Does growth hormone supplementation of in vitro fertilization/intracytoplasmic sperm injection improve cumulative live birth rates in women with poor embryonic development in the previous cycle?

BACKGROUND: Growth hormone (GH) has been proposed as an adjunct in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles, especially in women with poor ovarian response. However, it is unclear whether GH supplementation is effective in women with poor embryonic development in the previous IVF cycle. The aim of this study was to evaluate the effectiveness of GH supplementation in IVF/ICSI cycles in women with poor embryonic development in the previous cycle. METHODS: This is a retrospective cohort study from a public fertility center in China, in which we performed propensity score-matching (PSM) for female age and AFC in a ratio of 1:1. We compared the cumulative live birth rate per started cycle, as well as a series of secondary outcomes. We included 3,043 women with poor embryonic development in the previous IVF/ICSI cycle, of which 1,326 had GH as adjuvant therapy and 1,717 had not. After PSM, there were 694 women in each group. RESULTS: After PSM, multivariate analyses showed the cumulative live birth rate to be significantly higher in the GH group than the control group [N = 694, 34.7% vs. N = 694, 27.5%, risk ratio (RR): 1.4 (95%CI: 1.1-1.8)]. Endometrial thickness, number of oocytes retrieved, number of embryos available, and number of good-quality embryos were significantly higher in the GH group compared to controls. Pregnancy outcomes in terms of birth weight, gestational age, fetal sex, preterm birth rate, and type of delivery were comparable. When we evaluated the impact of GH on different categories of female age, the observed benefit in the GH group did not appear to be significant. When we assessed the effect of GH in different AFC categories, the effect of GH was strongest in women with an AFC5-6 (32.2% versus 19.5%; RR 2.0; 95% CI 1.2-3.3). CONCLUSIONS: Women with poor embryonic quality in the previous IVF/ICSI cycles have higher rates of cumulative live birth with GH supplementation.

The Immunomodulatory effect of exosomes in diabetes: a novel and attractive therapeutic tool in diabetes therapy.

Exosomes carry proteins, metabolites, nucleic acids and lipids from their parent cell of origin. They are derived from cells through exocytosis, are ingested by target cells, and can transfer biological signals between local or distant cells. Therefore, exosomes are often modified in reaction to pathological processes, including infection, cancer, cardiovascular diseases and in response to metabolic perturbations such as obesity and diabetes, all of which involve a significant inflammatory aspect. Here, we discuss how immune cell-derived exosomes origin from neutrophils, T lymphocytes, macrophages impact on the immune reprogramming of diabetes and the associated complications. Besides, exosomes derived from stem cells and their immunomodulatory properties and anti-inflammation effect in diabetes are also reviewed. Moreover, As an important addition to previous reviews, we describes promising directions involving engineered exosomes as well as current challenges of clinical applications in diabetic therapy. Further research on exosomes will explore their potential in translational medicine and provide new avenues for the development of effective clinical diagnostics and therapeutic strategies for immunoregulation of diabetes.

Immunosenescence-related T cell phenotypes and white matter in schizophrenia patients with tardive dyskinesia.

Schizophrenia patients with tardive dyskinesia (TD) are associated with accelerated biological aging, immunological dysfunction, and premature morbidity and mortality. Older individuals are particularly vulnerable to TD development. As a characteristic of immunosenescence, alterations in the relative proportions of naïve or memory T cell subpopulations may be negatively or positively associated with brain structure abnormalities; however, whether these changes are correlated with TD remains unclear. In this study, we investigated correlations between distributions of T cell phenotypes and brain structure abnormalities (especially white matter) in schizophrenia patients with (TD) and without (NTD) TD (n = 50 and 58, respectively) relative to healthy controls (HC, n = 41). Immune markers, including naïve (CD45RA+), memory (CD45RO+), and apoptotic (CD95+) CD4+ and CD8+ T cells, were examined by flow cytometry, as were the intracellular levels of cytokines (interferon (IFN)-γ, interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α) in CD8 + CD45RA + CD95+ and CD8 + CD45RO + CD95+ T cells. MRI was employed to evaluate the fractional anisotropy (FA) of white matter tracts and subcortical volumes, following published routines. The percentage of CD8 + CD45RO + CD95+ T cells was higher in TD compared with NTD and HC groups and correlated with the choroid plexus volume in TD group. The intracellular level of IFN-γ in CD8 + CD45RO + CD95+ T cells, the FA of the fornix/stria terminalis, and the pallidum volume were correlated with orofacial TD, whereas the FAs of the inferior fronto-occipital fasciculus, cingulum, and superior longitudinal fasciculus were correlated with limb-truncal TD. These findings provide preliminary evidence that the association between immunosenescence-related T cell subpopulations and brain structure may underline the pathological process of TD.

