High-resolution in vivo 4D-OCT fish-eye imaging using 3D-UNet with multi-level residue decoder.

Optical coherence tomography (OCT) allows high-resolution volumetric imaging of biological tissues in vivo. However, 3D-image acquisition often suffers from motion artifacts due to slow frame rates and involuntary and physiological movements of living tissue. To solve these issues, we implement a real-time 4D-OCT system capable of reconstructing near-distortion-free volumetric images based on a deep learning-based reconstruction algorithm. The system initially collects undersampled volumetric images at a high speed and then upsamples the images in real-time by a convolutional neural network (CNN) that generates high-frequency features using a deep learning algorithm. We compare and analyze both dual-2D- and 3D-UNet-based networks for the OCT 3D high-resolution image reconstruction. We refine the network architecture by incorporating multi-level information to accelerate convergence and improve accuracy. The network is optimized by utilizing the 16-bit floating-point precision for network parameters to conserve GPU memory and enhance efficiency. The result shows that the refined and optimized 3D-network is capable of retrieving the tissue structure more precisely and enable real-time 4D-OCT imaging at a rate greater than 10 Hz with a root mean square error (RMSE) of ∼0.03.

Association between cardiovascular health and all-cause mortality risk in patients with osteoarthritis.

BACKGROUND: This study was to explore the relationship between cardiovascular health (CVH) and the risk of all-cause mortality in patients with osteoarthritis (OA). METHODS: This cohort study retrieved the data of 3642 patients with OA aged ≥ 20 years from the 2007-2018 National Health and Nutrition Examination Survey (NHANES). CVH was evaluated based on Life's Essential 8 (LE8) includes diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure. The outcome of all-cause mortality was assessed using the death certificate records of participants from the National Death Index. Variables that might affect all-cause mortality were used as covariates. The weighted univariate COX proportional hazards model was used to explore the association between each covariate and all-cause mortality. The weighted univariate and multivariate COX proportional hazards models were used to explore the association between different CVH levels and all-cause mortality. A restricted cubic spline (RCS) curve was plotted to show the association between different CVH levels and all-cause mortality in OA patients. Hazard ratio (HR) and 95% confidence interval (CI) were calculated. RESULTS: Findings show that people with moderate CVH (HR = 0.67, 95% CI = 0.45-0.98) and high CVH (HR = 0.47, 95% CI = 0.26-0.87) were associated with reduced risk of all-cause mortality in patients with OA. The HR of all-cause mortality in patients with OA decreased by 0.12 as per 10 points increase of LE8 score (HR = 0.81, 95% CI = 0.73-0.90). The RCS curve revealed that the HR of all-cause mortality decreased with the increase in LE8 score. The survival probability of patients in the high CVH group was higher than the moderate CVH group and low CVH group (p = 0.002). CONCLUSION: Moderate-to-high CVH is associated with a decreased risk of all-cause mortality in patients with OA. These findings might provide a reference for the formulation of prognosis improvement strategies for the management of patients with OA.

High-Performance SnTe Thermoelectric Materials Enabled by the Synergy of Band Convergence and Phonon Scattering.

SnTe, an environmentally friendly thermoelectric material, has garnered widespread scholarly interest owing to its lead-free nature; however, its intrinsic thermoelectric performance is constrained by a relatively low Seebeck coefficient and an extremely high lattice thermal conductivity. In this investigation, we employ the alloying of Ge and AgSbTe2 to enhance the zT value of SnTe. The study found that Ge, Ag, and Sb can effectively enhance the Seebeck coefficient and power factor of SnTe by utilizing band convergence. At the same time, a multitude of point defects induce phonon scattering, consequently decreasing the lattice thermal conductivity of SnTe. Collectively, these synergistic effects result in Sn0.75Ge0.25Te-15% AgSbTe2 achieving its highest zT value of 1.28 at 823 K, with an average zT value of 0.77 between 400 and 823 K. Such high zT values of the SnTe-based thermoelectric material provide the potential for applications in high-performance solid-state thermoelectric devices.

Responses of CO2 and CH4 in the alpine wetlands of the Tibetan Plateau to warming and nitrogen and phosphorus additions.

