Long-term Outcomes of Mitral Valve Repair for Atrial Functional Mitral Regurgitation.

BACKGROUND: Atrial functional mitral regurgitation (AFMR), defined by normal left ventricular function, enlarged left atrium, and a dilated mitral valve annulus, has been a concept discussed for >10 years. However, there are still no established guidelines for its treatment in the American College of Cardiology/American Heart Association recommendations. This study aimed to determine the long-term outcomes of mitral annuloplasty as a treatment for AFMR. METHODS: We analyzed 1435 patients who underwent mitral valve repair at our institution between 2005 and 2020, with 162 classified as having AFMR. Exclusion criteria for AFMR were established based on preoperative echocardiography and operative notes. The primary outcome was overall mortality, and the secondary outcome was MR recurrence, which was defined as moderate or greater mitral regurgitation observed on echocardiography during the follow-up period, analyzed using our hospital's medical records and data from the National Statistical Office. RESULTS: The median follow-up duration for the entire patient cohort was 6.1 years (interquartile range, 3.2-11.2 years). Patients had a 5-year survival rate of 86% and a 10-year survival rate of 73%, with freedom from MR recurrence rates of 89% and 80% at 5 and 10 years, respectively. Although all 162 patients had moderate or greater MR before surgery, most experienced trivial or mild MR after mitral valve repair throughout the follow-up period. CONCLUSIONS: In summary, mitral valve repair effectively treats patients with AFMR, addressing survival and mitigating MR recurrence.

Study on the Therapeutic Effects and Mechanisms of Gintonin in Irritable Bowel Syndrome and Its Relationship with TRPV1, TRPV4, and NaV1.5.

Irritable bowel syndrome (IBS) is a gastrointestinal (GI) disease accompanied by changes in bowel habits without any specific cause. Gintonin is a newly isolated glycoprotein from ginseng that is a lysophosphatidic acid (LPA) receptor ligand. To investigate the efficacy and mechanisms of action of gintonin in IBS, we developed a zymosan-induced IBS murine model. In addition, electrophysiological experiments were conducted to confirm the relevance of various ion channels. In mice, gintonin restored colon length and weight to normal and decreased stool scores, whilst food intake remained constant. Colon mucosal thickness and inflammation-related tumor necrosis factor-α levels were decreased by gintonin, along with a reduction in pain-related behaviors. In addition, the fecal microbiota from gintonin-treated mice had relatively more Lactobacillaceae and Lachnospiraceae and less Bacteroidaceae than microbiota from the control mice. Moreover, gintonin inhibited transient receptor potential vanilloid (TRPV) 1 and TRPV4 associated with visceral hypersensitivity and voltage-gated Na+ 1.5 channels associated with GI function. These results suggest that gintonin may be one of the effective components in the treatment of IBS.

Convolutional Neural Network-Based Drone Detection and Classification Using Overlaid Frequency-Modulated Continuous-Wave (FMCW) Range-Doppler Images.

This paper proposes a novel drone detection method based on a convolutional neural network (CNN) utilizing range-Doppler map images from a frequency-modulated continuous-wave (FMCW) radar. The existing drone detection and identification techniques, which rely on the micro-Doppler signature (MDS), face challenges when a drone is small or located far away, leading to performance degradation due to signal attenuation and faint (MDS). In order to address these issues, this paper suggests a method where multiple time-series range-Doppler images from an FMCW radar are overlaid onto a single image and fed to a CNN. The experimental results, using actual data for three different drone sizes, show significant performance improvements in drone detection accuracy compared to conventional methods.

Conductive Bio-Harvesting Tonic (CBT) with an Anti-Dandruff Effect Enhances Hair Growth by Utilizing Naturally Generated Electric Energy during Human Activities.