Catalytic Oxidation of Chlorobenzene over Amorphous Manganese-Chromium Catalysts Supported by UiO-66-Derived ZrOx.

The development of efficient catalysts with longevity to remove chlorobenzene is challenging due to Cl poisoning. Herein, a series of Mn-Cr/ZrOx catalysts supported by Zr-based metal-organic framework (UiO-66)-derived ZrOx was prepared and investigated for chlorobenzene (CB) catalytic oxidation. MnCr/ZrOx-M prepared via a wet impregnation method presented an amorphous structure, indicating the homogeneous dispersion of Cr and Mn, which improved acid and redox properties. 40Mn7Cr3/ZrOx-M exhibited the best catalytic activity for chlorobenzene oxidation with T90 of 293 °C, which is mainly due to the strong interaction between manganese and chromium promoted by the large specific surface area of the ZrOx support. Furthermore, 40Mn7Cr3/ZrOx-M presented excellent stability for chlorobenzene oxidation.

Vesicle fusion and release in neurons under dynamic mechanical equilibrium.

Vesicular fusion plays a pivotal role in cellular processes, involving stages like vesicle trafficking, fusion pore formation, content release, and membrane integration or separation. This dynamic process is regulated by a complex interplay of protein assemblies, osmotic forces, and membrane tension, which together maintain a mechanical equilibrium within the cell. Changes in cellular mechanics or external pressures prompt adjustments in this equilibrium, highlighting the system's adaptability. This review delves into the synergy between intracellular proteins, structural components, and external forces in facilitating vesicular fusion and release. It also explores how cells respond to mechanical stress, maintaining equilibrium and offering insights into vesicle fusion mechanisms and the development of neurological disorders.

Tracheobronchopathia osteochondroplastica concurrent with peripheral lung cancer: a case report and perioperative considerations.

Background: Tracheobronchopathia osteochondroplastica (TPO) is a rare, benign, chronic disorder of unknown etiology. It is characterized by submucosal nodules, often calcified, which predominantly affect the anterolateral aspects of the trachea and main bronchi, while sparing the posterior bronchial wall. The co-occurrence of TPO and lung cancer is exceedingly rare. This report presents a case of TPO association with early-stage lung cancer, which was managed through surgical intervention. No active treatment was undertaken for the TPO. Case Description: A patient presented with a nodule in the right upper lobe, which was identified during a computed tomography (CT) scan of the chest, suggestive of early-stage lung cancer. Concurrently, multiple calcifications in the cartilaginous rings of the trachea were noted. Bronchoscopy revealed distinctive "pebblestone" nodules along the anterior and lateral tracheal walls, indicative of extensive TPO. The patient underwent bronchofiberscopy, which showed patency in the bronchial lumen of the right lung's upper lobe. A biopsy was not undertaken during this procedure. Comprehensive preoperative tests, including a blood biochemical examination, tumor-marker tests, lung-function tests, head-enhanced magnetic resonance imaging, abdominal ultrasound, and whole-body bone emission CT revealed no significant abnormalities. Despite this, the patient declined a whole-body positron emission tomography (PET)-CT scan. Given the potential malignancy of nodules in the right lung's upper lobe, the lobectomy for lung cancer was carried out, a procedure that would have proceeded irrespective of the presence or absence of TPO. Preoperative planning for potential tracheal intubation difficulties involved consultation with the anesthesiologist, resulting in a smooth intraoperative process. The pathology confirmed invasive adenocarcinoma. Post-surgery, the patient developed an infection in the right lung's lower lobe, identified as pseudomonas aeruginosa and Klebsiella pneumoniae through sputum culture and bronchoscopic lavage. Treatment with meropenem for 2 weeks, as guided by drug sensitivity results and respiratory advice, led to an improvement, allowing for discharge. A follow-up lung CT four months post-operation showed inflammation absorption in the right lower lobe. Conclusions: Surgical resection in cases of TPO association with lung cancer may have an increased risk of postoperative pulmonary infection. Proactive intraoperative sputum aspiration by anesthesiologists and the postoperative reinforcement of anti-infection measures, guided by drug sensitivity results, are recommended.

