RESUMEN

Synchronous fluorescence spectroscopy (SFS) technology exhibits significant advantages in identifying target fluorescence signals within complex mixtures of multiple fluorescent compounds, owing to their closely overlapping spectra. In this study, a SFS method is reported for the first time for the direct analysis of leonurine in drugs containing concurrent natural products. By setting the wavelength interval (Δλ) to 30 nm, the characteristic emission peak of leonurine is observed at 307 nm, which increases proportionally with the concentration of leonurine without spectral overlap from other fluorescent species. The limit of detection (LOD) is estimated to be about 0.22 µM, and a low linear range of 0 to 20 µM is obtained. The common cations, anions and concomitant compounds display no interference with the SFS signal of leonurine, supporting the practical application of this method. Thus, we successfully applied this SFS method to detect leonurine in several real samples (leonurus granules, capsules, ointment and pills), in which the good relative standard deviation (RSD) values (0.04-4.24%) and recoveries (95.63-113%) were obtained. As a result, this work provides an efficient and convenient method to identify the target active compound from natural products without complex pre-treatment to diminish the fluorescent chaos that might be serving a potential role in the study of traditional Chinese medicine.

RESUMEN

OBJECTIVE: To explore the clinical and genetic characteristics of two children with mental retardation and microcephaly. METHODS: Two children who had visited the Anhui Children's Hospital respectively on March 12 and June 22, 2021 were selected as the study subjects. Peripheral venous blood samples were collected from them and their parents, and subjected to chromosomal karyotyping and whole exome sequencing analyses. Candidate variants were verified by Sanger sequencing and pathogenicity analysis. RESULTS: Chromosomal karyotyping and copy number detection of the two children had found no abnormality. Whole exome sequencing revealed that child 1 has harbored a c.471delT (p.Pro157Profs*9) frameshifting variant of the CASK gene, whilst child 2 has harbored a c.1259_1269delCTGAGAATAAC (p.Pro420fs*27) frameshifting variant of the CASK gene. Sanger sequencing confirmed that both variants were de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), both variants were rated as pathogenic (PVS1+PS2+PP3). CONCLUSION: The de novo variants of the CASK gene probably underlay the pathogenesis of mental retardation and microcephaly in both children.

Asunto(s)

RESUMEN

BACKGROUND: Integrase strand transfer inhibitor (InSTI)-based antiretroviral therapies have been associated with greater weight gain in people living with HIV versus on protease inhibitor (PI)-based regimens. The DEFINE study investigated whether switching from an InSTI- to a PI-based regimen could mitigate/reverse weight gain. METHODS: DEFINE (NCT04442737) was a randomized, 48-week, open-label, prospective, phase 4 study in virologically suppressed adults with HIV-1 and ≥10% weight gain on InSTI+tenofovir alafenamide (TAF)/emtricitabine (FTC) (<36 months pre-screening). Participants either switched immediately to darunavir/cobicistat/emtricitabine/TAF (D/C/F/TAF) or continued InSTI+TAF/FTC during Weeks 0-24 then switched to D/C/F/TAF for Weeks 24-48. The primary endpoint was least squares (LS) mean (95% confidence interval [CI]) percent weight change from baseline to Week 24. RESULTS: Overall, 103 adults were randomized (D/C/F/TAF, n=53; InSTI+TAF/FTC, n=50); 30% female; 61% Black/African American. No significant difference in weight change was observed at Week 24 (LS mean change: D/C/F/TAF, 0.63% [95%CI: -0.44, 1.70] vs InSTI+TAF/FTC, -0.24% [-1.35, 0.87]; p=0.24); however, a trend towards weight loss was observed with extended time post-ARV switch to D/C/F/TAF (baseline to Week 48, -0.36% [-1.77, 1.06]), particularly in subgroups at higher weight gain risk (eg, females, Black/African Americans). Metabolic endpoints paralleled weight change over time. D/C/F/TAF was well tolerated, with comparable virologic efficacy between arms. CONCLUSIONS: While no significant change in body weight was observed at 24 weeks after switching from InSTI+TAF/FTC to D/C/F/TAF among adults with weight gain, a trend towards weight loss emerged with longer time post-ARV switch, supporting further investigation of antiretroviral selection/switch for weight management.