Alopecia, while not life-threatening, significantly impacts mental health, identity, and self-esteem of those afflicted. Current pharmacological and surgical treatments often have side effects and are limited in their ability to regenerate hair follicles (HF). Therefore, effective solutions for alopecia remain elusive. We developed an innovative hair tonic capable of stimulating HF regeneration by harnessing abandoned electric energy generated during human activities, such as the frictional electric field from walking and the electric fields from electronic devices. We devised a convenient, non-volatile, and conductive hair tonic to capture these naturally occurring electric fields. We identified 6-pentyl-α-pyrone (6PP) from Trichoderma gamsii as an antifungal agent effective against the dandruff-associated fungus Malassezia that can influence alopecia and adopted it into our conductive bio-harvesting tonic (CBT). Testing on hair follicle dermal papilla cells (HFDPC) and SKH1 mice showed that CBT significantly enhanced HF proliferation and increased growth factors in vitro and in vivo. In SKH1 mice, application of CBT under electric stimulation visibly increased hair shaft length and follicle counts. Additionally, tests on actual human hair follicles demonstrated delayed hair follicle regression when electric stimulation and 6PP were applied. In conclusion, our innovative CBT offers a promising and convenient approach for improving hair growth and combating alopecia.

Association between Use of Combustible Cigarettes and Noncombustible Nicotine or Tobacco Products and Health-Related Quality of Life in Korean Men: A Nationwide Population-Based Study.

Background: Although the association between smoking and health-related quality of life (HRQoL) has been established, the effects of tobacco products, including combustible cigarettes (CCs) and non-combustible nicotine or tobacco products (NNTPs), on HRQoL remain unclear. This study examined the association between tobacco use and HRQoL in Korean men. Methods: Data from the Korea National Health and Nutrition Examination Survey conducted between 2013 and 2020 were analyzed. A total of 16,429 male participants aged ≥19 years completed the European Quality of Life-5 Dimensions (EQ-5D). Impaired HRQoL was defined as scoring in the lowest 20% of the EQ-5D index and having some or extreme problems in the following five domains of the EQ-5D: mobility, self-care, usual activities, pain/ discomfort, and anxiety/depression. Multiple logistic regression was conducted to evaluate the risk of impaired HRQoL in current tobacco users. Results: Current tobacco users exhibited a significantly higher risk of impaired HRQoL compared with never users (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.05-1.92). Compared to never users, current tobacco users reported more problems with mobility and pain/discomfort (all P<0.05). Moreover, compared with former tobacco users, current tobacco users had a higher risk of impaired HRQoL (OR, 1.60; 95% CI, 1.18-2.17). Compared to former tobacco users, current tobacco users reported more problems with mobility and pain/discomfort (all P<0.05). Conclusion: Use of CCs and NNTPs is associated with impaired HRQoL in Korean men. Therefore, further interventions for lifestyle modification and smoking cessation treatments are required to reduce the risk of impaired HRQoL among current tobacco users.

Efficacy of KTP Laser-Assisted Marsupialization in the Treatment of Vocal Cysts.

OBJECTIVES: Vocal cysts, common benign laryngeal lesions, often lead to voice disturbances. Total surgical enucleation presents challenges due to the delicate nature of vocal tissues. Conventional surgery carries risks of recurrence and decreased voice quality due to incomplete removal and potential vocal fold damage. This study investigates the efficacy of Potassium-Titanyl-Phosphate (KTP) laser-assisted marsupialization for the treatment of vocal cysts. SUBJECTS AND METHODS: We retrospectively analyzed 78 patients who underwent either conventional surgery or KTP laser-assisted marsupialization to compare the voice outcomes and recurrence rates of the two groups. RESULTS: KTP laser-assisted group (B) demonstrated significantly higher recurrence rates (18.4%) compared to conventional surgery group (5%). The mean time to cyst recurrence were 12.4months in group A and 10.9months in group B. The degree of postoperative improvement in all voice parameters was not significantly different between the two groups. CONCLUSIONS: While KTP laser-assisted marsupialization may offer some advantages such as reduced vocal fold damage and ease technique, the higher recurrence rates observed in this study suggest that this technique may not achieve cure rates comparable to conventional surgery. Therefore, careful consideration is necessary when selecting patients for this procedure, and further research is needed to refine the technique and evaluate its long-term efficacy. LEVEL OF EVIDENCE: Level III.

