Revisiting the hormonal control of sexual dimorphism in chicken feathers.

Sexual dimorphism in plumage is widespread among avian species. In chickens, adult females exhibit countershading, characterized by dull-colored round feathers lacking fringe on the saddle, while adult males display vibrant plumage with deeply fringed bright feathers. This dimorphism is estrogen-dependent, and administering estrogen to males transforms their showy plumage into cryptic female-like plumage. Extensive studies have shown that estrogen's role in female plumage formation requires thyroid hormone; however, the precise mechanisms of their interaction remain unclear. In this study, we investigated the roles of estrogen and thyroid hormone in creating sexual dimorphism in the structure and coloration of saddle feathers by administering each hormone to adult males and observing the resulting changes in regenerated feathers induced by plucking. RT-PCR analysis revealed that the expression of type 3 deiodinase (DIO3), responsible for thyroid hormone inactivation, correlates with fringing. Estrogen suppressed DIO3 and agouti signaling protein (ASIP) expression while stimulating BlSK1, a marker of barbule cells, resulting in female-like feathers with mottled patterns and lacking fringes. Administration of thyroxine (T4) stimulated BlSK1 and proopiomelanocortin (POMC) expression, with no effect on ASIP, leading to the formation of solid black feathers lacking fringes. Triiodothyronine (T3) significantly increased POMC expression in pulp cells in culture. Taken together, these findings suggest that estrogen promotes the formation of solid vanes by suppressing DIO3 expression, while also inducing the formation of mottled patterns through inhibition of ASIP expression and indirect stimulation of melanocortin expression via changes in local T3 concentration. This is the first report describing molecular mechanism underlying hormonal crosstalk in creating sexual dimorphism in feathers.

Adherence, Persistence, Healthcare Resource Use, and Costs in Tofacitinib-Treated Patients with Psoriatic Arthritis: Data from Two United States Claims Databases.

INTRODUCTION: Associations between increased functional disability and higher healthcare resource utilization (HCRU) and costs were reported in patients with psoriatic arthritis (PsA). We assessed characteristics/outcomes of patients with PsA receiving tofacitinib monotherapy vs combination therapy with conventional synthetic disease-modifying antirheumatic drugs. METHODS: Claims data from Optum® Clinformatics® Data Mart (OC) and Merative™ MarketScan® (MS) databases between December 2017 and February 2020 were analyzed. Outcomes assessed were adherence/persistence by therapy type (monotherapy/combination therapy); HCRU/costs (per patient per month) by periods on-treatment (sum time on tofacitinib) and off-treatment (sum time off tofacitinib [gap of > 60 days]) plus therapy type. RESULTS: This analysis included 274 and 395 tofacitinib-treated patients in OC (70.4% female, mean age 54.4 years) and MS (68.9% female, mean age 51.4 years), respectively. Percentages of patients with a proportion of days covered ≥ 0.8 at 12 months for monotherapy vs combination therapy were OC, 44.5% vs 53.8%; MS, 36.4% vs 45.7%. Generally similar trends were seen over 24 months and for medication possession ratio ≥ 0.8. Median (95% confidence interval) times to treatment discontinuation for monotherapy vs combination therapy were OC, 10.1 (7.4-11.8) vs 16.7 (8.3-26.6) months; MS, 6.9 (5.6-9.4) vs 11.0 (6.1-13.9) months. During off-treatment vs on-treatment periods, numerical decreases were observed for all-cause (OC, $5383 vs $6149; MS, $4145 vs $5180) and PsA-related costs (OC, $3237 vs $4515; MS, $2703 vs $3907) regardless of therapy type. During off-treatment vs on-treatment periods, numerical increases in outpatient visits for all-cause (OC, 2.37 vs 2.05; MS, 2.15 vs 1.99) and PsA-related visits (OC, 0.60 vs 0.46; MS, 0.47 vs 0.44) were observed, and PsA-related medications numerically decreased (OC, 1.21 vs 1.53; MS, 1.05 vs 1.48). CONCLUSION: In this USA-based claims analysis, tofacitinib adherence was numerically lower for patients with PsA receiving monotherapy vs combination therapy. Costs numerically decreased off-treatment vs on-treatment, irrespective of therapy type, driven by lower medication costs.