RESUMEN

Cyclosporine is a potent immunosuppressive drug for various immune-mediated diseases in children. Cyclosporine's expected therapeutic effect also carries a wide range of side effects. One of the most common and intriguing dermatological side effects is hypertrichosis. However, recent reports have recognized alopecia as a potential adverse effect of cyclosporine. Here, we report a case of a 29-month-old boy diagnosed with aplastic anemia. During cyclosporine therapy, the patient presented with hair loss on the scalp, which and subsequently spread to the eyebrows and eyelashes. The alopecic symptoms were not relieved following topical minoxidil liniment interventions. When the cyclosporine was discontinued, a remarkable improvement was observed in the scalp, with complete hair regrowth. Data concerning cyclosporine from the FDA Adverse Event Reporting System (FAERS) database were extracted from January 2004 to January 2023. Within FAERS, our post-marketing pharmacovigilance analysis detected the reporting association of cyclosporine and alopecia. In monotherapy, cyclosporine-induced alopecia was observed in 118 cases, and tacrolimus-induced alopecia signals were detected in 197 cases. Although the potential mechanism of medication-induced hair loss is unclear, we identified a potential correlation between alopecia and cyclosporine, and it is still necessary to adequately recognize and clinically monitor this paradoxical reaction.

RESUMEN

Enzymatic therapy with nicotine-degrading enzyme is a new strategy in treating nicotine addiction, which can reduce nicotine concentrations and weaken withdrawal in the rat model. However, when O2 is used as the electron acceptor, no satisfactory performance has been achieved with one of the most commonly studied and efficient nicotine-catabolizing enzymes, NicA2. To obtain more efficient nicotine-degrading enzyme, we rationally designed and engineered a flavoenzyme Pnao, which shares high structural similarity with NicA2 (RMSD = 1.143 Å) and efficiently catalyze pseudooxynicotine into 3-succinoyl-semialdehyde pyridine using O2. Through amino acid alterations with NicA2, five Pnao mutants were generated, which can degrade nicotine in Tris-HCl buffer and retain catabolic activity on its natural substrate. Nicotine-1'-N-oxide was identified as one of the reaction products. Four of the derivative mutants showed activity in rat serum and Trp220 and Asn224 were found critical for enzyme specificity. Our findings offer a novel avenue for research into aerobic nicotine catabolism and provide a promising method of generating additional nicotine-catalytic enzymes. IMPORTANCE: Nicotine, the main active substance in tobacco, results in cigarette addiction and various diseases. There have been some attempts at using nicotine oxidoreductase, NicA2, as a therapeutic for nicotine cessation. However, it uses cytochrome c as it is electron acceptor, which is impractical for therapeutic use compared with using O2 as an oxidant. Thus, amino acid alteration was performed on Pnao using NicA2 as model. Five of the mutants generated degraded nicotine at a rate similar to NicA2, and one of the catabolic compounds was identified as nicotine-1'-N-oxide. Our research highlights a new direction in developing enzymes that efficiently catabolize nicotine without co-enzymes and suggests that structure-similar human original MAOA (or B) may assist with nicotine cessation after being engineered.

RESUMEN

Epilepsy is a chronic disease caused by repeated abnormal discharge of neurons in the brain. Accurately predicting the onset of epilepsy can effectively improve the quality of life for patients with the condition. While there are many methods for detecting epilepsy, EEG is currently considered one of the most effective analytical tools due to the abundant information it provides about brain activity. The aim of this study is to explore potential time-frequency and channel features from multi-channel epileptic EEG signals and to develop a patient-specific seizure prediction network. In this paper, an epilepsy EEG signal classification algorithm called Channel Recurrent Criss-cross Attention Network (CRCANet) is proposed. Firstly, the spectrograms processed by the short-time fourier transform is input into a Convolutional Neural Network (CNN). Then, the spectrogram feature map obtained in the previous step is input into the channel attention module to establish correlations between channels. Subsequently, the feature diagram containing channel attention characteristics is input into the recurrent criss-cross attention module to enhance the information content of each pixel. Finally, two fully connected layers are used for classification. We validated the method on 13 patients in the public CHB-MIT scalp EEG dataset, achieving an average accuracy of 93.8 %, sensitivity of 94.3 %, and specificity of 93.5 %. The experimental results indicate that CRCANet can effectively capture the time-frequency and channel characteristics of EEG signals while improving training efficiency.