Sinus Irrigation with N-Acetylcysteine after Endoscopic Sinus Surgery for Chronic Rhinosinusitis: A Preliminary Report of a Single-Blind Randomized Controlled Trial.

Nasal irrigation is crucial following endoscopic sinus surgery (ESS), especially for managing chronic rhinosinusitis (CRS). This study assessed the effectiveness of N-acetylcysteine (NAC) irrigation during the post-ESS period of patients with CRS without nasal polyposis. In this prospective, single-blind randomized controlled trial, 49 patients (NAC, n = 24; saline, n = 25) undergoing ESS were assigned to receive either NAC or saline irrigations twice daily for a month. The preoperative and postoperative assessments conducted included Lund-Macka (LM) and Lund-Kennedy (LK) endoscopic scores, the Nasal Obstruction Symptom Evaluation (NOSE) scale, and the Sino-Nasal Outcome Test-20 (SNOT-20). At 2 weeks, 1 month, and 3 months after the operation, endoscopic findings and symptoms were evaluated. Both groups showed no differences in age, sex, LM and LK scores, NOSE scale, and SNOT-20 preoperatively. In terms of the endoscopic findings regarding the sinonasal mucosa after ESS, the NAC group had slightly lower scores 2 weeks, 1 month, and 3 months after the operation, but this difference was not statistically significant. The NAC group showed significant improvement in VAS scores, namely, postnasal drip (1.0, p = 0.041), smell dysfunction (0.8, p = 0.003), and crust (1.5, p = 0.034), compared to the control group's scores of 2.6, 4.7, and 3.6, respectively, 2 weeks after the operation, although no significant differences were observed in VAS scores for any symptoms 1 and 3 months after the operation. NAC was well tolerated, and no adverse events were reported. NAC irrigation showed benefits over saline irrigation in terms of improving postnasal drip, smell dysfunction, and crust after ESS for CRS without nasal polyposis in the immediate postoperative period.

Association between Liver Function Markers and Menstrual Cycle Irregularity in Korean Female Population.

Background: The liver plays an important role in gonadal steroid hormone metabolism, which can affect reproductive health, including the menstrual cycle. However, evidence from large population-based studies is limited. Therefore, this study aimed to investigate the association between liver function markers and menstrual cycle irregularities in premenopausal Korean women using nationwide data. Methods: This study analyzed Data from the Korea National Health and Nutrition Examination Survey 2010-2011. We investigated 3,045 premenopausal women aged 19-59 years. Liver function markers including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase, and fatty liver index were analyzed. Multivariable logistic regression analysis was performed to investigate the association between liver function markers and menstrual cycle irregularity while adjusting for confounding factors. Values were presented as odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup analysis was also performed. Results: Baseline characteristic analysis showed that approximately 14.4% of the study population experienced menstrual cycle irregularity. The mean age was 34.5±0.7 years. The highest quartile of serum ALT and AST levels showed significantly higher ORs for menstrual cycle irregularity (adjusted OR, 1.83; 95% CI, 1.26-2.64 and adjusted OR, 1.67; 95% CI, 1.17-2.39, respectively). A similar result was observed in the subgroup analysis. Conclusion: Liver function markers were positively associated with menstrual cycle irregularities. In clinical settings, women of reproductive age with relatively decreased liver function should be considered for regular followup of their reproductive health status.

Evaluating 64Cu-DOTA-rituximab as a PET agent in patients with B-cell lymphoma: a head-to-head comparison with 18F-fluorodeoxyglucose PET/computed tomography.