Risk factors associated with intraoperative persistent hypotension in pancreaticoduodenectomy.

BACKGROUND: Intraoperative persistent hypotension (IPH) during pancreaticoduodenectomy (PD) is linked to adverse postoperative outcomes, yet its risk factors remain unclear. AIM: To clarify the risk factors associated with IPH during PD, ensuring patient safety in the perioperative period. METHODS: A retrospective analysis of patient records from January 2018 to December 2022 at the First Affiliated Hospital of Nanjing Medical University identified factors associated with IPH in PD. These factors included age, gender, body mass index, American Society of Anesthesiologists classification, comorbidities, medication history, operation duration, fluid balance, blood loss, urine output, and blood gas parameters. IPH was defined as sustained mean arterial pressure < 65 mmHg, requiring prolonged deoxyepinephrine infusion for > 30 min despite additional deoxyepinephrine and fluid treatments. RESULTS: Among 1596 PD patients, 661 (41.42%) experienced IPH. Multivariate logistic regression identified key risk factors: increased age [odds ratio (OR): 1.20 per decade, 95% confidence interval (CI): 1.08-1.33] (P < 0.001), longer surgery duration (OR: 1.15 per additional hour, 95%CI: 1.05-1.26) (P < 0.01), and greater blood loss (OR: 1.18 per 250-mL increment, 95%CI: 1.06-1.32) (P < 0.01). A novel finding was the association of arterial blood Ca2+ < 1.05 mmol/L with IPH (OR: 2.03, 95%CI: 1.65-2.50) (P < 0.001). CONCLUSION: IPH during PD is independently associated with older age, prolonged surgery, increased blood loss, and lower plasma Ca2+.

Twin-Field Quantum Key Distribution with Local Frequency Reference.

Twin-field quantum key distribution (TFQKD) overcomes the linear rate-loss limit, which promises a boost of secure key rate over long distance. However, the complexity of eliminating the frequency differences between the independent laser sources hinders its practical application. We analyzed and determined the frequency stability requirements for implementing TFQKD using frequency-stabilized lasers. Based on this analysis, we proposed and demonstrated a simple and practical approach that utilizes the saturated absorption spectroscopy of acetylene as an absolute reference, eliminating the need for fast frequency locking to achieve TFQKD. Adopting the 4-intensity sending-or-not-sending TFQKD protocol, we experimentally demonstrated the TFQKD over 502, 301, and 201 km ultralow-loss optical fiber, respectively. We expect this high-performance scheme will find widespread usage in future intercity and free-space quantum communication networks.

Plasma Deoxycholic Acid Levels are Associated with Hemodynamic and Clinical Outcomes in Acute Pulmonary Embolism Patients.

This study aimed to evaluate the correlation of plasma deoxycholic acid (DCA) levels with clinical and hemodynamic parameters in acute pulmonary embolism (APE) patients. Total 149 APE adult patients were prospectively recruited. Plasma DCA levels were measured using rapid resolution liquid chromatography-quadrupole time-of-flight mass spectrometry. Baseline clinical and hemodynamic parameters were evaluated according to plasma DCA levels. The plasma DCA levels were significantly lower in APE patients than in those without APE (P < 0.001). APE patients with adverse events had lower plasma DCA levels (P < 0.001). Low DCA group patients presented more adverse cardiac function, higher NT-proBNP levels (P = 0.010), and higher WHO functional class levels (P = 0.023). Low DCA group also presented with an adverse hemodynamic status, with higher pulmonary vascular resistance levels (P = 0.027) and lower cardiac index levels (P = 0.024). Both cardiac function and hemodynamic parameters correlated well with plasma DCA levels. Kaplan-Meier survival analysis demonstrated that APE patients with lower plasma DCA levels had a significantly higher event rate (P = 0.009). In the univariate and multivariate Cox regression analyses, the plasma DCA level was an independent predictor of clinical worsening events after adjusting for age, sex, WHO functional class, NT-proBNP level, pulmonary vascular resistance, and cardiac index (HR 0.370, 95% CI 0.161, 0.852; P = 0.019). Low plasma DCA levels predicted adverse cardiac function and hemodynamic collapse. A low DCA level was correlated with a higher clinical worsening event rate and could be an independent predictor of clinical outcomes in multivariate analysis.