Asunto(s)

RESUMEN

OBJECTIVE: Vascular invasion (VI) profoundly impacts the prognosis of hepatocellular carcinoma (HCC), yet the underlying biomarkers and mechanisms remain elusive. This study aimed to identify prognostic biomarkers for HCC patients with VI. METHODS: Transcriptome data from primary HCC tissues and HCC tissues with VI were obtained through the Genome Expression Omnibus database. Differentially expressed genes (DEGs) in the two types of tissues were analyzed using functional enrichment analysis to evaluate their biological functions. We examined the correlation between DEGs and prognosis by combining HCC transcriptome data and clinical information from The Cancer Genome Atlas database. Univariate and multivariate Cox regression analyses, along with the least absolute shrinkage and selection operator (LASSO) method were utilized to develop a prognostic model. The effectiveness of the model was assessed through time-dependent receiver operating characteristic (ROC) curve, calibration diagram, and decision curve analysis. RESULTS: In the GSE20017 and GSE5093 datasets, a total of 83 DEGs were identified. Gene Ontology analysis indicated that these DEGs were predominantly associated with xenobiotic stimulus, collagen-containing extracellular matrix, and oxygen binding. Additionally, Kyoto Encyclopedia of Genes and Genomes analysis revealed that the DEGs were primarily involved in immune defense and cellular signal transduction. Cox and LASSO regression further identified 7 genes (HSPA8, ABCF2, EAF1, MARCO, EPS8L3, PLA3G1B, C6), which were used to construct a predictive model in the training cohort. We used X-tile software to calculate the optimal cut-off value to stratify HCC patients into low-risk and high-risk groups. Notably, the high-risk group exhibited poorer prognosis than the low-risk group (P < 0.001). The model demonstrated area under the ROC curve (AUC) values of 0.815, 0.730, and 0.710 at 1-year, 3-year, and 5-year intervals in the training cohort, respectively. In the validation cohort, the corresponding AUC values were 0.701, 0.571, and 0.575, respectively. The C-index of the calibration curve for the training and validation cohorts were 0.716 and 0.665. Decision curve analysis revealed the model's efficacy in guiding clinical decision-making. CONCLUSIONS: The study indicates that 7 genes may be potential prognostic biomarkers and treatment targets for HCC patients with VI.

RESUMEN

State-of-the-art optical cavities are pivotal in pushing the envelope of laser frequency stability below 10-16. This is often achieved by extending the cavity length or cooling the system to cryogenic temperatures to reduce the thermal noise floor. In our study, we present a 30-cm-long cavity that operates at room temperature and is outfitted with crystalline coatings. The system has a predicted ultralow thermal noise floor of 4.4 × 10-17, comparable to what is observed in cryogenic silicon cavities. A 1397-nm laser is stabilized in this advanced cavity, and the stable frequency is then transferred to the clock transition in strontium optical lattice clocks via a frequency-doubling process. We have meticulously minimized and assessed the technical noise contributions through comparisons with an ultrastable reference laser that is locked to a commercially available 30-cm cavity. The frequency instability of the system is rigorously evaluated using a three-cornered-hat method. The results demonstrate that the laser frequency instability remains below 2 × 10-16 for averaging times ranging from 1 to 50 s. These findings underscore the significant potential of room-temperature cavities with crystalline coatings in high-precision metrology and pave the way for further improvements in optical lattice clocks.

RESUMEN

In multidimensional tests, the identification of latent traits measured by each item is crucial. In addition to item-trait relationship, differential item functioning (DIF) is routinely evaluated to ensure valid comparison among different groups. The two problems are investigated separately in the literature. This paper uses a unified framework for detecting item-trait relationship and DIF in multidimensional item response theory (MIRT) models. By incorporating DIF effects in MIRT models, these problems can be considered as variable selection for latent/observed variables and their interactions. A Bayesian adaptive Lasso procedure is developed for variable selection, in which item-trait relationship and DIF effects can be obtained simultaneously. Simulation studies show the performance of our method for parameter estimation, the recovery of item-trait relationship and the detection of DIF effects. An application is presented using data from the Eysenck Personality Questionnaire.