Wetland ecosystems store large amounts of carbon, and CO2 and CH4 fluxes from this ecosystem receive the double impact of climate change and human activities. Nonetheless, research on how multi-gradient warming and nitrogen and phosphorus additions affect these wetland greenhouse gas emissions is still limited, particularly in alpine wetland ecosystems. Therefore, we conducted a field experiment on the Tibetan Plateau wetlands, investigating the effects of warming and nitrogen and phosphorus additions on the CO2 and CH4 fluxes in alpine wetlands. Results indicated that warming enhanced the CO2 absorption and CH4 emission in the alpine meadow ecosystem, possibly related to changes in plant growth and microbial activity induced by warming, while we noticed that the promotion of CO2 uptake weakened with the increase in the magnitude of warming, suggesting that there may be a temperature threshold beyond which the ecosystem's capacity for carbon sequestration may be reduced. Nitrogen addition increased CH4 emission, with the effect on CO2 absorption shifting from inhibition to enhancement as the amount of applied nitrogen or phosphorus increased. The interaction between warming and nitrogen and phosphorus additions further influenced CH4 emission, exhibiting a synergistic enhancement effect. This study deepens our understanding of the greenhouse gas responses of alpine wetland ecosystems to warming and nitrogen and phosphorus additions, which is significant for predicting and managing ecosystem carbon balance under global change.

Clinical features, MRI, molecular alternations, and prognosis of astrocytoma based on WHO 2021 classification of central nervous system tumors: A single-center retrospective study.

BACKGROUND: The diagnosis of glioma has advanced since the release of the WHO 2021 classification with more molecular alterations involved in the integrated diagnostic pathways. Our study aimed to present our experience with the clinical features and management of astrocytoma, IDH mutant based on the latest WHO classification. METHODS: Patients diagnosed with astrocytoma, IDH-mutant based on the WHO 5th edition classification of CNS tumors at our center from January 2009 to January 2022 were included. Patients were divided into WHO 2-3 grade group and WHO 4 grade group. Integrate diagnoses were retrospectively confirmed according to WHO 2016 and 2021 classification. Clinical and MRI characteristics were reviewed, and survival analysis was performed. RESULTS: A total of 60 patients were enrolled. 21.67% (13/60) of all patients changed tumor grade from WHO 4th edition classification to WHO 5th edition. Of these, 21.43% (6/28) of grade II astrocytoma and 58.33% (7/12) of grade III astrocytoma according to WHO 4th edition classification changed to grade 4 according to WHO 5th edition classification. Sex (p = 0.042), recurrent glioma (p = 0.006), and Ki-67 index (p < 0.001) of pathological examination were statistically different in the WHO grade 2-3 group (n = 27) and WHO grade 4 group (n = 33). CDK6 (p = 0.004), FGFR2 (p = 0.003), and MYC (p = 0.004) alterations showed an enrichment in the WHO grade 4 group. Patients with higher grade showed shorter mOS (mOS = 75.9 m, 53.6 m, 26.4 m for grade 2, 3, and 4, respectively, p = 0.01). CONCLUSIONS: Patients diagnosed as WHO grade 4 according to the 5th edition WHO classification based on molecular alterations are more likely to have poorer prognosis. Therefore, treatment should be tailored to their individual needs. Further research is needed for the management of IDH-mutant astrocytoma is needed in the future.

Design and Evaluation of an Eye Mountable AutoDALK Robot for Deep Anterior Lamellar Keratoplasty.