Mechanism of action of the Banxia-Xiakucao herb pair in sleep deprivation: New comprehensive evidence from network pharmacology, transcriptomics and molecular biology experiments.

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herb pairs are the most basic and compressed examples of Chinese herbal combinations and can be used to effectively explain the fundamental concepts of traditional Chinese medicine prescriptions. These pairings have gained significant interest due to their subtle therapeutic benefits, minimal side effects, and efficacy in treating complicated chronic conditions. The Banxia-Xiakucao Chinese herb pair (BXHP) consists of Pinellia ternata (Thunb.) Breit. (Banxia) and Prunella vulgaris L. (Xiakucao). This formula was documented in The Medical Classic of the Yellow Emperor approximately 2000 years ago，and clinical research has demonstrated that BXHP effectively treats insomnia. AIM OF THE STUDY: This study aimed to evaluate the efficacy and therapeutic mechanism of the BXHP through a comprehensive strategy involving network pharmacology, molecular docking, transcriptomics, and molecular biology experimental validation. MATERIALS AND METHODS: The composition of BXHP was characterized using the UPLC-Q-TOF-MS. The active compounds were screened to find drug-likeness compounds by analyzing the ADME data. To predict the molecular mechanism of BXHP in sleep deprivation (SD) by network pharmacology and molecular docking. We established a rat model of SD and the in vivo efficacy of BXHP was verified through the pentobarbital sodium righting reflex test, behavioral assays, enzyme-linked immunosorbent assay, transmission electron microscopy, HE staining, and Nissl staining, and the underlying molecular mechanism of BXHP in SD was revealed through transcriptomic and bioinformatic analyses in conjunction with quantitative real-time PCR, Western blot, and immunofluorescence staining. RESULTS: In the present study, we showed for the first time that BXHP reduced sleep latency, prolongs sleep duration, and improves anxiety; lowered serum CORT, IL6, TNF-α and MDA levels; decreased hypothalamic Glu levels; and elevated hypothalamic GABA and 5-HT levels in SD rats. We found 16 active compounds that acted on 583 targets, 145 of which are related to SD. By modularly dissecting the PPI network, we discovered three critical targets, Akt1, CREB1, and PRKACA, all of which play important roles in the effects of BXHP on SD. Molecular docking resulted in the identification of 16 active compounds that strongly bind to key targets. The results of GO and KEGG enrichment analyses of network pharmacology and transcriptomics focused on both the regulation of circadian rhythm and the cAMP signaling pathway, which strongly demonstrated that BXHP affects SD via the cAMP-PKA-CREB-Circadian rhythm pathway. Molecular biology experiments verified this hypothesis. Following BXHP administration, PKA and CREB phosphorylation levels were elevated in SD rats, the cAMP-PKA-CREB signaling pathway was activated, the expression levels of the biological clock genes CLOCK, p-BMAL1/BMAL1, and PER3 were increased, and the rhythmicity of the biological clock was improved. CONCLUSIONS: The active compounds in BXHP can activate the cAMP-PKA-CREB-Circadian rhythm pathway, improve the rhythmicity of the biological clock, promote sleep and ameliorate anxiety, which suggests that BXHP improves SD through a multicomponent, multitarget, multipathway mechanism. This study is important for the development of herbal medicines and clinical therapies for improving sleep deprivation.

Real-world use and outcomes of targeted therapy and immunotherapy for adjuvant treatment of BRAF -mutated melanoma patients in the United States.