BACKGROUND: This study aimed to evaluate the biodistribution of 64Cu-DOTA-rituximab and its diagnostic feasibility for lymphoma using CD20-targeted 64Cu-DOTA-rituximab PET/computed tomography (PET/CT). METHODS: A prospective study involving six patients diagnosed with lymphoma was conducted between January 2022 and January 2023. These patients underwent 18F-fluorodeoxyglucose (18F-FDG) and 64Cu-DOTA-rituximab PET/CT scans. 64Cu-DOTA-rituximab PET/CT images were acquired at 1, 24, and 48 h after administering 64Cu-DOTA-rituximab to assess the biodistribution and dosimetry over time. The observed lymph nodes were categorized into specific regions, including cervical and supraclavicular, axillary and infraclavicular, mediastinal, hilar, abdominal paraaortic and retroperitoneal, iliac, mesenteric, and inguinal regions, to compare the diagnostic ability of 18F-FDG and 64Cu-DOTA-rituximab PET/CT in detecting lymphoma lesions. Furthermore, the tumor-to-background ratio was calculated and compared with the maximum standardized uptake (SUVmax) of the tumors and the mean standardized uptake (SUVmean) of normal organs. Internal radiation dosimetry was determined using the OLINDA/EXM software. RESULTS: 64Cu-DOTA-rituximab uptake in lymph nodes associated with lymphoma progressively increased from 1 to 48 h after injection. In contrast, 64Cu-DOTA-rituximab uptake in normal organs, such as blood, lung, kidney, bladder, muscle, bone, and brain, decreased over time, whereas it increased in the liver and spleen. When it comes to the comparison between 64Cu-DOTA-rituximab and 18F-FDG, the SUVmax of tumors was higher on 64Cu-DOTA-rituximab PET/CT (18.1 ±â€…8.3) than on 18F-FDG PET/CT (5.2 ±â€…1.5). Additionally, the tumor-to-background ratio, measured using the SUVmean of normal muscles, was higher on 64Cu-DOTA-rituximab PET/CT (55.7 ±â€…31.0) than on 18F-FDG PET/CT (8.6 ±â€…2.8). No adverse events related to 64Cu-DOTA-rituximab injection were reported. CONCLUSION: The results of this study demonstrate the feasibility of using 64Cu-DOTA-rituximab PET/CT to evaluate the CD20 expression. The increased 64Cu-DOTA-rituximab uptake in lymph nodes associated with tumors, higher SUVmax, and tumor-to-muscle ratios observed with 64Cu-DOTA-rituximab PET/CT compared with 18F-FDG PET/CT, highlight the diagnostic potential of this imaging modality.

Unraveling the molecular reason of opposing effects of α-mangostin and norfluoxetine on TREK-2 at the same binding site [[EQUATION]].

TWIK-related K(+) channel (TREK)-2, expressed in sensory neurons, is involved in setting membrane potential, and its modulations contributes to the generation of nociceptive signals. Although acute and chronic pain is a common symptom experienced by patients with various conditions, most existing analgesics exhibit low efficacy and are associated with adverse effects. For this reason, finding the novel modulator of TREK-2 is of significance for the development of new analgesics. Recent studies have shown that α-Mangostin (α-MG) activates TREK-2, facilitating analgesic effects, yet the underlying molecular mechanisms remain elusive. Intriguingly, even though norfluoxetine (NFx) is known to inhibit TREK-2, α-MG is also observed to share the same binding site with NFx, and this implies that TREK-2 might be modulated in a highly complicated manner. Therefore, we examine the mechanism of how TREK-2 is activated by α-MG using computational methods and patch clamp experiments in the present study. Based on these results, we offer an explanation of how α-MG and NFx exhibit opposing effects at the same binding site of TREK-2. These findings will broaden our understanding of TREK-2 modulation, providing clues for designing novel analgesic drugs.

Nucleolar actions in plant development and stress responses.