Exploring the Link Between Autophagy-Lysosomal Dysfunction and Early Heterotopic Ossification in Tendons.

Heterotopic ossification (HO), the pathological formation of bone within soft tissues such as tendon and muscle, is a notable complication resulting from severe injury. While soft tissue injury is necessary for HO development, the specific molecular pathology responsible for trauma-induced HO remains a mystery. The previous study detected abnormal autophagy function in the early stages of tendon HO. Nevertheless, it remains to be determined whether autophagy governs the process of HO generation. Here, trauma-induced tendon HO model is used to investigate the relationship between autophagy and tendon calcification. In the early stages of tenotomy, it is observed that autophagic flux is significantly impaired and that blocking autophagic flux promoted the development of more rampant calcification. Moreover, Gt(ROSA)26sor transgenic mouse model experiments disclosed lysosomal acid dysfunction as chief reason behind impaired autophagic flux. Stimulating V-ATPase activity reinstated both lysosomal acid functioning and autophagic flux, thereby reversing tendon HO. This present study demonstrates that autophagy-lysosomal dysfunction triggers HO in the stages of tendon injury, with potential therapeutic targeting implications for HO.

Improvement of Photovoltaic Performance of Perovskite Solar Cells by Synergistic Modulation of SnO2 and Perovskite via Interfacial Modification.

In the past decade, perovskite solar cell (PSC) photoelectric conversion efficiency has advanced significantly, and tin dioxide (SnO2) has been extensively used as the electron transport layer (ETL). Due to its high electron mobility, strong chemical stability, energy level matching with perovskite, and easy low-temperature fabrication, SnO2 is one of the most effective ETL materials. However, the SnO2 material as an ETL has its limitations. For example, SnO2 films prepared by low-temperature spin-coating contain a large number of oxygen vacancies, resulting in energy loss and high open-circuit voltage (VOC) loss. In addition, the crystal quality of perovskites is closely related to the substrate, and the disordered crystal orientation will lead to ion migration, resulting in a large number of uncoordinated Pb2+ defects. Therefore, interface optimization is essential to improve the efficiency and stability of the PSC. In this work, 2-(5-chloro-2-benzotriazolyl)-6-tert-butyl-p-cresol (CBTBC) was introduced for ETL modification. On the one hand, the hydroxyl group of CBTBC forms a Lewis mixture with the Sn atom, which reduces the oxygen vacancy defect and prevents nonradiative recombination. On the other hand, the SnO2/CBTBC interface can effectively improve the crystal orientation of perovskite by influencing the crystallization kinetics of perovskite, and the nitrogen element in CBTBC can effectively passivate the uncoordinated Pb2+ defects at the SnO2/perovskite interface. Finally, the prevailing PCE of PSC (1.68 eV) modified by CBTBC was 20.34% (VOC = 1.214 V, JSC = 20.49 mA/cm2, FF = 82.49%).

A review on intelligence of cellulose based materials.

Cellulose based materials are widely used in various fields such as papermaking, packaging, composite materials, textiles and clothing due to their diverse types, environmental friendliness, natural degradation, high specific strength, and low cost. The intelligence of cellulose based materials will further expand their application fields. This article first gives an in-depth analyzation on the intelligent structural design of these materials according to the two major categories of isotropic and anisotropic, then lists the main preparation methods of cellulose based intelligent materials. Subsequently, this article systematically summarizes the recent intelligent response methods and characteristics of cellulose based materials, and extensively elaborates on the intelligent application of these materials. Finally, the prospects for the intelligence of cellulose based materials are discussed.

Preformed Vesicle Approach to LNP Manufacturing Enhances Retinal mRNA Delivery.

Complete encapsulation of nucleic acids by lipid-based nanoparticles (LNPs) is often thought to be one of the main prerequisites for successful nucleic acid delivery, as the lipid environment protects mRNA from degradation by external nucleases and assists in initiating delivery processes. However, delivery of mRNA via a preformed vesicle approach (PFV-LNPs) defies this precondition. Unlike traditional LNPs, PFV-LNPs are formed via a solvent-free mixing process, leading to a superficial mRNA localization. While demonstrating low encapsulation efficiency in the RiboGreen assay, PFV-LNPs improved delivery of mRNA to the retina by up to 50% compared to the LNP analogs across several benchmark formulations, suggesting the utility of this approach regardless of the lipid composition. Successful mRNA and gene editors' delivery is observed in the retinal pigment epithelium and photoreceptors and validated in mice, non-human primates, and human retinal organoids. Deploying PFV-LNPs in gene editing experiments result in a similar extent of gene editing compared to analogous LNP (up to 3% on genomic level) in the Ai9 reporter mouse model; but, remarkably, retinal tolerability is significantly improved for PFV-LNP treatment. The study findings indicate that the LNP formulation process can greatly influence mRNA transfection and gene editing outcomes, improving LNP treatment safety without sacrificing efficacy.