Using a customized, harmonized US electronic health record database, real-world prescription patterns of first-line adjuvant immunotherapy and targeted therapy were retrospectively assessed for BRAF V600-mutated melanoma. Adults with BRAF V600 mutation-positive stage IIIA-D cutaneous melanoma who received first-line adjuvant immunotherapy (nivolumab or pembrolizumab) or targeted therapy (dabrafenib plus trametinib) between 1 January 2014 and 30 August 2020 in the NOBLE database were included. Patients were followed from first-line adjuvant therapy initiation for at least 6 months, until death, progression, follow-up loss, or data cutoff. Primary endpoints were proportion of patients receiving either therapy in first-line and second-line, treatment switching, treatment timing, and status at the end of first-line therapy. Secondary endpoints included discontinuation rates, recurrence-free survival (RFS), and overall survival (OS). Of 318 patients evaluated, 67.6% received nivolumab, 14.2% pembrolizumab, and 18.2% targeted therapy as first-line adjuvant therapy. Median treatment duration was longest for nivolumab (292 days) and shortest for targeted therapy (115 days). Reason for discontinuation was recorded for 195 of 274 patients who discontinued first-line therapy; most common reasons were treatment completion and treatment-related toxicity [87/158 (55.0%) and 29/158 (18.4%), respectively, in immunotherapy-treated patients; 9/37 (24.3%) and 21/37 (56.8%) in targeted therapy-treated patients]. Median RFS and OS for targeted therapy and nivolumab were not reached and were 34.6 and 38.1 months, respectively, for pembrolizumab. These results inform on prescription preferences and clinical outcomes for BRAF V600-mutated melanoma patients in the first-line adjuvant setting.

Clinical and genetic characteristics of patients with TRG 0 and TRG III in esophageal squamous cell carcinoma after neoadjuvant therapy.

Neoadjuvant therapy (NAT) is an important treatment for patients with resectable locally advanced esophageal squamous cell carcinoma (ESCC), but neoadjuvant resistance affects the overall treatment outcome. Therefore, it is particularly important to accurately screen the population for NAT and explore the mechanism of resistance. Usually, different chemotherapy regimens cause different drug resistance mechanisms. Prior to combining immunotherapy with chemotherapy, extensive research has been conducted on previous drug resistance mechanisms. Currently, the mainstream NAT for ESCC involves chemotherapy combined with immunotherapy. We have witnessed the remarkable effect of this combination therapy; however, there are still a considerable number of patients whose tumor tissues show no change or even progress after NAT, and their drug resistance mechanisms remain unclear. Hence, we aim to identify relevant evidence that can distinguish and predict the effectiveness of NAT from a clinical perspective in order to provide a clinical basis for future screening of suitable populations for NAT and discovery of drug resistance mechanisms. This study is based in China's high incidence area of esophageal cancer, where enrolled patients all receive the current mainstream NAT regimen resulting in more reliable outcomes.

Accumulation and Quantitative Assessment of Terrigenous Organic Matter in Upper Oligocene to Lower Miocene Marine Source Rocks of the Qiongdongnan Basin.

The intense collision between marine and terrestrial agents results in the dual-source (marine and terrigenous) characteristics of marine source rocks. Our research quantitatively assessed terrestrial organic matter and revealed the crucial role of terrestrial organic materials in the organic matter enrichment of lower Miocene to upper Oligocene marine source rocks in the Qiongdognnan Basin. The quantitative assessment was achieved using partial least-squares analysis with eight biomarker parameters associated with n-alkanes, isoprenoids, bicadinanes, taraxerane, tricyclic terpanes, and gammacerane. Differential unloading of terrestrial organic materials based on sedimentary facies of the delta-marginal sea system were observed through oleanane and bicadinane contents. It should be noted that the diagnostic ratio of oleanane was excluded from the quantitative analysis due to the dual influence from differential unloading and contact with seawater of the terrestrial organic materials. Calculation results show that the terrestrial organic matter was highest in the delta front at 70%, followed by prodelta at 59% and inner shallow marine at 57%. From the late Oligocene to the early Miocene, the proportion of terrestrial organic matter in marine source rocks continuously increased, with the highest average value observed in the second member of the Sanya Formation at 69% and the lowest occurring in the third member of the Lingshui Formation at 46%. Increasing terrestrial organic material inputs and preservation driven by the East Asian summer monsoon provided first-order control of the accumulation of organic carbon in the Qiongdongnan Basin during late Oligocene to early Miocene, rather than the bioproductivity of marine algae. The redox conditions of the water column determine the enrichment extent of organic matter.

Free-space coupled, large-active-area superconducting microstrip single-photon detector for photon-counting time-of-flight imaging.

Numerous applications at the photon-starved regime require a free-space coupling single-photon detector with a large active area, low dark count rate (DCR), and superior time resolutions. Here, we developed a superconducting microstrip single-photon detector (SMSPD), with a large active area of 260 µm in diameter, a DCR of ∼5k c p s, and a low time jitter of ∼171p s, operated at a near-infrared of 1550 nm and a temperature of ∼2.0K. As a demonstration, we applied the detector to a single-pixel galvanometer scanning system and successfully reconstructed the object information in depth and intensity using a time-correlated photon counting technology.

