Clearance of senescent cells enhances skin wound healing in type 2 diabetic mice.

Background: Diabetic foot ulcers (DFUs) pose a substantial healthcare challenge due to their high rates of morbidity, recurrence, disability, and mortality. Current DFU therapeutics continue to grapple with multiple limitations. Senescent cells (SnCs) have been found to have a beneficial effect on acute wound healing, however, their roles in chronic wounds, such as DFU, remain unclear. Methods and results: We collected skin, fat, and muscle samples from clinical patients with DFU and lower limb fractures. RNA-sequencing combined with qPCR analyses on these samples demonstrate a significant accumulation of SnCs at DFU, as indicated by higher senescence markers (e.g., p16 and p21) and a senescence-associated secretory phenotype (SASP). We constructed a type 2 diabetic model of db/db mice, fed with a high-fat diet (Db-HFD), which were wounded using a 6 mm punch to the dorsal skin. HFD slightly affected wound healing in wild-type (WT) mice, but high glucose significantly delayed wound healing in the Db-HFD mice. We injected the mice with a previously developed fluorescent probe (XZ1208), which allows the detection of SnCs in vivo, and observed a strong senescence signal at the wound site of the Db-HFD mice. Contrary to the beneficial effects of SnCs in acute wound healing, our results demonstrated that clearance of SnCs using the senolytic compound ABT263 significantly accelerated wound healing in Db-HFD mice. Conclusion: Collectively, these findings suggest that SnCs critically accumulate at wound sites, delaying the healing process in DFUs. Thus, targeting SnCs with senolytic therapy represents a promising approach for DFU treatment, potentially improving the quality of life for patients with DFUs.

Chemical profile and in-vitro bioactivities of three types of yellow teas processed from different tenderness of young shoots of Huoshanjinjizhong (Camellia sinensis var. sinensis).

In the present study, bud yellow tea (BYT), small-leaf yellow tea (SYT) and large-leaf yellow tea (LYT) were produced from the same local "population" variety Huoshanjinjizhong (Camellia sinensis var. sinensis), and the effects of raw material tenderness on the chemical profile and bioactivities of these teas were investigated. The results showed that 11 crucial compounds were screened by headspace solid-phase microextraction-gas chromatography-mass spectrometry from 64 volatiles in these yellow teas, among which the heterocyclic compounds showed the greatest variations. In addition, 43 key compounds including organic acids, flavan-3-ols, amino acids, saccharides, glycosides and other compounds were screened by liquid chromatography-mass spectrometry from 1781 non-volatile compounds. BYT showed the best α-glucosidase inhibitory activity and antioxidant capacity among the selected yellow teas, which might be contributed by the higher content of galloylated catechins. These findings provided a better understanding of the chemical profile and bioactivities of yellow teas.

Nicotinamide N-methyltransferase (NNMT): A key enzyme in cancer metabolism and therapeutic target.

Emerging research has positioned Nicotinamide N-methyltransferase (NNMT) as a key player in oncology, with its heightened expression frequently observed across diverse cancers. This increased presence is tightly linked to tumor initiation, proliferation, and metastasis. The enzymatic function of NNMT is centered on the methylation of nicotinamide (NAM), utilizing S-adenosylmethionine (SAM) as the methyl donor, which results in the generation of S-adenosyl-L-homocysteine (SAH) and methyl nicotinamide (MNAM). This metabolic process reduces the availability of NAM, necessary for Nicotinamide adenine dinucleotide (NAD+) synthesis, and generates SAH, precursor to homocysteine (Hcy). These alterations are theorized to foster the resilience, expansion, and invasiveness of cancer cells. Furthermore, NNMT is implicated in enhancing cancer malignancy by affecting multiple signaling pathways, such as phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), cancer-associated fibroblasts (CAFs) and 5-Methyladenosine (5-MA), epithelial-mesenchymal transition (EMT), and epigenetic mechanisms. Upregulation of NNMT metabolism plays a key role in the formation and maintenance of the tumour microenvironment. While the use of small molecule inhibitors and RNA interference (RNAi) to target NNMT has shown therapeutic promise, the full extent of NNMT's influence on cancer is not yet fully understood, and clinical evidence is limited. This article systematically describes the relationship between the functional metabolism of NNMT enzymes and the cancer and tumour microenvironments, describing the mechanisms by which NNMT contributes to cancer initiation, proliferation, and metastasis, as well as targeted therapies. Additionally, we discuss the future opportunities and challenges of NNMT in targeted anti-cancer treatments.

Urinary bladder matrix scaffold improves the impact of adipose-mesenchymal stem cells on the function and structure of transplanted rat ovaries.