Pore walls as high-way for efficient bulk charge transfer in porous SrTiO3 single crystals boosting photocatalytic overall water splitting.

Suppressing carrier recombination in bulk and facilitating carrier transfer to surface via rational structure design is of great significance to improve solar-to-H2 conversion efficiency. We demonstrate a facile hydrothermal method to synthesize porous SrTiO3 single crystals (SrTiO3-P) with exposed (001) facets by introducing carbon spheres as templates. The obviously increased surface photovoltage and photocurrent response indicate that the interconnected pore walls act as enormous charge transfer "highways", accelerating carrier transport from bulk to surface. Furthermore, the absence of grain boundaries and high crystallinity could also lower the carrier recombination rate. Thus, the SrTiO3-P photocatalyst loaded with Rh/Cr2O3 as cocatalyst exhibits 1.5 times higher overall water splitting activity than that of solid SrTiO3, with gas evolution rate of 19.99 µmol h-1 50 mg-1 for H2 and 11.37 µmol h-1 50 mg-1 for O2. Additionally, SrTiO3-P also shows superior stability without any decay during cycling testing. This work provides a new insight into designing efficient multicomponent photocatalysts with a single-crystal porous structure.

miR-133a and miR-135a Regulate All-Trans Retinoic Acid-Mediated Differentiation in Pediatric Acute Myeloid Leukemia by Inhibiting CDX2 Translation and Serve as Prognostic Biomarkers.

Background: Acute myeloid leukemia (AML) is a type of blood cancer characterized by excessive growth of immature myeloid cells. Unfortunately, the prognosis of pediatric AML remains unfavorable. It is imperative to further our understanding of the mechanisms underlying leukemogenesis and explore innovative therapeutic approaches to enhance overall disease outcomes for patients with this condition. Methods: Quantitative reverse-transcription PCR was used to quantify the expression levels of microRNA (miR)-133a and miR-135a in 68 samples from 59 pediatric patients with AML. Dual-luciferase reporter transfection assay, Cell Counting Kit-8 assay, and western blot analysis were used to investigate the functions of miR-133a and miR-135a. Results: Our study found that all-trans-retinoic acid (ATRA) promoted the expression of miR-133a and miR-135a in AML cells, inhibited caudal type homeobox 2 (CDX2) expression, and subsequently inhibited the proliferation of AML cells. Additionally, miR-133a and miR-135a were highly expressed in patients with complete remission and those with better survival. Conclusions: miR-133a and miR-135a may play an antioncogenic role in pediatric AML through the ATRA-miRNA133a/135a-CDX2 pathway. They hold promise as potentially favorable prognostic indicators and novel therapeutic targets for pediatric AML.

Improvement of antibacterial activity of polysaccharides via chemical modification: A review.

Antibiotic residue and bacterial resistance induced by antibiotic abuse have seriously threatened food safety and human healthiness. Thus, the development and application of safe, high-efficiency, and environmentally friendly antibiotic alternatives are urgently necessary. Apart from antitumor, antivirus, anti-inflammatory, gut microbiota regulation, immunity improvement, and growth promotion activities, polysaccharides also have antibacterial activity, but such activity is relatively low, which cannot satisfy the requirements of food preservation, clinical sterilization, livestock feeding, and agricultural cultivation. Chemical modification not only provides polysaccharides with better antibacterial activity, but also promotes easy operation and large-scale production. Herein, the enhancement of the antibacterial activity of polysaccharides via acetylation, sulfation, phosphorylation, carboxymethylation, selenation, amination, acid graft, and other chemical modifications is reviewed. Meanwhile, a new trend on the application of loading chemically modified polysaccharides into nanostructures is discussed. Furthermore, possible limitations and future recommendations for the development and application of chemically modified polysaccharides with better antibacterial activity are suggested.

Exploration of a machine learning approach for diagnosing sarcopenia among Chinese community-dwelling older adults using sEMG-based data.