Partial-thickness corneal transplants using a deep anterior lamellar keratoplasty (DALK) approach has demonstrated better patient outcomes than a full-thickness cornea transplant. However, despite better clinical outcomes from the DALK procedure, adoption of the technique has been limited because the accurate insertion of the needle into the deep stroma remains technically challenging. In this work, we present a novel hands-free eye mountable robot for automatic needle placement in the cornea, AutoDALK, that has the potential to simplify this critical step in the DALK procedure. The system integrates dual light-weight linear piezo motors, an OCT A-scan distance sensor, and a vacuum trephine-inspired design to enable the safe, consistent, and controllable insertion of a needle into the cornea for the pneumodissection of the anterior cornea from the deep posterior cornea and Descemet's membrane. AutoDALK was designed with feedback from expert corneal surgeons and performance was evaluated by finite element analysis simulation, benchtop testing, and ex vivo experiments to demonstrate the feasibility of the system for clinical applications. The mean open-loop positional deviation was 9.39 µm, while the system repeatability and accuracy were 39.48 µm and 43.18 µm, respectively. The maximum combined thrust of the system was found to be 1.72 N, which exceeds the clinical penetration force of the cornea. In a head-to-head ex vivo comparison against an expert surgeon using a freehand approach, AutoDALK achieved more consistent needle depth, which resulted in fewer perforations of Descemet's membrane and significantly deeper pneumodissection of the stromal tissue. The results of this study indicate that robotic needle insertion has the potential to simplify the most challenging task of the DALK procedure, enable more consistent surgical outcomes for patients, and standardize partial-thickness corneal transplants as the gold standard of care if demonstrated to be more safe and more effective than penetrating keratoplasty.

The molecular signature and prognosis of glioma with preoperative intratumoral hemorrhage: a retrospective cohort analysis.

BACKGROUND: Intratumoral hemorrhage, though less common, could be the first clinical manifestation of glioma and is detectable via MRI; however, its exact impacts on patient outcomes remain unclear and controversial. The 2021 WHO CNS 5 classification emphasised genetic and molecular features, initiating the necessity to establish the correlation between hemorrhage and molecular alterations. This study aims to determine the prevalence of intratumoral hemorrhage in glioma subtypes and identify associated molecular and clinical characteristics to improve patient management. METHODS: Integrated clinical data and imaging studies of patients who underwent surgery at the Department of Neurosurgery at Peking Union Medical College Hospital from January 2011 to January 2022 with pathological confirmation of glioma were retrospectively reviewed. Patients were divided into hemorrhage and non-hemorrhage groups based on preoperative magnetic resonance imaging. A comparison and survival analysis were conducted with the two groups. In terms of subgroup analysis, we classified patients into astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant, 1p/19q-codeleted; glioblastoma, IDH-wildtype; pediatric-type gliomas; or circumscribed glioma using integrated histological and molecular characteristics, according to WHO CNS 5 classifications. RESULTS: 457 patients were enrolled in the analysis, including 67 (14.7%) patients with intratumoral hemorrhage. The hemorrhage group was significantly older and had worse preoperative Karnofsky performance scores. The hemorrhage group had a higher occurrence of neurological impairment and a higher Ki-67 index. Molecular analysis indicated that CDKN2B, KMT5B, and PIK3CA alteration occurred more in the hemorrhage group (CDKN2B, 84.4% vs. 62.2%, p = 0.029; KMT5B, 25.0% vs. 8.9%, p = 0.029; and PIK3CA, 81.3% vs. 58.5%, p = 0.029). Survival analysis showed significantly worse prognoses for the hemorrhage group (hemorrhage 18.4 months vs. non-hemorrhage 39.1 months, p = 0.01). In subgroup analysis, the multivariate analysis showed that intra-tumoral hemorrhage is an independent risk factor only in glioblastoma, IDH-wildtype (162 cases of 457 overall, HR = 1.72, p = 0.026), but not in other types of gliomas. The molecular alteration of CDK6 (hemorrhage group p = 0.004, non-hemorrhage group p < 0.001), EGFR (hemorrhage group p = 0.003, non-hemorrhage group p = 0.001), and FGFR2 (hemorrhage group p = 0.007, non-hemorrhage group p = 0.001) was associated with shorter overall survival time in both hemorrhage and non-hemorrhage groups. CONCLUSIONS: Glioma patients with preoperative intratumoral hemorrhage had unfavorable prognoses compared to their nonhemorrhage counterparts. CDKN2B, KMT5B, and PIK3CA alterations were associated with an increased occurrence of intratumoral hemorrhage, which might be future targets for further investigation of intratumoral hemorrhage.

Factors influencing senior care and living preferences among older adults in Jiangsu, China: a cross-sectional survey study.