Ovarian transplantation presents significant advantages for the preservation of female fertility. Nonetheless, a substantial number of follicles are apoptosis during the process of ovarian tissue transplantation as a result of ischemic conditions. This study aimed to assess whether adipose-derived mesenchymal stem cells combined with urinary bladder matrix (ADSC/UBM) confer a greater therapeutic benefit compared to ADSCs alone. To achieve this, ADSC/UBM was applied during the autotransplantation of rat ovaries. Thirty rats were divided into five sets of six: the untreated control group (Normal), the oophorectomy group, the autograft group, the autograft + ADSCs group (ADSC), and the autograft + ADSC/UBM group (ADSC/UBM). After transplantation, the number of follicles in the ADSC/UBM group was significantly higher than that in the autograft group. Angiogenesis was enhanced following ADSC/UBM transplantation. Follicle-stimulating hormone (FSH) levels were significantly lower, and Anti-Müllerian hormone (AMH) levels were significantly higher in rats in the ADSC/UBM group than in the Autograft group. The apoptosis rate in the ADSC/UBM group decreased. The estrous cycle in the ADSC/UBM group recovered more quickly than the ADSC group. The data indicate that UBM improves ADSC retention in graft ovaries and aids in permanently restoring ovarian function, making ADSC/UBM a promising option for ovarian transplantation.

Can AI Predict the Magnitude and Direction of Ortho-K Contact Lens Decentration to Limit Induced HOAs and Astigmatism?

Background: The aim is to investigate induced higher-order aberrations (HOA)s and astigmatism as a result of non-toric ortho-k lens decentration and utilise artificial intelligence (AI) to predict its magnitude and direction. Methods: Medmont E300 Video topographer was used to scan 249 corneas before and after ortho-k wear. Custom-built MATLAB codes extracted topography data and determined lens decentration from the boundary and midpoint of the central flattened treatment zone (TZ). An evaluation was carried out by conducting Zernike polynomial fittings via a computer-coded digital signal processing procedure. Finally, an AI-based machine learning neural network algorithm was developed to predict the direction and magnitude of TZ decentration. Results: Analysis of the first 21 Zernike polynomial coefficients indicate that the four low-order and four higher-order aberration terms were changed significantly by ortho-k wear. While baseline astigmatism was not correlated with lens decentration (R = 0.09), post-ortho-k astigmatism was moderately correlated with decentration (R = 0.38) and the difference in astigmatism (R = 0.3). Decentration was classified into three groups: ≤0.50 mm, reduced astigmatism by -0.9 ± 1 D; 0.5~1 mm, increased astigmatism by 0.8 ± 0.1 D; >1 mm, increased astigmatism by 2.7 ± 1.6 D and over 50% of lenses were decentred >0.5 mm. For lenses decentred >1 mm, 29.8% of right and 42.7% of left lenses decentred temporal-inferiorly and 13.7% of right and 9.4% of left lenses decentred temporal-superiorly. AI-based prediction successfully identified the decentration direction with accuracies of 70.2% for right and 71.8% for left lenses and predicted the magnitude of decentration with root-mean-square (RMS) of 0.31 mm and 0.25 mm for right and left eyes, respectively. Conclusions: Ortho-k lens decentration is common when fitting non-toric ortho-k lenses, resulting in induced HOAs and astigmatism, with the magnitude being related to the amount of decentration. AI-based algorithms can effectively predict decentration, potentially allowing for better control over ortho-k fitting and, thus, preferred clinical outcomes.

18F-Fluorodeoxyglucose positron emission tomography/computed tomography imaging reveals the protective effect of docosahexaenoic acid on glucose metabolism by reducing brain 27-hydroxycholesterol.

Total cholesterol (TC) and the cholesterol oxidation product 27-hydroxycholesterol (27-OHC) are both increased in the elderly. Accumulating evidence has linked 27-OHC to glucose metabolism in the brain, while docosahexaenoic acid (DHA) has been shown to positively regulate the 27-OHC levels. However, it is unclear whether DHA may affect glucose metabolism in the brain by regulating 27-OHC levels. In this study, we hypothesized that DHA supplementation would modulate TC levels and reduce 27-OHC levels, thereby improving brain glucose metabolism in SAMP8 mice. The mice were assigned into the Control group and DHA dietary supplementation group. The study evaluated cholesterol levels, 27-OHC levels, and glucose metabolism in the brain. The results showed that DHA supplementation decreased serum levels of TC, low-density lipoprotein cholesterol (LDL-C), and increased levels of high-density lipoprotein cholesterol (HDL-C); and improved the glucose-corrected standardized uptake value of cortex, hippocampus, and whole brain regions in SAMP8 mice. In conclusion, supplementation of DHA could regulate the cholesterol composition and reduce the level of 27-OHC, thereby improving brain glucose metabolism in SAMP8 mice.