BACKGROUND: In the practical application of sarcopenia screening, there is a need for faster, time-saving, and community-friendly detection methods. The primary purpose of this study was to perform sarcopenia screening in community-dwelling older adults and investigate whether surface electromyogram (sEMG) from hand grip could potentially be used to detect sarcopenia using machine learning (ML) methods with reasonable features extracted from sEMG signals. The secondary aim was to provide the interpretability of the obtained ML models using a novel feature importance estimation method. METHODS: A total of 158 community-dwelling older residents (≥ 60 years old) were recruited. After screening through the diagnostic criteria of the Asian Working Group for Sarcopenia in 2019 (AWGS 2019) and data quality check, participants were assigned to the healthy group (n = 45) and the sarcopenic group (n = 48). sEMG signals from six forearm muscles were recorded during the hand grip task at 20% maximal voluntary contraction (MVC) and 50% MVC. After filtering recorded signals, nine representative features were extracted, including six time-domain features plus three time-frequency domain features. Then, a voting classifier ensembled by a support vector machine (SVM), a random forest (RF), and a gradient boosting machine (GBM) was implemented to classify healthy versus sarcopenic participants. Finally, the SHapley Additive exPlanations (SHAP) method was utilized to investigate feature importance during classification. RESULTS: Seven out of the nine features exhibited statistically significant differences between healthy and sarcopenic participants in both 20% and 50% MVC tests. Using these features, the voting classifier achieved 80% sensitivity and 73% accuracy through a five-fold cross-validation. Such performance was better than each of the SVM, RF, and GBM models alone. Lastly, SHAP results revealed that the wavelength (WL) and the kurtosis of continuous wavelet transform coefficients (CWT_kurtosis) had the highest feature impact scores. CONCLUSION: This study proposed a method for community-based sarcopenia screening using sEMG signals of forearm muscles. Using a voting classifier with nine representative features, the accuracy exceeds 70% and the sensitivity exceeds 75%, indicating moderate classification performance. Interpretable results obtained from the SHAP model suggest that motor unit (MU) activation mode may be a key factor affecting sarcopenia.

A BRD4-Targeting Photothermal Agent for Controlled Protein Degradation.

BRD4 protein plays a pivotal role in cell cycle regulation and differentiation. Disrupting the activity of BRD4 has emerged as a promising strategy for inhibiting the growth and proliferation of cancer cells. Herein, we introduced a BRD4-targeting photothermal agent for controlled protein degradation, aiming to enhance low-temperature photothermal therapy (PTT) for cancer treatment. By incorporating a BRD4 protein inhibitor into a cyanine dye scaffold, the photothermal agent specifically bond to the bromodomain of BRD4. Upon low power density laser irradiation, the agent induced protein degradation, directly destroying the BRD4 structure and inhibiting its transcriptional regulatory function. This strategy not only prolonged the retention time of the photothermal agent in cancer cells but also confined the targeted protein degradation process solely to the tumor tissue, minimizing side effects on normal tissues through the aid of exogenous signals. This work established a simple and feasible platform for future PTT agent design in clinical cancer treatment.

Identification of hub genes and therapeutic siRNAs to develop novel adjunctive therapy for Duchenne muscular dystrophy.

OBJECTIVE: Duchenne muscular dystrophy (DMD) is a devastating X-linked neuromuscular disorder caused by various defects in the dystrophin gene and still no universal therapy. This study aims to identify the hub genes unrelated to excessive immune response but responsible for DMD progression and explore therapeutic siRNAs, thereby providing a novel treatment. METHODS: Top ten hub genes for DMD were identified from GSE38417 dataset by using GEO2R and PPI networks based on Cytoscape analysis. The hub genes unrelated to excessive immune response were identified by GeneCards, and their expression was further verified in mdx and C57 mice at 2 and 4 months (M) by (RT-q) PCR and western blotting. Therapeutic siRNAs were deemed as those that could normalize the expression of the validated hub genes in transfected C2C12 cells. RESULTS: 855 up-regulated and 324 down-regulated DEGs were screened from GSE38417 dataset. Five of the top 10 hub genes were considered as the candidate genes unrelated to excessive immune response, and three of these candidates were consistently and significantly up-regulated in mdx mice at 2 M and 4 M when compared with age-matched C57 mice, including Col1a2, Fbn1 and Fn1. Furthermore, the three validated up-regulated candidate genes can be significantly down-regulated by three rational designed siRNA (p < 0.0001), respectively. CONCLUSION: COL1A2, FBN1 and FN1 may be novel biomarkers for DMD, and the siRNAs designed in our study were help to develop adjunctive therapy for Duchenne muscular dystrophy.