BACKGROUND: As the population ages, senior care for older adults in China has become increasingly important and has attracted the attention of both government and society. This study aimed to explore preferences and influencing factors related to senior care among older Chinese adults and thus propose effective and targeted strategies for the development of a comprehensive care system for older adults in the aging Chinese population. METHODS: Data were obtained from a cross-sectional survey conducted in sixteen communities or villages in Jiangsu Province, China, from July to September 2021. Guided by the Andersen Behavioral Model, multivariate logistic regression was conducted to identify factors associated with preferences for senior care arrangements. RESULTS: A total of 870 respondents were included in the study, 60.11% of whom preferred receiving care in their own homes, while only 13.68% chose residential care facilities (RCFs). For predisposing factors, rural respondents preferred receiving care in their own homes compared to urban respondents (children's home: OR = 0.55, P < 0.01; RCF: OR = 0.58, P < 0.01). Concerning enabling factors, respondents who were not employed (OR = 2.30, P < 0.01) and those without financial support (OR = 2.73, P < 0.05) preferred RCFs to their own homes. Respondents receiving life assistance (sometimes: OR = 2.76, P < 0.001; regularly: OR = 2.57, P < 0.01; every day: OR = 3.57, P < 0.001) preferred their children's homes to their own homes. In terms of need factors, respondents with noncommunicable diseases (NCDs, OR > 1, P < 0.05), those who knew about RCFs (some: OR = 0.53, P < 0.005; no: OR = 0.10, P < 0.001) and those with a good impression of RCFs (fair: OR = 3.72, P < 0.05; good: OR = 11.91, P < 0.001) preferred receiving care in RCFs compared to their counterparts. CONCLUSIONS: Older Chinese adults' senior care preferences were affected by predisposing factors, enabling factors, and need factors. Policy-makers should consider targeted measures to identify more precise senior care services and thus address aging challenges in China.

Artificial neural network identified a 20-gene panel in predicting immunotherapy response and survival benefits after anti-PD1/PD-L1 treatment in glioblastoma patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are a promising immunotherapy approach, but glioblastoma clinical trials have not yielded satisfactory results. OBJECTIVE: To screen glioblastoma patients who may benefit from immunotherapy. METHODS: Eighty-one patients receiving anti-PD1/PD-L1 treatment from a large-scale clinical trial and 364 patients without immunotherapy from The Cancer Genome Atlas (TCGA) were included. Patients in the ICI-treated cohort were divided into responders and nonresponders according to overall survival (OS), and the most critical responder-relevant features were screened using random forest (RF). We constructed an artificial neural network (ANN) model and verified its predictive value with immunotherapy response and OS. RESULTS: We defined two groups of ICI-treated glioblastoma patients with large differences in survival benefits as nonresponders (OS ≤6 months, n = 18) and responders (OS ≥17 months, n = 8). No differentially mutated genes were observed between responders and nonresponders. We performed RF analysis to select the most critical responder-relevant features and developed an ANN with 20 input variables, five hidden neurons and one output neuron. Receiver operating characteristic analysis and the DeLong test demonstrated that the ANN had the best performance in predicting responders, with an AUC of 0.97. Survival analysis indicated that ANN-predicted responders had significantly better OS rates than nonresponders. CONCLUSION: The 20-gene panel developed by the ANN could be a promising biomarker for predicting immunotherapy response and prognostic benefits in ICI-treated GBM patients and may guide oncologists to accurately select potential responders for the preferential use of ICIs.

Covariate modeling in pharmacometrics: General points for consideration.

Modeling the relationships between covariates and pharmacometric model parameters is a central feature of pharmacometric analyses. The information obtained from covariate modeling may be used for dose selection, dose individualization, or the planning of clinical studies in different population subgroups. The pharmacometric literature has amassed a diverse, complex, and evolving collection of methodologies and interpretive guidance related to covariate modeling. With the number and complexity of technologies increasing, a need for an overview of the state of the art has emerged. In this article the International Society of Pharmacometrics (ISoP) Standards and Best Practices Committee presents perspectives on best practices for planning, executing, reporting, and interpreting covariate analyses to guide pharmacometrics decision making in academic, industry, and regulatory settings.

