Aldehyde dehydrogenase 1 family: A potential molecule target for diseases.

Aldehyde dehydrogenase 1 (ALDH1), a crucial aldehyde metabolizing enzyme, has six family members. The ALDH1 family is expressed in various tissues, with a significant presence in the liver. It plays a momentous role in several pathophysiological processes, including aldehyde detoxification, oxidative stress, and lipid peroxidation. Acetaldehyde detoxification is the fundamental function of the ALDH1 family in participating in vital pathological mechanisms. The ALDH1 family can catalyze retinal to retinoic acid (RA) that is a hormone-signaling molecule and plays a vital role in the development and adult tissues. Furthermore, there is a need for further and broader research on the role of the ALDH1 family as a signaling molecule. The ALDH1 family is widely recognized as a cancer stem cell (CSC) marker and plays a significant role in the proliferation, invasion, metastasis, prognosis, and drug resistance of cancer. The ALDH1 family also participates in other human diseases, such as neurodegenerative diseases, osteoarthritis, diabetes, and atherosclerosis. It can inhibit disease progression by inhibiting/promoting the expression/activity of the ALDH1 family. In this review, we comprehensively analyze the tissue distribution, and functions of the ALDH1 family. Additionally, we review the involvement of the ALDH1 family in diseases, focusing on the underlying pathological mechanisms and briefly talk about the current status and development of ALDH1 family inhibitors. The ALDH1 family presents new possibilities for treating diseases, with both its upstream and downstream pathways serving as promising targets for therapeutic intervention. This offers fresh perspectives for drug development in the field of disease research.

Chloroplast genome analysis and evolutionary insights in the versatile medicinal plant Calendula officinalis L.

Calendula officinalis L.is a versatile medicinal plant with numerous applications in various fields. However, its chloroplast genome structure, features, phylogeny, and patterns of evolution and mutation remain largely unexplored. This study examines the chloroplast genome, phylogeny, codon usage bias, and divergence time of C. officinalis, enhancing our understanding of its evolution and adaptation. The chloroplast genome of C. officinalis is a 150,465 bp circular molecule with a G + C content of 37.75% and comprises 131 genes. Phylogenetic analysis revealed a close relationship between C. officinalis, C. arvensis, and Osteospermum ecklonis. A key finding is the similarity in codon usage bias among these species, which, coupled with the divergence time analysis, supports their close phylogenetic proximity. This similarity in codon preference and divergence times underscores a parallel evolutionary adaptation journey for these species, highlighting the intricate interplay between genetic evolution and environmental adaptation in the Asteraceae family. Moreover unique evolutionary features in C. officinalis, possibly associated with certain genes were identified, laying a foundation for future research into the genetic diversity and medicinal value of C. officinalis.

MCU complex: Exploring emerging targets and mechanisms of mitochondrial physiology and pathology.

BACKGROUND: Globally, the onset and progression of multiple human diseases are associated with mitochondrial dysfunction and dysregulation of Ca2+ uptake dynamics mediated by the mitochondrial calcium uniporter (MCU) complex, which plays a key role in mitochondrial dysfunction. Despite relevant studies, the underlying pathophysiological mechanisms have not yet been fully elucidated. AIM OF REVIEW: This article provides an in-depth analysis of the current research status of the MCU complex, focusing on its molecular composition, regulatory mechanisms, and association with diseases. In addition, we conducted an in-depth analysis of the regulatory effects of agonists, inhibitors, and traditional Chinese medicine (TCM) monomers on the MCU complex and their application prospects in disease treatment. From the perspective of medicinal chemistry, we conducted an in-depth analysis of the structure-activity relationship between these small molecules and MCU and deduced potential pharmacophores and binding pockets. Simultaneously, key structural domains of the MCU complex in Homo sapiens were identified. We also studied the functional expression of the MCU complex in Drosophila, Zebrafish, and Caenorhabditis elegans. These analyses provide a basis for exploring potential treatment strategies targeting the MCU complex and provide strong support for the development of future precision medicine and treatments. KEY SCIENTIFIC CONCEPTS OF REVIEW: The MCU complex exhibits varying behavior across different tissues and plays various roles in metabolic functions. It consists of six MCU subunits, an essential MCU regulator (EMRE), and solute carrier 25A23 (SLC25A23). They regulate processes, such as mitochondrial Ca2+ (mCa2+) uptake, mitochondrial adenosine triphosphate (ATP) production, calcium dynamics, oxidative stress (OS), and cell death. Regulation makes it a potential target for treating diseases, especially cardiovascular diseases, neurodegenerative diseases, inflammatory diseases, metabolic diseases, and tumors.

