Insight into telomere regulation: road to discovery and intervention in plasma drug-protein targets.

BACKGROUND: Telomere length is a critical metric linked to aging, health, and disease. Currently, the exploration of target proteins related to telomere length is usually limited to the context of aging and specific diseases, which limits the discovery of more relevant drug targets. This study integrated large-scale plasma cis-pQTLs data and telomere length GWAS datasets. We used Mendelian randomization(MR) to identify drug target proteins for telomere length, providing essential clues for future precision therapy and targeted drug development. METHODS: Using plasma cis-pQTLs data from a previous GWAS study (3,606 Pqtls associated with 2,656 proteins) and a GWAS dataset of telomere length (sample size: 472,174; GWAS ID: ieu-b-4879) from UK Biobank, using MR, external validation, and reverse causality testing, we identified essential drug target proteins for telomere length. We also performed co-localization, Phenome-wide association studies and enrichment analysis, protein-protein interaction network construction, search for existing intervening drugs, and potential drug/compound prediction for these critical targets to strengthen and expand our findings. RESULTS: After Bonferron correction (p < 0.05/734), RPN1 (OR: 0.96; 95%CI: (0.95, 0.97)), GDI2 (OR: 0.94; 95%CI: (0.92, 0.96)), NT5C (OR: 0.97; 95%CI: (0.95, 0.98)) had a significant negative causal association with telomere length; TYRO3 (OR: 1.11; 95%CI: (1.09, 1.15)) had a significant positive causal association with telomere length. GDI2 shared the same genetic variants with telomere length (coloc.abf-PPH 4 > 0.8). CONCLUSION: Genetically determined plasma RPN1, GDI2, NT5C, and TYRO3 have significant causal effects on telomere length and can potentially be drug targets. Further exploration of the role and mechanism of these proteins/genes in regulating telomere length is needed.

Data-Based Optimal Synchronization of Heterogeneous Multiagent Systems in Graphical Games via Reinforcement Learning.

This article studies the optimal synchronization of linear heterogeneous multiagent systems (MASs) with partial unknown knowledge of the system dynamics. The object is to realize system synchronization as well as minimize the performance index of each agent. A framework of heterogeneous multiagent graphical games is formulated first. In the graphical games, it is proved that the optimal control policy relying on the solution of the Hamilton-Jacobian-Bellmen (HJB) equation is not only in Nash equilibrium, but also the best response to fixed control policies of its neighbors. To solve the optimal control policy and the minimum value of the performance index, a model-based policy iteration (PI) algorithm is proposed. Then, according to the model-based algorithm, a data-based off-policy integral reinforcement learning (IRL) algorithm is put forward to handle the partially unknown system dynamics. Furthermore, a single-critic neural network (NN) structure is used to implement the data-based algorithm. Based on the data collected by the behavior policy of the data-based off-policy algorithm, the gradient descent method is used to train NNs to approach the ideal weights. In addition, it is proved that all the proposed algorithms are convergent, and the weight-tuning law of the single-critic NNs can promote optimal synchronization. Finally, a numerical example is proposed to show the effectiveness of the theoretical analysis.

The therapeutic potential of quercetin for cigarette smoking-induced chronic obstructive pulmonary disease: a narrative review.

Quercetin is a flavonoid with antioxidant and anti-inflammatory properties. Quercetin has potentially beneficial therapeutic effects for several diseases, including cigarette smoking-induced chronic obstructive pulmonary disease (CS-COPD). Many studies have shown that quercetin's antioxidant and anti-inflammatory properties have positive therapeutic potential for CS-COPD. In addition, quercetin's immunomodulatory, anti-cellular senescence, mitochondrial autophagy-modulating, and gut microbiota-modulating effects may also have therapeutic value for CS-COPD. However, there appears to be no review of the possible mechanisms of quercetin for treating CS-COPD. Moreover, the combination of quercetin with common therapeutic drugs for CS-COPD needs further refinement. Therefore, in this article, after introducing the definition and metabolism of quercetin, and its safety, we comprehensively presented the pathogenesis of CS-COPD related to oxidative stress, inflammation, immunity, cellular senescence, mitochondrial autophagy, and gut microbiota. We then reviewed quercetin's anti-CS-COPD effects, performed by influencing these mechanisms. Finally, we explored the possibility of using quercetin with commonly used drugs for treating CS-COPD, providing a basis for future screening of excellent drug combinations for treating CS-COPD. This review has provided meaningful information on quercetin's mechanisms and clinical use in treating CS-COPD.

Bibliometric Analysis of Geriatric Sarcopenia Therapies: Highlighting Publication Trends and Leading-Edge Research Directions.

The bibliometric analysis assesses the productivity of scholarship in a given field and provides information on the frontiers of relevant developments. However, no bibliometric analysis study has quantitatively analyzed publications in geriatric sarcopenia therapies. This study investigates the scholarly productivity and frontiers of publications in geriatric sarcopenia therapies. The bibliometric data came from English-language Web of Science Core Collection articles published between 1995 and October 19, 2022. Three software programs, R version 3.5.6, VOSviewer, and CiteSpace, were applied for this bibliometric analysis. In twenty-eight years, the annual publications in geriatric sarcopenia therapies have increased yearly, with an annual growth rate of 21.23 %. A total of 1379 publications have been published. The United States was the country with the highest number of publication signatures (n=1,537) (including joint publication releases), followed by Japan (n=1099). Journal of Cachexia, Sarcopenia, and Muscle contributed the best journal publications (n=80). The newest hot subjects in the study about geriatric sarcopenia therapy include malnutrition, obesity, insulin resistance, and cancer. This bibliometric study presents a comprehensive overview of the current and future research directions in geriatric sarcopenia therapies over the past 28 years. Overall, this study has complemented the gaps in bibliometric analysis in geriatric sarcopenia therapies. This paper will provide a valuable reference for future research in geriatric sarcopenia therapies.