Coordination-Driven Self-Assembly of Metal Ion-Antisense Oligonucleotide Nanohybrids for Chronic Bacterial Infection Therapy.

Bacterial infection poses a significant challenge to wound healing and skin regeneration, leading to substantial economic burdens on patients and society. Therefore, it is crucial to promptly explore and develop effective methodologies for bacterial infections. Herein, we propose a novel approach for synthesizing nanostructures based on antisense oligonucleotides (ASOs) through the coordination-driven self-assembly of Zn2+ with ASO molecules. This approach aims to provide effective synergistic therapy for chronic wound infections caused by Staphylococcus aureus (S. aureus). The resulting hybrid nanoparticles successfully preserve the structural integrity and biological functionalities of ASOs, demonstrating excellent ASO encapsulation efficiency and bioaccessibility. In vitro antibacterial experiments reveal that Zn-ASO NPs exhibit antimicrobial properties against Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. This antibacterial ability is attributed to the high concentration of metal zinc ions and the generation of high levels of reactive oxygen species. Additionally, the ftsZ-ASO effectively inhibits the expression of the ftsZ gene, further enhancing the antimicrobial effect. In vivo antibacterial assays demonstrate that the Zn-ASO NPs promote optimal skin wound healing and exhibit favorable biocompatibility against S. aureus infections, resulting in a residual infected area of less than 8%. This combined antibacterial strategy, which integrates antisense gene therapy and metal-coordination-directed self-assembly, not only achieves synergistic and augmented antibacterial outcomes but also expands the horizons of ASO coordination chemistry. Moreover, it addresses the gap in the antimicrobial application of metal-coordination ASO self-assembly, thereby advancing the field of ASO-based therapeutic approaches.

Postponed endoscopic necrosectomy results in a lower rate of additional intervention for infected walled-off necrosis.

Although endoscopic necrosectomy (EN) is more frequently used to manage walled-off necrosis (WON), there is still debate over how much time should pass between the initial stent placement and the first necrosectomy. This study aims to determine the effect of performing EN within different timings after placing the initial stent on clinical outcomes for WON. A retrospective study on infected WON patients compared an early necrosectomy within one week after the initial stent placement with a necrosectomy that was postponed after a week. The primary outcomes compared the rate of clinical success and the need for additional intervention after EN to achieve WON resolution. 77 patients were divided into early and postponed necrosectomy groups. The complete resolution of WON within six months of follow-up was attained in 73.7% and 74.3% of patients in both the early and postponed groups. The early group tended to a greater need for additional intervention after EN (26.8% early necrosectomy vs. 8.3% postponed necrosectomy, P = 0.036). Our study does not demonstrate that early necrosectomy is superior to postponed necrosectomy in terms of clinical success rate, total count of necrosectomy procedures, procedure-related complications, length of hospitalization and prognosis. Conversely, patients in the postponed group received fewer additional interventions.

Cardiac conduction diseases: understanding the molecular mechanisms to uncover targets for future treatments.

INTRODUCTION: The cardiac conduction system (CCS) is crucial for maintaining adequate cardiac frequency at rest and modulation during exercise. Furthermore, the atrioventricular node and His-Purkinje system are essential for maintaining atrioventricular and interventricular synchrony and consequently maintaining an adequate cardiac output. AREAS COVERED: In this review article, we examine the anatomy, physiology, and pathophysiology of the CCS. We then discuss in detail the most common genetic mutations and the molecular mechanisms of cardiac conduction disease (CCD) and provide our perspectives on future research and therapeutic opportunities in this field. EXPERT OPINION: Significant advancement has been made in understanding the molecular mechanisms of CCD, including the recognition of the heterogeneous signaling at the subcellular levels of sinoatrial node, the involvement of inflammatory and autoimmune mechanisms, and the potential impact of epigenetic regulations on CCD. However, the current treatment of CCD manifested as bradycardia still relies primarily on cardiovascular implantable electronic devices (CIEDs). On the other hand, an If specific inhibitor was developed to treat inappropriate sinus tachycardia and sinus tachycardia in heart failure patients with reduced ejection fraction. More work is needed to translate current knowledge into pharmacologic or genetic interventions for the management of CCDs.