Elabela-apelin-12, 17, 36/APJ system promotes platelet aggregation and thrombosis via activating the PANX1-P2X7 signaling pathway.

The elabela-apelin/angiotensin domain type 1 receptor-associated protein (APJ) system is an important regulator in certain thrombosis-related diseases such as atherosclerosis, myocardial infarction, and cerebral infarction. Our previous reports have revealed that apelin exacerbates atherosclerotic lesions. However, the relationship between the elabela-apelin/APJ system and platelet aggregation and atherothrombosis is unclear. The results of the present study demonstrate that elabela and other endogenous ligands such as apelin-12, -17, and -36 induce platelet aggregation and thrombosis by activating the pannexin1(PANX1)-P2X7 signaling pathway. Interestingly, the diuretic, spironolactone, a novel PANX1 inhibitor, alleviated elabela- and apelin isoforms-induced platelet aggregation and thrombosis. Significantly, two potential antithrombotic drugs were screened out by targeting APJ receptors, including the anti-HIV ancillary drug cobicistat and the traditional Chinese medicine monomer Schisandrin A. Both cobicistat and Schisandrin A abolished the effects of elabela and apelin isoforms on platelet aggregation, thrombosis, and cerebral infarction. In addition, cobicistat significantly attenuated thrombosis in a ponatinib-induced zebrafish trunk model. Overall, the elabela-apelin/APJ axis mediated platelet aggregation and thrombosis via the PANX1-P2X7 signaling pathway in vitro and in vivo. Blocking the APJ receptor with cobicistat/Schisandrin A or inhibiting PANX1 with spironolactone may provide novel therapeutic strategies against thrombosis.

Identification and Development of an Age-Related Classification and Signature to Predict Prognosis and Immune Landscape in Osteosarcoma.

Background: In childhood and adolescence, the prevailing bone tumor is osteosarcoma associated with frequent recurrence and lung metastasis. This research focused on predicting the survival and immune landscape of osteosarcoma by developing a prognostic signature and establishing aging-related genes (ARGs) subtypes. Methods: The training group comprised of the transcriptomic and associated clinical data of 84 patients with osteosarcoma accessed at the TARGET database and the validation group consisted of 53 patients from GSE21257. The aging-related subtypes were identified using unsupervised consensus clustering analysis. The ARG signature was developed utilizing multivariate Cox analysis and LASSO regression. The prognostic value was assessed using the univariate and multivariate Cox analyses, Kaplan-Meier plotter, time-dependent ROC curve, and nomogram. The functional enrichment analyses were performed by GSEA, GO, and KEGG analysis, while the ssGSEA, ESTIMATE, and CIBERSORT analyses were conducted to reveal the immune landscape in osteosarcoma. Results: The two clusters of osteosarcoma patients formed based on 543 ARGs, depicted a considerable difference in the tumor microenvironment, and the overall survival and immune cell infiltration rate varied as well. Among these, the selected 23 ARGs were utilized for the construction of an efficient predictive prognostic signature for the overall survival prediction. The testing in the validation group of osteosarcoma patients confirmed the status of the high-risk score as an independent indicator for poor prognosis, which was already identified as such using the univariate and multivariate Cox analyses. Furthermore, the ARG signature could distinguish different immune-related functions, infiltration status of immune cells, and tumor microenvironment, as well as predict the immunotherapy response of osteosarcoma patients. Conclusion: The aging-related subtypes were identified and a prognostic signature was developed in this research, which determined different prognoses and allowed for treatment of osteosarcoma patients to be tailored. Additionally, the immunotherapeutic response of individuals with osteosarcoma could also be predicted by the ARG signature.

Comparison of Two Different Percutaneous Screw Fixations for Treating Herbert B2-Type Acute Scaphoid Fractures.