The nucleolus is conventionally acknowledged for its role in ribosomal RNA (rRNA) synthesis and ribosome biogenesis. Recent research has revealed its multifaceted involvement in plant biology, encompassing regulation of the cell cycle, development, and responses to environmental stresses. This comprehensive review explores the diverse roles of the nucleolus in plant growth and responses to environmental stresses. The introduction delves into its traditional functions in rRNA synthesis and potential participation in nuclear liquid-liquid phase separation. By examining the multifaceted roles of nucleolar proteins in plant development, we highlight the impacts of various nucleolar mutants on growth, development, and embryogenesis. Additionally, we reviewed the involvement of nucleoli in responses to abiotic and biotic stresses. Under abiotic stress conditions, the nucleolar structure undergoes morphological changes. In the context of biotic stress, the nucleolus emerges as a common target for effectors of pathogens for manipulation of host immunity to enhance pathogenicity. The detailed exploration of how pathogens interact with nucleoli and manipulate host responses provides valuable insights into plant stress responses as well as plant growth and development. Understanding these processes may pave the way for promising strategies to enhance crop resilience and mitigate the impact of biotic and abiotic stresses in agricultural systems.

Agrimonia coreana Extract Exerts Its Therapeutic Effect through CRAC Channel Inhibition for Atopic Dermatitis Treatment.

Atopic dermatitis (AD) is a common allergic inflammatory skin condition marked by severe itching, skin lichenification, and chronic inflammation. AD results from a complex immune response, primarily driven by T lymphocytes and environmental triggers, leading to a disrupted epidermal barrier function. Traditional treatments, such as topical corticosteroids, have limitations due to long-term side effects, highlighting the need for safer alternatives. Here, we aimed to show that Agrimonia coreana extract (ACext) can be used in treating AD-related dermatologic symptoms. ACext could inhibit CRAC (Calcium Release-Activated Calcium) channel activity, reducing Orai1/CRAC currents and decreasing intracellular calcium signaling. This inhibition was further confirmed by the reduced IL-2 levels and T cell proliferation upon ACext treatment. In a mouse model of AD, ACext significantly ameliorates symptoms, improves histological parameters, and enhances skin barrier function, demonstrating its potential for treating AD.

Impact of the Korea Early Childhood Home-visiting Intervention (KECHI) on child health and development and maternal health: a randomised controlled trial protocol.

INTRODUCTION: Randomised controlled trials (RCTs) of early childhood home-visiting interventions led by nurses have been conducted mainly in Western countries, whereas such trials have been limited in non-Western cultures, including Asia. In South Korea, a national nurse home visit programme (Korea Early Childhood Home-visiting Intervention (KECHI)) was developed in 2020 and launched throughout the country. We designed a pragmatic RCT to evaluate the effectiveness of KECHI on child health and development and maternal health. METHODS AND ANALYSIS: Eligible participants will be pregnant women at <37 weeks of gestation with risk factor scores of 2 or over, who are sufficiently fluent in Korean to read and answer the questionnaire written in Korean and live in districts where the KECHI services are available. Eight hundred participants will be recruited from the general community and through the District Public Health Centres. The participants will be randomised 1:1 to KECHI plus usual care or usual care. KECHI encompasses 25-29 home visits, group activities and community service linkage. Participants will complete assessments at baseline (<37 weeks gestation), 6 weeks, 6 months, 12 months, 18 months and 24 months post partum. The six primary outcomes will be (1) home environment (assessed by Infant/Toddler Home Observation for Measurement of the Environment), (2) emergency department visits due to injuries, (3) child development (assessed using Korean Bayley Scales of Infant and Toddler Development-III), (4) breastfeeding duration, (5) maternal self-rated health and (6) community service linkage. ETHICS AND DISSEMINATION: This trial has received full ethical approval from the Institutional Review Board of the Seoul National University Hospital. Written consent will be obtained from the participants. The results will be reported at conferences, disseminated through peer-reviewed publications and used by the Korean government to expand the KECHI services. TRIAL REGISTRATION NUMBER: NCT04749888.