RESUMEN

Endometriosis is an estrogen-dependent inflammatory gynecological disease whose pathogenesis is unclear. C-C motif chemokine ligand 18 (CCL18), a chemokine, is involved in several inflammatory diseases. In this study, we aimed to investigate the role of CCL18 in endometriosis and its underlying mechanisms. Human endometrium and peritoneal fluid were obtained from women with and without endometriosis for molecular studies. The expression level of CCL18 in each tissue sample was examined by RNA sequencing analysis, quantitative PCR analysis and immunohistochemistry staining. The effects of CCL18 on cell migration, tube formation and neurite growth were investigated in vitro using primary endometrial cells, human umbilical vein endothelial cells (HUVECs) and dorsal root ganglion (DRG) neurons, respectively. Moreover, the development of endometriosis in mice was studied in vivo by blocking CCL18. CCL18 was shown to be overexpressed in endometrial foci and peritoneal fluid in women with endometriosis and was positively correlated with endometriosis pain. In vitro, CCL18 promoted the migration of ectopic endometrial cells, tube formation of HUVECs, and nerve outgrowth of DRG neurons. More importantly, inhibition of CCL18 significantly suppressed lesion development, angiogenesis, and nerve infiltration in a mouse model of endometriosis. In conclusion, CCL18 may play a role in the progression of endometriosis by increasing endometrial cell migration and promoting neuroangiogenesis.

Asunto(s)

RESUMEN

BACKGROUND: Venous thromboembolism is the leading cause of death in cancer patients, second only to tumor progression. The Khorana score is recommended by clinical guidelines for identifying ambulatory cancer patients at high risk of venous thromboembolism during chemotherapy. However, its predictive performance is debated among cancer patients. OBJECTIVES: To map the applicability of the Khorana score in cancer patients and to assess its predictive performance across various cancer types, providing guidance for clinicians and nurses to use it more appropriately. DESIGN: Systematic review and meta-analysis. METHODS: A comprehensive literature search of the electronic database was first conducted on August 30, 2023, and updated on May 20, 2024. Studies examining the Khorana score's predictive performance (including but not limited to the areas under the curve, C-index, and calibration plot) in cancer patients were included. The Prediction Model Risk of Bias Assessment Tool (PROBAST) was applied to evaluate the methodological quality of the included studies. Data synthesis was achieved via random-effects meta-analysis using the R studio software. The subgroup analysis was performed according to the study design, clinical setting, cancer type, anti-cancer treatment stage, and country. RESULTS: The review incorporated 67 studies, including 58 observational studies and nine randomized controlled trials. All included studies assessed the Khorana score's discrimination, with the C-index ranging from 0.40 to 0.84. The pooled C-index for randomized controlled trials was 0.61 (95 % CI 0.51-0.70), while observational studies showed a pooled C-index of 0.59 (95 % CI 0.57-0.60). Subgroup analyses revealed the pooled C-index for lung cancer, lymphoma, gastrointestinal cancer, and mixed cancer patients as 0.60 (95 % CI 0.53-0.67), 0.56 (95 % CI 0.51-0.61), 0.59 (95 % CI 0.39-0.76), and 0.60 (95 % CI 0.58-0.61), respectively. Inpatient and outpatient settings had the pooled C-index of 0.60 (95 % CI 0.58-0.63) and 0.58 (95 % CI 0.55-0.61), respectively. Calibration was assessed in only four studies. All included studies were identified to have a high risk of bias according to PROBAST. CONCLUSION: The Khorana score has been widely validated in various types of cancer patients; however, it exhibited poor capability (pooled C-index<0.7) in accurately discriminating VTE risk among most types of cancer patients either in inpatient or outpatient settings. The Khorana score should be used with caution, and high-quality studies are needed to further validate its predictive performance. REGISTRATION: The protocol for this study is registered with PROSPERO (registration number: CRD42023470320).