Human skeletal muscle aging atlas.

Skeletal muscle aging is a key contributor to age-related frailty and sarcopenia with substantial implications for global health. Here we profiled 90,902 single cells and 92,259 single nuclei from 17 donors to map the aging process in the adult human intercostal muscle, identifying cellular changes in each muscle compartment. We found that distinct subsets of muscle stem cells exhibit decreased ribosome biogenesis genes and increased CCL2 expression, causing different aging phenotypes. Our atlas also highlights an expansion of nuclei associated with the neuromuscular junction, which may reflect re-innervation, and outlines how the loss of fast-twitch myofibers is mitigated through regeneration and upregulation of fast-type markers in slow-twitch myofibers with age. Furthermore, we document the function of aging muscle microenvironment in immune cell attraction. Overall, we present a comprehensive human skeletal muscle aging resource ( https://www.muscleageingcellatlas.org/ ) together with an in-house mouse muscle atlas to study common features of muscle aging across species.

Automatic and real-time tissue sensing for autonomous intestinal anastomosis using hybrid MLP-DC-CNN classifier-based optical coherence tomography.

Anastomosis is a common and critical part of reconstructive procedures within gastrointestinal, urologic, and gynecologic surgery. The use of autonomous surgical robots such as the smart tissue autonomous robot (STAR) system demonstrates an improved efficiency and consistency of the laparoscopic small bowel anastomosis over the current da Vinci surgical system. However, the STAR workflow requires auxiliary manual monitoring during the suturing procedure to avoid missed or wrong stitches. To eliminate this monitoring task from the operators, we integrated an optical coherence tomography (OCT) fiber sensor with the suture tool and developed an automatic tissue classification algorithm for detecting missed or wrong stitches in real time. The classification results were updated and sent to the control loop of STAR robot in real time. The suture tool was guided to approach the object by a dual-camera system. If the tissue inside the tool jaw was inconsistent with the desired suture pattern, a warning message would be generated. The proposed hybrid multilayer perceptron dual-channel convolutional neural network (MLP-DC-CNN) classification platform can automatically classify eight different abdominal tissue types that require different suture strategies for anastomosis. In MLP, numerous handcrafted features (∼1955) were utilized including optical properties and morphological features of one-dimensional (1D) OCT A-line signals. In DC-CNN, intensity-based features and depth-resolved tissues' attenuation coefficients were fully exploited. A decision fusion technique was applied to leverage the information collected from both classifiers to further increase the accuracy. The algorithm was evaluated on 69,773 testing A-line data. The results showed that our model can classify the 1D OCT signals of small bowels in real time with an accuracy of 90.06%, a precision of 88.34%, and a sensitivity of 87.29%, respectively. The refresh rate of the displayed A-line signals was set as 300 Hz, the maximum sensing depth of the fiber was 3.6 mm, and the running time of the image processing algorithm was ∼1.56 s for 1,024 A-lines. The proposed fully automated tissue sensing model outperformed the single classifier of CNN, MLP, or SVM with optimized architectures, showing the complementarity of different feature sets and network architectures in classifying intestinal OCT A-line signals. It can potentially reduce the manual involvement of robotic laparoscopic surgery, which is a crucial step towards a fully autonomous STAR system.

Old people's preference for nursing homes in East China: a discrete choice experiment.

BACKGROUND: The aged people who live in nursing home are predicted to keep growing in the following decades. There are both quantitative imbalance and structural imbalance in the utilization of nursing homes in China. This study aimed to analyze old people's preference for nursing homes and help the government optimize resource allocation. METHODS: A discrete choice experiment (DCE) was conducted and six attributes of nursing homes including monthly fee, distance from home, geographical location, medical facilities, environment of nursing homes and nursing staff were determined. Respondents were recruited from Nantong and Yangzhou city, China. In each city, two communities or villages were randomly selected. In each community/village, about 65 old people were randomly selected. Analysis was conducted using mixed logit regression models to determine preferences for potential attributes. RESULTS: A total of 233 old people were included in the analysis. The findings indicated that all six attributes were statistically significant factors for participants. "Professional nursing staff" was the most important characteristic to participants, followed by "Medical facilities". Compared with female, the males preferred professional nursing staff (ß = 2.939 vs. ß = 2.643, P < 0.001), medical facilities (ß = 1.890 vs. ß = 1.498, P < 0.001), and the environment (ß = 0.752, P < 0.01). For different age groups, participants aged 60-69 didn't pay attention to distance and location, while those aged 80 and above only paid attention to professional nursing staff and medical facilities. CONCLUSIONS: The present study provides important insights into the characteristics of nursing home that are most preferred by old people. Authorities should take into account old people's preference in the planning, design and evaluation of nursing homes.