A novel indole derivative, 2-{3-[1-(benzylsulfonyl)piperidin-4-yl]-2-methyl-1H-indol-1-yl}-1-(pyrrolidin-1-yl)ethenone, suppresses hedgehog signaling and drug-resistant tumor growth.

The Hedgehog (Hh) signaling pathway plays important roles in various physiological functions. Several malignancies, such as basal cell carcinoma (BCC) and medulloblastoma (MB), have been linked to the aberrant activation of Hh signaling. Although therapeutic drugs have been developed to inhibit Hh pathway-dependent cancer growth, drug resistance remains a major obstacle in cancer treatment. Here, we show that the newly identified, 2-{3-[1-(benzylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-2-methyl-1H-indol-1-yl}-1-(pyrrolidin-1-yl)ethenone analog (LKD1214) exhibits comparable potency to vismodegib in suppressing the Hh pathway activation. LKD1214 represses Smoothened (SMO) activity by blocking its ciliary translocation. Interestingly, we also identified that it has a distinctive binding interface with SMO compared with other SMO-regulating chemicals. Notably, it maintains an inhibitory activity against the SmoD477H mutant, as observed in a patient with vismodegib-resistant BCC. Furthermore, LKD1214 inhibits tumor growth in the mouse model of MB. Collectively, these findings suggest that LKD1214 has the therapeutic potential to overcome drug-resistance in Hh-dependent cancers.

Bioceramic-mediated chondrocyte hypertrophy promotes calcified cartilage formation for rabbit osteochondral defect repair.

Osteochondral tissue is a highly specialized and complex tissue composed of articular cartilage and subchondral bone that are separated by a calcified cartilage interface. Multilayered or gradient scaffolds, often in conjunction with stem cells and growth factors, have been developed to mimic the respective layers for osteochondral defect repair. In this study, we designed a hyaline cartilage-hypertrophic cartilage bilayer graft (RGD/RGDW) with chondrocytes. Previously, we demonstrated that RGD peptide-modified chondroitin sulfate cryogel (RGD group) is chondro-conductive and capable of hyaline cartilage formation. Here, we incorporated whitlockite (WH), a Mg2+-containing calcium phosphate, into RGD cryogel (RGDW group) to induce chondrocyte hypertrophy and form collagen X-rich hypertrophic cartilage. This is the first study to use WH to produce hypertrophic cartilage. Chondrocytes-laden RGDW cryogel exhibited significantly upregulated expression of hypertrophy markers in vitro and formed ectopic hypertrophic cartilage in vivo, which mineralized into calcified cartilage in bone microenvironment. Subsequently, RGD cryogel and RGDW cryogel were combined into bilayer (RGD/RGDW group) and implanted into rabbit osteochondral defect, where RGD layer supports hyaline cartilage regeneration and bioceramic-containing RGDW layer promotes calcified cartilage formation. While the RGD group (monolayer) formed hyaline-like neotissue that extends into the subchondral bone, the RGD/RGDW group (bilayer) regenerated hyaline cartilage tissue confined to its respective layer and promoted osseointegration for integrative defect repair.

Lactitol Alleviates Loperamide-Induced Constipation in Sprague Dawley Rats by Regulating Serotonin, Short-Chain Fatty Acids, and Gut Microbiota.

The objective of this study was to examine the impact of lactitol on constipation caused by loperamide in Sprague Dawley rats, with a particular emphasis on its underlying mechanisms and potential health advantages. The lactitol effectively improved fecal parameters, intestinal tissue structure, and the expression of constipation-related gene expression and proteins. Lactitol alleviated fecal weight and water content altered by loperamide and enhanced gastrointestinal transit. The administration also restored mucosal and muscular layer thickness. Mechanistically, lactitol upregulated the mRNA expression and/or protein levels of mucins (MUC2 and MUC4), occludin, claudin-1, and zonula occludens, indicating improved intestinal barrier function. Lactitol positively regulated the composition of cecal microbiota, leading to an increased relative abundance of Bifidobacterium, Lactobacillus, and Romboutsia. Conversely, lactitol decreased the relative abundance of Prevotella, Aerococcus, Muribaculum, Blautia, and Ruminococcus. This study demonstrated the potential of lactitol to relieve constipation by modulating the gut microbiota. These findings suggest that lactitol is an alternative to traditional laxatives and has potential as a health-promoting food sweetener.