OBJECTIVE: Scaphoid fracture was the most common carpal fracture and the most challenging. The purpose of this study was to investigate and compare the clinical effects of closed reduction and percutaneous cannulated screw internal fixation under fluoroscopy and arthroscopy-assisted percutaneous cannulated screw internal fixation in the treatment of Herbert B2-type of acute scaphoid fractures. METHODS: A retrospective controlled study was conducted on 29 patients with Herbert B2-type acute scaphoid fracture with a displacement of >1 mm admitted to our hospital from January 2017 to June 2021. Patients were divided into two groups, 11 patients were treated with closed reduction percutaneous cannulated screw internal fixation under fluoroscopy and 18 patients were treated with percutaneous cannulated screw internal fixation assisted by arthroscopy. The operative time, intraoperative fluoroscopy times, fracture healing time, complications, and postoperative wrist function score of the two groups were compared. RESULTS: All patients were followed up for 6-18 months (mean follow-up duration: 10.38 ± 2.69 months). The respective operation times in the arthroscopy group and fluoroscopy group was 51.50 ± 6.69 min and 56.73 ± 11.48 min, respectively (p > 0.05). The number of fluoroscopies performed in the arthroscopy group was (6.83 ± 1.30), which was less than that in the fluoroscopy group (10.91 ± 2.62) (p < 0.05). All fractures in the arthroscopy group healed after the operation, and the fracture healing time was 11.44 ± 1.25W. Ten patients in the fluoroscopy group healed. The fracture healing time was 13.60 ± 2.32 W. The fracture healing time in arthroscopy group was less than that in the fluoroscopy group (p < 0.05). One patient in the fluoroscopy group had nonunion and healed after bone grafting and internal fixation. At the postoperative 6-month follow-up, the modified Mayo wrist function score was used to evaluate the clinical results. The wrist function score of patients in the arthroscopy group was 90 (85, 95), which was >80 (80, 90) in the fluoroscopy group (z = 2.74, p < 0.05). CONCLUSION: For Herbert B2-type acute scaphoid fracture with fracture displacement > 1 mm, the arthroscopy-assisted percutaneous cannulated screw internal fixation has less fluoroscopy times, short fracture healing time, and good recovery effect of wrist function compared to the fluoroscopy.

Development and validation of apoptosis-related signature and molecular subtype to improve prognosis prediction in osteosarcoma patients.

BACKGROUND: Previous evidence has shown that apoptosis performs integral functions in the tumorigenesis and development of various tumors. Therefore, this study aimed to establish a molecular subtype and prognostic signature based on apoptosis-related genes (ARGs) to understand the molecular mechanisms and predict prognosis in patients with osteosarcoma. METHODS: The GEO and TARGET databases were utilized to obtain the expression levels of ARGs and clinical information of osteosarcoma patients. Consensus clustering analysis was used to explore the different molecular subtypes based on ARGs. GO, KEGG, GSEA, ESTIMATE, and ssGSEA analyses were performed to examine the differences in biological functions and immune characteristics between the distinct molecular subtypes. Then, we constructed an ARG signature by LASSO analysis. The prognostic significance of the ARG signature in osteosarcoma was determined by Kaplan-Meier plotter, Cox regression, and nomogram analyses. RESULTS: Two apoptosis-related subtypes were identified. Cluster 1 had a better prognosis, higher immunogenicity, and immune cell infiltration, as well as a better response to immunotherapy than Cluster 2. We discovered that patients in the high-risk cohort had a lower survival rate than those in the low-risk cohort according to the ARG signature. Furthermore, Cox regression analysis confirmed that a high risk score independently acted as an unfavorable prognostic marker. Additionally, the nomogram combining risk scores with clinical characteristics can improve prediction efficiency. CONCLUSION: We demonstrated that patients suffering from osteosarcoma may be classified into two apoptosis-related subtypes. Moreover, we developed an ARG prognostic signature to predict the prognosis status of osteosarcoma patients.

A Multitask Deep Learning Framework for DNER.

Over the years, the explosive growth of drug-related text information has resulted in heavy loads of work for manual data processing. However, the domain knowledge hidden is believed to be crucial to biomedical research and applications. In this article, the multi-DTR model that can accurately recognize drug-specific name by joint modeling of DNER and DNEN was proposed. Character features were extracted by CNN out of the input text, and the context-sensitive word vectors were obtained using ELMo. Next, the pretrained biomedical words were embedded into BiLSTM-CRF and the output labels were interacted to update the task parameters until DNER and DNEN would support each other. The proposed method was found with better performance on the DDI2011 and DDI2013 datasets.

Comparison of 3 treatment methods for midshaft clavicle fractures: A systematic review and network meta-analysis of randomized clinical trials.