The role of cellular senescence in neurodegenerative diseases.

Increasing evidence has revealed that cellular senescence drives NDs, including Alzheimer's disease (AD) and Parkinson's disease. Different senescent cell populations secrete senescence-associated secretory phenotypes (SASP), including matrix metalloproteinase-3, interleukin (IL)-1α, IL-6, and IL-8, which can harm adjacent microglia. Moreover, these cells possess high expression levels of senescence hallmarks (p16 and p21) and elevated senescence-associated ß-galactosidase activity in in vitro and in vivo ND models. These senescence phenotypes contribute to the deposition of ß-amyloid and tau-protein tangles. Selective clearance of senescent cells and SASP regulation by inhibiting p38/mitogen-activated protein kinase and nuclear factor kappa B signaling attenuate ß-amyloid load and prevent tau-protein tangle deposition, thereby improving cognitive performance in AD mouse models. In addition, telomere shortening, a cellular senescence biomarker, is associated with increased ND risks. Telomere dysfunction causes cellular senescence, stimulating IL-6, tumor necrosis factor-α, and IL-1ß secretions. The forced expression of telomerase activators prevents cellular senescence, yielding considerable neuroprotective effects. This review elucidates the mechanism of cellular senescence in ND pathogenesis, suggesting strategies to eliminate or restore senescent cells to a normal phenotype for treating such diseases.

New strategies to study in depth the metabolic mechanism of astaxanthin biosynthesis in Phaffia rhodozyma.

Astaxanthin, a ketone carotenoid known for its high antioxidant activity, holds significant potential for application in nutraceuticals, aquaculture, and cosmetics. The increasing market demand necessitates a higher production of astaxanthin using Phaffia rhodozyma. Despite extensive research efforts focused on optimizing fermentation conditions, employing mutagenesis treatments, and utilizing genetic engineering technologies to enhance astaxanthin yield in P. rhodozyma, progress in this area remains limited. This review provides a comprehensive summary of the current understanding of rough metabolic pathways, regulatory mechanisms, and preliminary strategies for enhancing astaxanthin yield. However, further investigation is required to fully comprehend the intricate and essential metabolic regulation mechanism underlying astaxanthin synthesis. Specifically, the specific functions of key genes, such as crtYB, crtS, and crtI, need to be explored in detail. Additionally, a thorough understanding of the action mechanism of bifunctional enzymes and alternative splicing products is imperative. Lastly, the regulation of metabolic flux must be thoroughly investigated to reveal the complete pathway of astaxanthin synthesis. To obtain an in-depth mechanism and improve the yield of astaxanthin, this review proposes some frontier methods, including: omics, genome editing, protein structure-activity analysis, and synthetic biology. Moreover, it further elucidates the feasibility of new strategies using these advanced methods in various effectively combined ways to resolve these problems mentioned above. This review provides theory and method for studying the metabolic pathway of astaxanthin in P. rhodozyma and the industrial improvement of astaxanthin, and provides new insights into the flexible combined use of multiple modern advanced biotechnologies.

Quantifying the mutual effects of water trading and systematic water saving in a water-scarce watershed of China.

In this study, a conjunctive water management model based on interval stochastic bi-level programming method (CM-ISBP) is proposed for planning water trading program as well as quantifying mutual effects of water trading and systematic water saving. CM-ISBP incorporates water resources assessment with soil and water assessment tool (SWAT), systematic water-saving simulation combined with water trading, and interval stochastic bi-level programming (ISBP) within a general framework. Systematic water saving involves irrigation water-saving technologies (sprinkler irrigation, micro-irrigation, low-pressure pipe irrigation), enterprise water-saving potential and water-saving subsidy. The CM-ISBP is applied to a real case of a water-scarce watershed (i.e. Dagu River watershed, China). Mutual effects of water trading and water-saving activities are simulated with model establishment and quantified through mechanism analysis. The fate of saved water under the systematic water saving is also revealed. The coexistence of the two systems would increase system benefits by [11.89, 12.19]%, and increase the water use efficiency by [40.04, 40.46]%. Thus mechanism that couples water trading and water saving is optimal and recommended according to system performance.