Asunto(s)

RESUMEN

BACKGROUND: Motor neuron disease (MND) is a chronic and progressive neurodegenerative disorder with an unknown cause. The development of amyotrophic lateral sclerosis (ALS) is believed to be linked to an immune response. Monocytes/macrophages and T cells are key players in the disease's advancement. Monitoring levels of cytokines in the blood can help forecast patient outcomes, while immunotherapy shows promise in alleviating symptoms for certain individuals. CASE PRESENTATION: A 56-year-old male patient was admitted to the hospital due to progressive limb weakness persisting for eight months. The neurological examination revealed impairments in both upper and lower motor neurons, as well as sensory anomalies, without corresponding signs. Electrophysiological examination results indicated extensive neuronal damage and multiple peripheral nerve impairments, thereby the diagnosis was ALS. One month ago, the patient began experiencing symptoms of dry mouth and a bitter taste. Following tests for rheumatic immune-related antibodies and a lip gland biopsy, a diagnosis of Sjögren's syndrome (SS) was proposed. Despite treatment with medications such as hormones (methylprednisolone), immunosuppressants (hydroxychloroquine sulfate), and riluzole, the symptoms did not significantly improve, but also did not worsen. CONCLUSION: It is recommended to include screening for SS in the standard assessment of ALS. Furthermore, research should focus on understanding the immune mechanisms involved in ALS, providing new insights for the diagnosis and treatment of ALS in conjunction with SS.

Asunto(s)

RESUMEN

The aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism commonly exists in the East Asian populations and is associated with high risks of cardiovascular disease (CVD). However, the cellular and molecular mechanisms that underlie the ALDH2 rs671 mutant-linked high CVD remain elusive. Here, we show that macrophages derived from human ALDH2 rs671 carriers and ALDH2 knockout mice exhibited an enhanced pro-inflammatory macrophage phenotype and an impaired anti-inflammatory macrophage phenotype. Transplanting bone marrow from ALDH2-/-ApoE-/- to ApoE-/- mice significantly increased atherosclerotic plaque growth and pro-inflammatory macrophage polarization in vivo. Mechanistically, ALDH2 inhibited activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in macrophages. Pharmacological inhibition of cGAS by RU.521 completely neutralized ALDH2-deficiency-induced macrophage polarization. In-depth mechanistic investigation showed that ALDH2 accelerated cGAS K48-linked polyubiquitination degradation at lysine 282 in macrophages by reducing the interaction between ubiquitin-specific protease 14 (USP14) and cGAS, mainly through its enzymatic role in mitigating 4-hydroxy-2-nonenal (4-HNE) accumulation. Consistently, USP14 knockdown in bone marrow cells alleviated proinflammatory responses in macrophages and protected against atherosclerosis. Our findings provide new mechanistic insights of ALDH2 deficiency-associated proinflammation and atherosclerosis and new therapeutic and preventive paradigms for treatment of atherosclerosis-associated CVD.

RESUMEN

Background: Current studies mostly suggest that hyperhidrosis is caused by relative sympathetic hyperactivity. Sympathetic radiofrequency thermocoagulation is widely used in clinics. Previous studies have demonstrated that surgery at T3 is effective and safe compared with higher levels, so craniofacial hyperhidrosis in our hospital is selected to be treated at T3. However, some patients pursue repeat medical treatment due to an increase in hyperhidrosis at the original site after surgery. Previous studies have demonstrated the significance of Perfusion index (PI) value in the recurrence of palmar hyperhidrosis, but there is no relevant study on craniofacial hyperhidrosis. Methods: Clinical data from patients with craniofacial hyperhidrosis, who underwent T3 sympathetic radiofrequency thermocoagulation at Jiaxing First Hospital (Jiaxing, China) between January 1, 2018 and December 31, 2021, were analyzed. Recurrence in patients 1 year after surgery was recorded through a case search and telephone follow-up system that registered patient information. Clinical data were analyzed using binary logistic regression analysis to investigate risk factors associated with recurrence in patients with craniofacial hyperhidrosis 1 year after surgery. Results: Of 83 patients included in the present study, 34 (40%) experienced increased craniofacial sweating 1 year after surgery. Results of univariate logistic regression analysis revealed that computed tomography (CT) scan count, increase in pulse index (PI) at the fingertips, and differences in forehead temperature were potential risk factors for postoperative recurrence in patients with craniofacial hyperhidrosis (p<0.2), and the results were consistent on both sides. Three potential risk factors were included in the multivariate logistic regression analysis and results revealed that the risk for recurrence was reduced by 48% (left side) and 67% (right side) for every 1 unit increase in PI value. Conclusion: A small increase in PI was an independent risk factor for recurrence of hyperhidrosis in patients with craniofacial hyperhidrosis after undergoing T3 sympathetic radiofrequency thermocoagulation.