BACKGROUND: Our study aims to evaluate the fracture nonunion rate and the functional score of plate and screw fixation, intramedullary nailing and non-surgical treatment in midshaft clavicle fractures patients using a network meta-analysis of data from clinical randomized controlled trials. MATERIAL/METHODS: The studies were abstracted from Medline, Embase, Web of Science, Google Scholar and the Cochrane Central Register of Controlled Trials. RCTs meeting the inclusion and exclusion criteria were selected. Statistical analyses were conducted using Stata software, version 14.0 (Stata Corporation, College Station, Texas, USA). RESULTS: 24 randomized controlled trials involving 2161 participants were included. The studies were published between 2007 and 2019. A total of 3 treatment methods-plate and screw fixation, intramedullary nailing and non-surgical treatment- were included in the literature. The treatments were ranked based on the Surface Under the Cumulative Ranking Curve (SUCRA) probability. In terms of the constant score, the treatment methods were ranked as follows: intramedullary nailing, plate and screw fixation and non-surgical treatment. In terms of the DASH index, the treatment methods were ranked as follows: intramedullary nailing, plate and screw fixation and non-surgical treatment. In terms of the nonunion rate, the treatment methods were ranked as follows: intramedullary nailing, plate and screw fixation and non-surgical treatment. CONCLUSION: Non-surgical treatment has a high rate of nonunion for clavicular fractures with obvious displacement and notable comminution. Surgical treatment reduces the nonunion rate leads to better functional scores at long-term follow-up, although there may be no significant clinical differences. The fracture nonunion rate of plate screw fixation group and intramedullary nail group was low and the functional prognosis was similar. More RCTs focused on clavicular fractures are needed to further substantiate this conclusion.

Molecular mechanisms of centipede toxin SsTx-4 inhibition of inwardly rectifying potassium channels.

Inwardly rectifying potassium channels (Kirs) are important drug targets, with antagonists for the Kir1.1, Kir4.1, and pancreatic Kir6.2/SUR1 channels being potential drug candidates for treating hypertension, depression, and diabetes, respectively. However, few peptide toxins acting on Kirs are identified and their interacting mechanisms remain largely elusive yet. Herein, we showed that the centipede toxin SsTx-4 potently inhibited the Kir1.1, Kir4.1, and Kir6.2/SUR1 channels with nanomolar to submicromolar affinities and intensively studied the molecular bases for toxin-channel interactions using patch-clamp analysis and site-directed mutations. Other Kirs including Kir2.1 to 2.4, Kir4.2, and Kir7.1 were resistant to SsTx-4 treatment. Moreover, SsTx-4 inhibited the inward and outward currents of Kirs with different potencies, possibly caused by a K+ "knock-off" effect, suggesting the toxin functions as an out pore blocker physically occluding the K+-conducting pathway. This conclusion was further supported by a mutation analysis showing that M137 located in the outer vestibule of the Kir6.2/ΔC26 channel was the key residue mediating interaction with SsTx-4. On the other hand, the molecular determinants within SsTx-4 for binding these Kir channels only partially overlapped, with K13 and F44 being the common key residues. Most importantly, K11A, P15A, and Y16A mutant toxins showed improved affinity and/or selectivity toward Kir6.2, while R12A mutant toxin had increased affinity for Kir4.1. To our knowledge, SsTx-4 is the first characterized peptide toxin with Kir4.1 inhibitory activity. This study provides useful insights for engineering a Kir6.2/SUR1 channel-specific antagonist based on the SsTx-4 template molecule and may be useful in developing new antidiabetic drugs.

Iterative normalized cross-correlation method for absolute optical path difference demodulation of dual interferometers.

It is still a challenge to realize the absolute optical path difference (OPD) demodulation of multi-interference systems with a narrow spectral interval and small OPD interval. In this paper, an iterative normalized cross-correlation algorithm is firstly proposed for demodulating the multiple absolute OPDs of a dual-interference system and applied to optical fiber sensing system. By constructing a template function in combined form, the optimal solutions of its components and OPDs are solved iteratively based on the reconstruction matrix method and cross-correlation algorithm, respectively. The simulation and experiment show that the demodulation accuracies near the OPDs of 560 µm and 660 µm are both up to 5 nm in different spectral intervals from 45 to 80 nm. The simulation results show that all demodulation precisions at the spectral interval of 55 nm do not exceed 4 nm when the OPD changes in the range of 650-670 µm. Besides, the experimental verification shows the temperature accuracy (0.125 °C) with 95% confidence of T-distribution is very close to the control accuracy (0.1 °C). The proposed algorithm can improve the multiplexing capability of optical fiber sensor system and reduce its cost.

Propeller perforator flaps from the dorsal digital artery perforator chain for repairing soft tissue defects of the finger.