Experimental Generation of Spin-Photon Entanglement in Silicon Carbide.

A solid-state approach for quantum networks is advantageous, as it allows the integration of nanophotonics to enhance the photon emission and the utilization of weakly coupled nuclear spins for long-lived storage. Silicon carbide, specifically point defects within it, shows great promise in this regard due to the easy of availability and well-established nanofabrication techniques. Despite of remarkable progresses made, achieving spin-photon entanglement remains a crucial aspect to be realized. In this Letter, we experimentally generate entanglement between a silicon vacancy defect in silicon carbide and a scattered single photon in the zero-phonon line. The spin state is measured by detecting photons scattered in the phonon sideband. The photonic qubit is encoded in the time-bin degree of freedom and measured using an unbalanced Mach-Zehnder interferometer. Photonic correlations not only reveal the quality of the entanglement but also verify the deterministic nature of the entanglement creation process. By harnessing two pairs of such spin-photon entanglement, it becomes straightforward to entangle remote quantum nodes at long distance.

Single-Shot Readout of a Nuclear Spin in Silicon Carbide.

Solid-state qubits with a photonic interface is very promising for quantum networks. Color centers in silicon carbide have shown excellent optical and spin coherence, even when integrated with membranes and nanostructures. Additionally, nuclear spins coupled with electron spins can serve as long-lived quantum memories. Pioneering work previously has realized the initialization of a single nuclear spin and demonstrated its entanglement with an electron spin. In this Letter, we report the first realization of single-shot readout for a nuclear spin in SiC. We obtain a deterministic nuclear spin initialization and readout fidelity of 94.95% with a measurement duration of 1 ms. With a dual-step readout scheme, we obtain a readout fidelity as high as 99.03% within 0.28 ms by sacrificing the success efficiency. Our Letter complements the experimental toolbox of harnessing both electron and nuclear spins in SiC for future quantum networks.

Quantum Light Generation Based on GaN Microring toward Fully On-Chip Source.

An integrated quantum light source is increasingly desirable in large-scale quantum information processing. Despite recent remarkable advances, a new material platform is constantly being explored for the fully on-chip integration of quantum light generation, active and passive manipulation, and detection. Here, for the first time, we demonstrate a gallium nitride (GaN) microring based quantum light generation in the telecom C-band, which has potential toward the monolithic integration of quantum light source. In our demonstration, the GaN microring has a free spectral range of 330 GHz and a near-zero anomalous dispersion region of over 100 nm. The generation of energy-time entangled photon pair is demonstrated with a typical raw two-photon interference visibility of 95.5±6.5%, which is further configured to generate a heralded single photon with a typical heralded second-order autocorrelation g_{H}^{(2)}(0) of 0.045±0.001. Our results pave the way for developing a chip-scale quantum photonic circuit.

Gut-Derived Trimethylamine N-Oxide Promotes CCR2-Mediated Macrophage Infiltration in acute kidney injury.

BACKGROUND: Inflammation is crucial in the development of AKI and subsequent CKD following renal ischemia-reperfusion (IR) injury. Gut microbiota metabolites trigger inflammation and affect IR-induced renal damage. Yet, the driving factors and mechanisms are unclear. Trimethylamine N-oxide (TMAO), a gut-derived choline metabolite, is a strong pro-inflammatory factor that increases in patients with AKI and CKD. We hypothesized that TMAO can promote renal injury caused by IR. METHODS: Mice subjected to unilateral renal IR to induce AKI and CKD were fed a high-choline diet to observe the effects of TMAO on kidney inflammation, fibrosis, and macrophage dynamics. RESULTS: A choline-rich diet altered the gut microbiota and elevated TMAO levels, which exacerbated IR-induced AKI and subsequent CKD. Single-cell analysis identified a distinct subset of CCR2+ macrophages derived from monocytes as key responders to TMAO, intensifying immune cell interactions and worsening renal injury. TMAO promoted sustained CCR2 expression after IR, increasing macrophage infiltration. CCR2 deletion and antagonist RS-102895 improved TMAO-induced inflammation and fibrosis, alleviated renal injury induced by IR. CONCLUSIONS: Our study provides valuable insights into the link between TMAO and IR-incited renal inflammation and fibrosis, emphasizing the critical role of TMAO-mediated macrophage infiltration via CCR2 as a key therapeutic target in the acute and chronic phase after IR.