EgMADS3 directly regulates EgLPAAT to mediate medium-chain fatty acids (MCFA) anabolism in the mesocarp of oil palm.

KEY MESSAGE: EgMADS3, a pivotal transcription factor, positively regulates MCFA accumulation via binding to the EgLPAAT promoter, advancing lipid content in mesocarp of oil palm. Lipids function as the structural components of cell membranes, which serve as permeable barriers to the external environment of cells. The medium-chain fatty acid in the stored lipids of plants is an important renewable energy. Most research on MCFA production in plant lipid synthesis is based on biochemical methods, and the importance of transcriptional regulation in MCFA synthesis and its incorporation into TAGs needs further research. Oil palm is the most productive oil crop in the world and has the highest productivity among the main oil crops. In this study, the MADS transcription factor (EgMADS3) in the mesocarp of oil palm was characterized. Through the VIGS-virus induced gene silencing, it was determined that the potential target gene of EgMADS3 was related to the biosynthesis of medium-chain fatty acid (MCFA). Transient transformation in protoplasts and qRT-PCR analysis showed that EgMADS3 positively regulated the expression of EgLPAAT. The results of the yeast one-hybrid assays and EMSA indicated the interaction between EgMADS3 and EgLPAAT promoter. Through genetic transformation and fatty acid analysis, it is concluded that EgMADS3 directly regulates the mid-chain fatty acid synthesis pathway of the potential target gene EgLPAAT, thus promotes the accumulation of MCFA and improves the total lipid content. This study is innovative in the functional analysis of the MADS family transcription factor in the metabolism of medium-chain fatty acids (MCFA) of oil palm, provides a certain research basis for improving the metabolic pathway of chain fatty acids in oil palm, and improves the synthesis of MCFA in plants. Our results will provide a reference direction for further research on improving the oil quality through biotechnology of oil palm.

Clinical roles of EGFR amplification in diffuse gliomas: a real-world study using the 2021 WHO classification of CNS tumors.

Background: The 2021 World Health Organization Classification of Central Nervous System Tumors updates glioma subtyping and grading system, and incorporates EGFR amplification (Amp) as one of diagnostic markers for glioblastoma (GBM). Purpose: This study aimed to describe the frequency, clinical value and molecular correlation of EGFR Amp in diffuse gliomas based on the latest classification. Methods: We reviewed glioma patients between 2011 and 2022 at our hospital, and included 187 adult glioma patients with available tumor tissue for detection of EGFR Amp and other 59 molecular markers of interest. Clinical, radiological and pathological data was analyzed based on the status of EGFR Amp in different glioma subtypes. Results: 163 gliomas were classified as adult-type diffuse gliomas, and the number of astrocytoma, oligodendroglioma and GBM was 41, 46, and 76. EGFR Amp was more common in IDH-wildtype diffuse gliomas (66.0%) and GBM (85.5%) than IDH-mutant diffuse gliomas (32.2%) and its subtypes (astrocytoma, 29.3%; oligodendroglioma, 34.8%). EGFR Amp did not stratify overall survival (OS) in IDH-mutant diffuse gliomas and astrocytoma, while was significantly associated with poorer OS in IDH-wildtype diffuse gliomas, histologic grade 2 and 3 IDH-wildtype diffuse astrocytic gliomas and GBM. Conclusion: Our study validated EGFR Amp as a diagnostic marker for GBM and still a useful predictor for shortened OS in this group.

Thiamine-modified metabolic reprogramming of human pluripotent stem cell-derived cardiomyocyte under space microgravity.