BACKGROUND: When restoring the appearance and function of the fingers, hand surgeons face a challenge in choosing a suitable surgical method to repair finger skin defects. METHODS: In this study, we designed a long elliptical flap based on a propeller perforator flap and located slightly toward the dorsal lateral aspect of the finger. The flap with a pedicle consisting of the dorsal perforator of the distal digital artery and dorsal digital artery perforator chain is rotated to cover a large wound on the distal end. From December 2014 to December 2017, 10 patients with finger soft tissue defects were treated with the propeller perforator flap described in this study. RESULTS: All flaps survived after surgery, and 2 had a transient venous congestion. After a follow-up period of 3 to 12 months, the static two-point discrimination of the flap was 8.06 ± 1.75 mm, and the range of motion was 149.4 ± 12.9°. This designed flap can span several angiosomes supplied by the perforators. Due to the inclusion of a vessel chain between the dorsal digital artery perforators, the length-to-width ratio of the flap can be up to 3:1. CONCLUSIONS: This technique increases the size of flap that can be harvested safely while retaining a reliable blood supply. The present study describes a new method for repairing soft tissue defects of the finger by using the technique of propeller perforator flaps based on dorsal digital artery perforator chains. TRIAL REGISTRATION: The registration number of this study is ChiCTR1800014588; it has been retrospectively registered with Chinese Clinical Trial Registry (chictr.org.cn), 18/11/2019.

Region-resolved proteomics profiling of monkey heart.

Nonhuman primates (NHPs) play an indispensable role in biomedical research because of their similarities in genetics, physiological, and neurological function to humans. Proteomics profiling of monkey heart could reveal significant cardiac biomarkers and help us to gain a better understanding of the pathogenesis of heart disease. However, the proteomic study of monkey heart is relatively lacking. Here, we performed the proteomics profiling of the normal monkey heart by measuring three major anatomical regions (vessels, valves, and chambers) based on iTRAQ-coupled LC-MS/MS analysis. Over 3,200 proteins were identified and quantified from three heart tissue samples. Furthermore, multiple bioinformatics analyses such as gene ontology analysis, protein-protein interaction analysis, and gene-diseases association were used to investigate biological network of those proteins from each area. More than 60 genes in three heart regions are implicated with heart diseases such as hypertrophic cardiomyopathy, heart failure, and myocardial infarction. These genes associated with heart disease are mainly enriched in citrate cycle, amino acid degradation, and glycolysis pathway. At the anatomical level, the revelation of molecular characteristics of the healthy monkey heart would be an important starting point to investigate heart disease. As a unique resource, this study can serve as a reference map for future in-depth research on cardiac disease-related NHP model and novel biomarkers of cardiac injury.

[Mini locked-plate trans-carpometacarpal joint internal fixation for treating comminuted fracture of base of the fifth metacarpal].

Objective: To evaluate the effectiveness of open reduction and trans-carpometacarpal joint internal fixation with mini locked-plate for treatment of comminuted fracture of base of the fifth metacarpal. Methods: Between July 2015 and December 2017, 8 cases of comminuted fractures of base of the fifth metacarpals were treated with open reduction and trans-carpometacarpal joint internal fixation with mini locked-plate. There were 7 males and 1 female with an age of 19-45 years (mean, 32.5 years). The causes of injury included 2 cases of hitting hard objects while clenching fist, 6 cases of falling injury. There were 2 cases of subluxation of fifth carpal joints and 1 case of dislocation. The time from injury to operation was 1-5 days (mean, 3.5 days). The stability of fracture ends could not be maintained by preoperative evaluation without over articular fixation or short time over articular fixation. Postoperative complications and fracture healing were observed, and hand function was evaluated at last follow-up according to the total active motion (TAM) recommended by the Branch of Hand Surgery of Chinese Medicine Association. Results: All the incisions healed by first intention without complications such as wound infection, cutaneous necrosis, tendon or nerve injury. All the patients were followed up 6-18 months (mean, 12 months). All fractures healed with the healing time of 12-16 weeks (mean, 13 weeks). Within 4 months after operation, all patients were able to return to pre-injury job. At last follow-up, according to the TAM recommended by the Branch of Hand Surgery of Chinese Medicine Association, the results were excellent in 7 cases, good in 1 case, with the excellent and good rate of 100%. Conclusion: Applying of mini locked-plate for treatment of comminuted fractures of base of the fifth metacarpal, of which cannot obtain stable fixation through non-transarticular or short-time transarticular fixation, can achieve satisfactory functional results with very few complications through trans-carpometacarpal joint approach, thus the procedure can be used as an alternative operation scheme.