RESUMEN

In this work, we report the synthesis of a new thiosemicarbazone-based drug of N'-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (HL) featuring a thiazole spectator for efficient coordination with Cu(II) to give [CuCl(L)]2 (1) and [Cu(NO3)(L)]2 (2). Both 1 and 2 exhibit dimeric structures ascribed to the presence of di-2-pyridylketone moieties that demonstrate dual functions of chelation and intermolecular bridging. HL, 1, and 2 are highly toxic against hepatocellular carcinoma cell lines Hep-G2, PLC/PRF/5, and HuH-7 with half maximal inhibitory concentration (IC50) values as low as 3.26 nmol/mL (HL), 2.18 nmol/mL (1), and 2.54 × 10-5 nmol/mL (2) for PLC/PRF/5. While the free ligand HL may elicit its anticancer effect via the sequestration of bio-relevant metal ions (i.e., Fe3+ and Cu2+), 1 and 2 are also capable of generating cytotoxic reactive oxygen species (ROS) to inhibit cancer cell proliferation. Our preliminary pharmacokinetic studies revealed that oral administration (per os, PO) of HL has a significantly longer half-life t1/2 of 21.61 ± 9.4 h, nearly doubled as compared with that of the intravenous (i.v.) administration of 11.88 ± 1.66 h, certifying HL as an effective chemotherapeutic drug via PO administration.

Asunto(s)

RESUMEN

Rhein, a component derived from rhubarb, has been proven to possess anti-inflammatory properties. Here, we show that rhein mitigates obesity by promoting adipose tissue thermogenesis in diet-induced obese mice. We construct a macrophage-adipocyte co-culture system and demonstrate that rhein promotes adipocyte thermogenesis through inhibiting NLRP3 inflammasome activation in macrophages. Moreover, clues from acetylome analysis identify SIRT2 as a potential drug target of rhein. We further verify that rhein directly interacts with SIRT2 and inhibits NLRP3 inflammasome activation in a SIRT2-dependent way. Myeloid knockdown of SIRT2 abrogates adipose tissue thermogenesis and metabolic benefits in obese mice induced by rhein. Together, our findings elucidate that rhein inhibits NLRP3 inflammasome activation in macrophages by regulating SIRT2, and thus promotes white adipose tissue thermogenesis during obesity. These findings uncover the molecular mechanism underlying the anti-inflammatory and anti-obesity effects of rhein, and suggest that rhein may become a potential drug for treating obesity.

Asunto(s)

RESUMEN

Stachydrine, also known as proline betaine, is a prominent constituent of traditional Chinese herb Leonurus japonicus, renowned for its significant pharmacological effects. Widely distributed in plants like Leonurus and Citrus aurantium, as well as various bacteria, stachydrine serves pivotal physiological functions across animal, plant, and bacterial kingdoms. This review aims to summarizes diverse roles and mechanisms of stachydrine in addressing cardiovascular and cerebrovascular diseases, neuroprotection, anticancer activity, uterine regulation, anti-inflammatory response, obesity management, and respiratory ailments. Notably, stachydrine exhibits cardioprotective effects via multiple pathways encompassing anti-inflammatory, antioxidant, anti-apoptotic, and modulation of calcium handling functions. Furthermore, its anti-cancer properties inhibit proliferation and migration of numerous cancer cell types. With a bi-directional regulatory effect on uterine function, stachydrine holds promise for obstetrics and gynecology-related disorders. In plants, stachydrine serves as a secondary metabolite, contributing to osmotic pressure regulation, nitrogen fixation, pest resistance, and stress response. Similarly, in bacteria, it plays a crucial osmoprotective role, facilitating adaptation to high osmotic pressure environments. This review also addresses ongoing research on the anabolic metabolism of stachydrine. While the biosynthetic pathway remains incompletely understood, the metabolic pathway is well-established. A deeper understanding of stachydrine biosynthesis holds significance for elucidating its mechanism of action, advancing the study of plant secondary metabolism, enhancing drug quality control, and fostering new drug development endeavors.