During spaceflight, the cardiovascular system undergoes remarkable adaptation to microgravity and faces the risk of cardiac remodeling. Therefore, the effects and mechanisms of microgravity on cardiac morphology, physiology, metabolism, and cellular biology need to be further investigated. Since China started constructing the China Space Station (CSS) in 2021, we have taken advantage of the Shenzhou-13 capsule to send human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) to the Tianhe core module of the CSS. In this study, hPSC-CMs subjected to space microgravity showed decreased beating rate and abnormal intracellular calcium cycling. Metabolomic and transcriptomic analyses revealed a battery of metabolic remodeling of hPSC-CMs in spaceflight, especially thiamine metabolism. The microgravity condition blocked the thiamine intake in hPSC-CMs. The decline of thiamine utilization under microgravity or by its antagonistic analog amprolium affected the process of the tricarboxylic acid cycle. It decreased ATP production, which led to cytoskeletal remodeling and calcium homeostasis imbalance in hPSC-CMs. More importantly, in vitro and in vivo studies suggest that thiamine supplementation could reverse the adaptive changes induced by simulated microgravity. This study represents the first astrobiological study on the China Space Station and lays a solid foundation for further aerospace biomedical research. These data indicate that intervention of thiamine-modified metabolic reprogramming in human cardiomyocytes during spaceflight might be a feasible countermeasure against microgravity.

Application of Model-Informed Drug Development in Dose Selection and Optimization for siRNA Therapies.

The application of model-informed drug development (MIDD) has revolutionized drug development and regulatory decision making, transforming the process into one that is more efficient, effective, and patient centered. A critical application of MIDD is to facilitate dose selection and optimization, which play a pivotal role in improving efficacy, safety, and tolerability profiles of a candidate drug. With the surge of interest in small interfering RNA (siRNA) drugs as a promising class of therapeutics, their applications in various disease areas have been extensively studied preclinically. However, dosing selection and optimization experience for siRNA in humans is limited. Unique challenges exist for the dose evaluation of siRNA due to the temporal discordance between pharmacokinetic and pharmacodynamic profiles, as well as limited available clinical experience and considerable interindividual variability. This review highlights the pivotal role of MIDD in facilitating dose selection and optimization for siRNA therapeutics. Based on past experiences with approved siRNA products, MIDD has demonstrated its ability to aid in dose selection for clinical trials and enabling optimal dosing for the general patient population. In addition, MIDD presents an opportunity for dose individualization based on patient characteristics, enhancing the precision and effectiveness of siRNA therapeutics. In conclusion, the integration of MIDD offers substantial advantages in navigating the complex challenges of dose selection and optimization in siRNA drug development, which in turn accelerates the development process, supports regulatory decision making, and ultimately improves the clinical outcomes of siRNA-based therapies, fostering advancements in precision medicine across a diverse range of diseases.

Identification of TMZ resistance-associated histone post-translational modifications in glioblastoma using multi-omics data.

BACKGROUD: Glioblastoma multiforme (GBM) is among the most aggressive cancers, with current treatments limited in efficacy. A significant hurdle in the treatment of GBM is the resistance to the chemotherapeutic agent temozolomide (TMZ). The methylation status of the MGMT promoter has been implicated as a critical biomarker of response to TMZ. METHODS: To explore the mechanisms underlying resistance, we developed two TMZ-resistant GBM cell lines through a gradual increase in TMZ exposure. Transcriptome sequencing of TMZ-resistant cell lines revealed that alterations in histone post-translational modifications might be instrumental in conferring TMZ resistance. Subsequently, multi-omics analysis suggests a strong association between histone H3 lysine 9 acetylation (H3K9ac) levels and TMZ resistance. RESULTS: We observed a significant correlation between the expression of H3K9ac and MGMT, particularly in the unmethylated MGMT promoter samples. More importantly, our findings suggest that H3K9ac may enhance MGMT transcription by facilitating the recruitment of the SP1 transcription factor to the MGMT transcription factor binding site. Additionally, by analyzing single-cell transcriptomics data from matched primary and recurrent GBM tumors treated with TMZ, we modeled the molecular shifts occurring upon tumor recurrence. We also noted a reduction in tumor stem cell characteristics, accompanied by an increase in H3K9ac, SP1, and MGMT levels, underscoring the potential role of H3K9ac in tumor relapse following TMZ therapy. CONCLUSIONS: The increase in H3K9ac appears to enhance the recruitment of the transcription factor SP1 to its binding sites within the MGMT locus, consequently upregulating MGMT expression and driving TMZ resistance in GBM.

