , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Cobre/metabolismo , Biomarcadores/metabolismo , Factor de Transcripción Asociado a Microftalmía/metabolismo , Factor de Transcripción Asociado a Microftalmía/genética , Redes Reguladoras de Genes , Biología Computacional/métodos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Perfilación de la Expresión Génica

RESUMEN

Objective: This study aims to investigate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) in patients with idiopathic facial nerve palsy. Methods: The clinical data of patients with idiopathic facial nerve palsy were retrospectively analyzed. After three months of follow-up, patients were divided into good prognosis and poor prognosis, and the correlation between NLR, CRP and idiopathic facial nerve palsy was analyzed. Results: Negative correlation of NLR with Portmann score in idiopathic facial nerve palsy (r=-0.788, P<0.05); In contrast to the group with poor prognosis, patients in good prognosis group had low levels of body mass index (BMI), NLR, and C-reactive protein (CRP), and high Portmann score (P<0.05); Multivariate logistic regression analysis showed Portmann score (OR=1.268, 95% CI (1.005-1.616)), NLR (OR=0.262, 95% CI (0.128-0.533)) and CRP levels (OR=0.949, 95% CI (0.895-0.989)) were risk factors of poor prognosis for patients with idiopathic facial nerve palsy. The area under the receiver operator characteristic (ROC) curve of NLR and CRP levels in predicting poor facial nerve function was 0.764 and 0.697, the specificity was 85.5% and 75.0%, and the sensitivity was 74. 0% and 76.0%, respectively. The ROC curve of the combined diagnosis was 0.829, the specificity was 80.7%, and the sensitivity was 82.0%. Conclusion: Elevated NLR and CRP are associated with a poor prognosis of idiopathic facial nerve palsy and can serve as an indicator for clinical prognosis, and can be widely used in clinical.