Matrix mechanics regulates muscle regeneration by modulating kinesin-1 activity.

Sarcopenia, a prevalent muscle disease characterized by muscle mass and strength reduction, is associated with impaired skeletal muscle regeneration. However, the influence of the biomechanical properties of sarcopenic skeletal muscle on the efficiency of the myogenic program remains unclear. Herein, we established a mouse model of sarcopenia and observed a reduction in stiffness within the sarcopenic skeletal muscle in vivo. To investigate whether the biomechanical properties of skeletal muscle directly impact the myogenic program, we established an in vitro system to explore the intrinsic mechanism involving matrix stiffness control of myogenic differentiation. Our findings identify the microtubule motor protein, kinesin-1, as a mechano-transduction hub that senses and responds to matrix stiffness, crucial for myogenic differentiation and muscle regeneration. Specifically, kinesin-1 activity is positively regulated by stiff matrices, facilitating its role in transporting mitochondria and enhancing translocation of the glucose transporter GLUT4 to the cell surface for glucose uptake. Conversely, the softer matrices significantly suppress kinesin-1 activity, leading to the accumulation of mitochondria around nuclei and hindering glucose uptake by inhibiting GLUT4 membrane translocation, consequently impairing myogenic differentiation. The insights gained from the in-vitro system highlight the mechano-transduction significance of kinesin-1 motor proteins in myogenic differentiation. Furthermore, our study confirms that enhancing kinesin-1 activity in the sarcopenic mouse model restores satellite cell expansion, myogenic differentiation, and muscle regeneration. Taken together, our findings provide a potential target for improving muscle regeneration in sarcopenia.

Dual RNA sequencing of Helicobacter pylori and host cell transcriptomes reveals ontologically distinct host-pathogen interaction.

Helicobacter pylori is a highly successful pathogen that poses a substantial threat to human health. However, the dynamic interaction between H. pylori and the human gastric epithelium has not been fully investigated. In this study, using dual RNA sequencing technology, we characterized a cytotoxin-associated gene A (cagA)-modulated bacterial adaption strategy by enhancing the expression of ATP-binding cassette transporter-related genes, metQ and HP_0888, upon coculturing with human gastric epithelial cells. We observed a general repression of electron transport-associated genes by cagA, leading to the activation of oxidative phosphorylation. Temporal profiling of host mRNA signatures revealed the downregulation of multiple splicing regulators due to bacterial infection, resulting in aberrant pre-mRNA splicing of functional genes involved in the cell cycle process in response to H. pylori infection. Moreover, we demonstrated a protective effect of gastric H. pylori colonization against chronic dextran sulfate sodium (DSS)-induced colitis. Mechanistically, we identified a cluster of propionic and butyric acid-producing bacteria, Muribaculaceae, selectively enriched in the colons of H. pylori-pre-colonized mice, which may contribute to the restoration of intestinal barrier function damaged by DSS treatment. Collectively, this study presents the first dual-transcriptome analysis of H. pylori during its dynamic interaction with gastric epithelial cells and provides new insights into strategies through which H. pylori promotes infection and pathogenesis in the human gastric epithelium. IMPORTANCE: Simultaneous profiling of the dynamic interaction between Helicobacter pylori and the human gastric epithelium represents a novel strategy for identifying regulatory responses that drive pathogenesis. This study presents the first dual-transcriptome analysis of H. pylori when cocultured with gastric epithelial cells, revealing a bacterial adaptation strategy and a general repression of electron transportation-associated genes, both of which were modulated by cytotoxin-associated gene A (cagA). Temporal profiling of host mRNA signatures dissected the aberrant pre-mRNA splicing of functional genes involved in the cell cycle process in response to H. pylori infection. We demonstrated a protective effect of gastric H. pylori colonization against chronic DSS-induced colitis through both in vitro and in vivo experiments. These findings significantly enhance our understanding of how H. pylori promotes infection and pathogenesis in the human gastric epithelium and provide evidence to identify targets for antimicrobial therapies.