Bioreactor development for skeletal muscle hypertrophy and atrophy by manipulating uniaxial cyclic strain: proof of concept.

Skeletal muscles overcome terrestrial, gravitational loading by producing tensile forces that produce movement through joint rotation. Conversely, the microgravity of spaceflight reduces tensile loads in working skeletal muscles, causing an adaptive muscle atrophy. Unfortunately, the design of stable, physiological bioreactors to model skeletal muscle tensile loading during spaceflight experiments remains challenging. Here, we tested a bioreactor that uses initiation and cessation of cyclic, tensile strain to induce hypertrophy and atrophy, respectively, in murine lineage (C2C12) skeletal muscle myotubes. Uniaxial cyclic stretch of myotubes was conducted using a StrexCell® (STB-1400) stepper motor system (0.75 Hz, 12% strain, 60 min day^-1). Myotube groups were assigned as follows: (a) quiescent over 2- or (b) 5-day (no stretch), (c) experienced 2-days (2dHY) or (d) 5-days (5dHY) of cyclic stretch, or (e) 2-days of cyclic stretch followed by a 3-day cessation of stretch (3dAT). Using ß-sarcoglycan as a sarcolemmal marker, mean myotube diameter increased significantly following 2dAT (51%) and 5dAT (94%) vs. matched controls. The hypertrophic, anabolic markers talin and Akt phosphorylation (Thr308) were elevated with 2dHY but not in 3dAT myotubes. Inflammatory, catabolic markers IL-1ß, IL6, and NF-kappaB p65 subunit were significantly higher in the 3dAT group vs. all other groups. The ratio of phosphorylated FoxO3a/total FoxO3a was significantly lower in 3dAT than in the 2dHY group, consistent with elevated catabolic signaling during unloading. In summary, we demonstrated proof-of-concept for a spaceflight research bioreactor, using uniaxial cyclic stretch to produce myotube hypertrophy with increased tensile loading, and myotube atrophy with subsequent cessation of stretch.

Synthesis and evaluation of antibody-drug conjugates with high drug-to-antibody ratio using dimaleimide-DM1 as a linker- payload.

The notable characteristics of recently emerged Antibody-Drug Conjugates (ADCs) encompass the targeting of Human Epidermal growth factor Receptor 2 (HER2) through monoclonal antibodies (mAbs) and a high ratio of drug to antibody (DAR). The achievements of Kadcyla® (T-DM1) and Enhertu® (T-Dxd) have demonstrated that HER2-targeting antibodies, such as trastuzumab, have shown to be competitive in terms of efficacy and price for development. Furthermore, with the arrival of T-Dxd and Trodelvy®, high-DAR (7-8) ADCs, which differ from the moderate DAR (3-4) ADCs that were formerly regarded as conventional, are being acknowledged for their worth. Following this trend of drug development, we endeavored to develop a high-DAR ADC using a straightforward approach involving the utilization of DM1, a highly potent substance, in combination with the widely recognized trastuzumab. To achieve a high DAR, DM1 was conjugated to reduced cysteine through the simple design and synthesis of various dimaleimide linkers with differing lengths. Using LC and MS analysis, we have demonstrated that our synthesis methodology is uncomplicated and efficacious, yielding trastuzumab-based ADCs that exhibit a remarkable degree of uniformity. These ADCs have been experimentally substantiated to exert an inhibitory effect on cancer cells in vitro, thus affirming their value as noteworthy additions to the realm of ADCs.