Turning point: A new global COVID-19 wave or a signal of the beginning of the end of the global COVID-19 pandemic?

A new variant named Omicron (B.1.1.529), first identified in South Africa, has become of considerable interest to the World Health Organization. This variant differs from the other known major variants, as it carries a large number of unusual mutations, particularly in the spinous process protein and receptor binding domains. Some specific mutation sites make it vaccine resistant, highly infectious, and highly pathogenic. The world fears that the Omicron variant could be even more harmful than the previous major variant, given that it has emerged amid fierce competition to trigger a new global pandemic peak as infections in South Africa rise. However, some epidemiological evidence has emerged that the Omicron variant may produce milder patient symptoms. We speculate if the virulence of the Omicron variant will diminish as transmissibility increases, thereby signaling the beginning of the end for the global COVID-19 pandemic. Based on this view, we make recommendations for COVID-19 mitigation in the present and future. However, it will take a few weeks to determine the true threat posed by the Omicron variant and we need to be fully prepared for future outbreaks, regardless of their severity.

Psychological assessment in 355 Chinese college students with androgenetic alopecia.

Although the association of the psychological problems and androgenetic alopecia (AGA) gained the increasing attention, the psychosocial state in college students with AGA remains unknown. We recruited a total number of 355 college students with AGA from 18 universities in Southern China for interview. The Symptom Checklist-90-R (SCL-90-R) survey was used to assess the psychological state of these students. There were significant differences in somatization, obsessive-compulsive, interpersonal sensitivity, depression, phobic anxiety, psychoticism, and global severity index (GSI) between college students with AGA and the controls. Moreover, regarding the impact of specialty, scores for the interpersonal sensitivity, depression, and phobic anxiety in medical students and art students with AGA were significantly higher than other professions. In addition, obsessive-compulsive and GSI in art students with AGA were significantly higher compared with other professions. These findings suggested that the therapeutic approach for the psychological problems should be considered in the tailored treatment for AGA in the college students.

Common and uncommon adverse cutaneous reactions to erlotinib: a study of 20 Chinese patients with cancer.

OBJECTIVE: This study presented common lesions with systemic toxicities and uncommon adverse cutaneous reactions such as anaphylactic dermatitis in patients undergoing treatment with erlotinib for the benefit of practicing dermatologists and oncologists. METHODS: Adverse cutaneous reactions associated with erlotinib were reported in 20 Chinese patients with cancer. RESULTS: Adverse cutaneous reactions reported included six cases of anaphylactic dermatitis, 12 cases of acneiform rash, nine cases of xerosis, five cases of nail changes and four cases of hair changes. One case of anaphylactic dermatitis manifested as erythema with swelling on the face and neck, and others as erosive and scaly erythema on the fold of skin, or red macules, papules, plaques and pigmentation on the whole body. Clinical details indicated anaphylactic reactions, including a high percentage of eosinophils in the peripheral blood, eosinophilic infiltration in the dermis layer and good response to antihistamines and topical steroids. Systemic toxicities accompanied by cutaneous reactions occurred in five patients including one case of anaphylactic dermatitis and four cases of acneiform rash. Elevated hepatic enzymes were observed among all the patients with grade-3 or grade-4 acneiform rashes. One patient with anaphylactic dermatitis and one with acneiform rash discontinued erlotinib administration due to severe lesions, high fever or severe elevation of hepatic enzymes. CONCLUSIONS: Anaphylactic cutaneous reactions caused by erlotinib are rarely described hitherto. Systemic toxicities should be emphasized especially in cases with severe skin disorders. Timely detection and appropriate early intervention in patients who develop severe cutaneous reaction while on erlotinib therapy should be considered clinically.

Successful treatment with bortezomib and thalidomide for POEMS syndrome associated with multicentric mixed-type Castleman's disease.

Polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome is a rare multi-systematic disorder of uncertain etiology, if associated with multicentric Castleman's disease, it can lead to a more serious condition. We here presented a case of polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome in a 37-year-old male patient who initially presented with progressive lower limb weakness accompanied by pain, low skin temperature, and hyperpigmentation. He was admitted with increasingly serious dyspnea and lower leg edema. Fluid of serous cavities in the patient were also indicated in ultrasonic inspection and X-ray. Furthermore, biopsy of a left axillary lymph node showed mixed hyaline-vascular and plasma cell type of multicentric Castleman's disease. Administration of bortezomib (Velcade) (1.3 mg/m(2) on days 1, 4, 8 and 11 of a 21-day cycle) combined with thalidomide (100 mg/day and 21-day cycle) dramatically improved the condition of this disease. Of note, in our study, combination therapy of bortezomib and thalidomide successfully improved the condition of the patient with polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome associated with multicentric Castleman's disease, suggesting that the combination therapy may be an effective therapeutic strategy for the intractable polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome associated with multicentric Castleman's disease.