RESUMEN

Catechins constitute abundant metabolites in tea and have potential health benefits and high economic value. Intensive study has shown that the biosynthesis of tea catechins is regulated by environmental factors and hormonal signals. However, little is known about the coordination of phosphate (Pi) signaling and the jasmonic acid (JA) pathway on biosynthesis of tea catechins. We found that Pi deficiency caused changes in the content of catechins and modulated the expression levels of genes involved in catechin biosynthesis. Herein, we identified two transcription factors of phosphate signaling in tea, named CsPHR1 and CsPHR2, respectively. Both regulated catechin biosynthesis by activating the transcription of CsANR1 and CsMYB5c. We further demonstrated CsSPX1, a Pi pathway repressor, suppressing the activation by CsPHR1/2 of CsANR1 and CsMYB5c. JA, one of the endogenous plant hormones, has been reported to be involved in the regulation of secondary metabolism. Our work demonstrated that the JA signaling repressor CsJAZ3 negatively regulated catechin biosynthesis via physical interaction with CsPHR1 and CsPHR2. Thus, the CsPHRs-CsJAZ3 module bridges the nutrition and hormone signals, contributing to targeted cultivation of high-quality tea cultivars with high fertilizer efficiency.

RESUMEN

In distributed learning systems, robustness threat may arise from two major sources. On the one hand, due to distributional shifts between training data and test data, the trained model could exhibit poor out-of-sample performance. On the other hand, a portion of working nodes might be subject to Byzantine attacks, which could invalidate the learning result. In this article, we propose a new research direction that jointly considers distributional shifts and Byzantine attacks. We illuminate the major challenges in addressing these two issues simultaneously. Accordingly, we design a new algorithm that equips distributed learning with both distributional robustness and Byzantine robustness. Our algorithm is built on recent advances in distributionally robust optimization (DRO) as well as norm-based screening (NBS), a robust aggregation scheme against Byzantine attacks. We provide convergence proofs in three cases of the learning model being nonconvex, convex, and strongly convex for the proposed algorithm, shedding light on its convergence behaviors and endurability against Byzantine attacks. In particular, we deduce that any algorithm employing NBS (including ours) cannot converge when the percentage of Byzantine nodes is [Formula: see text] or higher, instead of [Formula: see text] , which is the common belief in current literature. The experimental results verify our theoretical findings (on the breakpoint of NBS and others) and also demonstrate the effectiveness of our algorithm against both robustness issues, justifying our choice of NBS over other widely used robust aggregation schemes. To the best of our knowledge, this is the first work to address distributional shifts and Byzantine attacks simultaneously.

RESUMEN

The Ten-Eleven Translocation (TET) family genes are implicated in a wide array of biological functions across various human cancers. Nonetheless, there is a scarcity of studies that comprehensively analyze the correlation between TET family members and the molecular phenotypes and clinical characteristics of different cancers. Leveraging updated public databases and employing several bioinformatics analysis methods, we assessed the expression levels, somatic variations, methylation levels, and prognostic values of TET family genes. Additionally, we explored the association between the expression of TET family genes and pathway activity, tumor microenvironment (TME), stemness score, immune subtype, clinical staging, and drug sensitivity in pan-cancer. Molecular biology and cytology experiments were conducted to validate the potential role of TET3 in tumor progression. Each TET family gene displayed distinct expression patterns across at least ten detected tumors. The frequency of Single Nucleotide Variant (SNV) in TET genes was found to be 91.24%, primarily comprising missense mutation types, with the main types of copy number variant (CNV) being heterozygous amplifications and deletions. TET1 gene exhibited high methylation levels, whereas TET2 and TET3 genes displayed hypomethylation in most cancers, which correlated closely with patient prognosis. Pathway activity analysis revealed the involvement of TET family genes in multiple signaling pathways, including cell cycle, apoptosis, DNA damage response, hormone AR, PI3K/AKT, and RTK. Furthermore, the expression levels of TET family genes were shown to impact the clinical staging of tumor patients, modulate the sensitivity of chemotherapy drugs, and thereby influence patient prognosis by participating in the regulation of the tumor microenvironment, cellular stemness potential, and immune subtype. Notably, TET3 was identified to promote cancer progression across various tumors, and its silencing was found to inhibit tumor malignancy and enhance chemotherapy sensitivity. These findings shed light on the role of TET family genes in cancer progression and offer insights for further research on TET3 as a potential therapeutic target for pan-cancer.