A prognostic model for overall survival in recurrent glioma patients treated with bevacizumab-containing therapy.

Predictive markers and prognostic models are useful for the individualization of cancer treatment. In this study, we sought to identify clinical and molecular factors to predict overall survival in recurrent glioma patients receiving bevacizumab-containing regimens. A cohort of 102 patients was retrospectively collected from June 2011 to January 2022 at our institution. A nomogram was generated by Cox regression and feature selection algorithms based on 19 clinicopathological and 60 molecular variables. The model's performance was internally evaluated by bootstrapping in terms of discrimination and calibration. The median overall survival from the initiation of bevacizumab administration to death or last follow-up was 11.6 months (95% CI: 9.2-13.8 months) for all 102 patients, 10.2 months (95% CI: 6.4-13.3 months) for 66 patients with grade 4 tumors, and 13.8 months (lower limit of 95% CI: 11.5 months) for 36 patients with tumors of grade lower or not available. In the final model, a lower WHO 2021 grade (Grade lower or not available vs. Grade 4, HR: 0.398, 95% CI: 0.223-0.708, p = 0.00172), having received adjuvant radiochemotherapy (Yes vs. No, HR: 0.488, 95% CI: 0.268-0.888, p = 0.0189), and wildtype EGFR (Wildtype vs. Altered, HR: 0.193, 95% CI: 0.0506-0.733, p = 0.0157; Not available vs. Altered, HR: 0.386, 95% CI: 0.184-0.810, p = 0.0118) were significantly associated with longer overall survival in multivariate Cox regression. The overall concordance index was 0.652 (95% CI: 0.566-0.714), and the areas under the time-dependent curves for 6-, 12-, and 18-month overall survival were 0.677 (95% CI: 0.516-0.816), 0.654 (95% CI: 0.470-0.823), and 0.675 (95% CI: 0.491-0.860), respectively. A prognostic model for overall survival in recurrent glioma patients treated with bevacizumab-based therapy was established and internally validated. It could serve as a reference tool for clinicians to assess the extent the patients may benefit from bevacizumab and stratify their treatment response.

Self-assembled hydrated copper coordination compounds as ionic conductors for room temperature solid-state batteries.

As the core component of solid-state batteries, neither current inorganic solid-state electrolytes nor solid polymer electrolytes can simultaneously possess satisfactory ionic conductivity, electrode compatibility and processability. By incorporating efficient Li+ diffusion channels found in inorganic solid-state electrolytes and polar functional groups present in solid polymer electrolytes, it is conceivable to design inorganic-organic hybrid solid-state electrolytes to achieve true fusion and synergy in performance. Herein, we demonstrate that traditional metal coordination compounds can serve as exceptional Li+ ion conductors at room temperature through rational structural design. Specifically, we synthesize copper maleate hydrate nanoflakes via bottom-up self-assembly featuring highly-ordered 1D channels that are interconnected by Cu2+/Cu+ nodes and maleic acid ligands, alongside rich COO- groups and structural water within the channels. Benefiting from the combination of ion-hopping and coupling-dissociation mechanisms, Li+ ions can preferably transport through these channels rapidly. Thus, the Li+-implanted copper maleate hydrate solid-state electrolytes shows remarkable ionic conductivity (1.17 × 10-4 S cm-1 at room temperature), high Li+ transference number (0.77), and a 4.7 V-wide operating window. More impressively, Li+-implanted copper maleate hydrate solid-state electrolytes are demonstrated to have exceptional compatibility with both cathode and Li anode, enabling long-term stability of more than 800 cycles. This work brings new insight on exploring superior room-temperature ionic conductors based on metal coordination compounds.