Effects of a food supplement containing phosphatidylserine on cognitive function in Chinese older adults with mild cognitive impairment: A randomized double-blind, placebo-controlled trial.

BACKGROUND: Phosphatidylserine (PS) and α-Linolenic acid (ALA), are positively associated with cognitive function, but their combination effects and possible mechanisms remain unclear. We aimed to explore the effects on cognition and potential mechanism of the supplements. METHODS: This randomized, double-blind, placebo-controlled trial recruited 190 MCI patients in Tianjin, China, and randomly assigned in intervention group and placebo group. Each group consumed two capsules every day for 12 months. Each capsule for intervention group contains 144 mg ALA, 31.5 mg PS and 3.6 mg Ginkgo total flavonoids as main functional components, with 0.48 mg Vitamin B1 (as thiamine hydrochloride), 0.48 mg Vitamin B6 (as pyridoxine hydrochloride) and 90 µg folic acid as supplement. Capsules for placebo group were identical but contain no active ingredients. Cognitive function, serum n-3 polyunsaturated fatty acids (PUFAs) and neurotransmitters were assessed at baseline and 12 months. Linear mixed effects model and causal mediation analysis were conducted to explore the effects and potential mechanism of the intervention. RESULTS: A total of 190 participants (mean [SD] age, 67.95 [5.62] years; 70 (36.8 %) male and 120 (63.2 %) female) were randomized to the placebo group (n = 95) and intervention group (n = 95). Compared with placebo group, the intervention group had statistically significant improvements in arithmetic testing (ß, 0.688; 95 % CI, 0.103-1.274), the similarity test (ß, 1.070; 95 % CI, 0.472-1.667) and short-term memory (ß, 0.600; 95 % CI, 0.399-0.800). Besides, the intervention group had statistically significant increases in serum ALA (ß, 1.620; 95 % CI, 0.967-2.265), DHA (ß, 2.797; 95 % CI, 1.075-4.532), EPA (ß, 1.472; 95 % CI, 0.296-2.643), acetylcholine (ß, 0.441; 95 % CI, 0.415-0.468), GABA (ß, 0.009; 95 % CI, 0.001-0.016) and 5-HT (ß, 0.160; 95 % CI, 0.081-0.238) compared to the placebo group. And the intervention may improve short-term memory by increasing serum ALA levels (average causal mediation effect = 0.132, 95 % CI, 0.053-0.225) with 19.7 % mediation proportion. CONCLUSIONS: This food supplement containing phosphatidylserine could improve different cognitive functions of MCI patients, especially short-term memory, and increase serum n-3 PUFAs and neurotransmitters levels. Serum ALA level might play a mediation role.

Prognostic factors of early recurrence after complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Although cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) offer the potential for long-term survival in peritoneal carcinomatosis, outcomes following CRS/HIPEC vary significantly. AIM: To identify the clinical factors associated with progression-free survival (PFS) after complete CRS/HIPEC in patients with colorectal/high-grade appendiceal, ovarian, and gastric cancers. METHODS: We retrospectively evaluated the risk of recurrence within 1 year after CRS/HIPEC and its impact on overall survival (OS) in patients recruited between 2015 and 2020. Logistic regression models were used to assess the prognostic factors for the risk of recurrence within 1 year. Kaplan-Meier survival curves and Cox proportional hazards models were used to evaluate the association between recurrence and OS. RESULTS: Of the 80 enrolled patients, 39 had an unfavorable PFS (< 1 year) and 41 had a favorable PFS (≥ 1 year). Simple logistic models revealed that the patients with a completeness of cytoreduction score of 0 (CC-0) or length of CRS ≤ 6 h had a favorable PFS [odds ratio (OR) = 0.141, P = 0.004; and OR = 0.361, P = 0.027, respectively]. In multiple logistic regression, achieving CC-0 was the strongest prognostic factor for a favorable PFS (OR = 0.131, P = 0.005). A peritoneal cancer index score > 12 was associated with a lower rate of achieving CC-0 (P = 0.027). The favorable PFS group had a significantly longer OS (median 81.7 mo vs 17.0 mo, P < 0.001). CONCLUSION: Achieving CC-0 was associated with a lower early recurrence rate and improved long-term survival. This study underscores the importance of selecting appropriate candidates for CRS/HIPEC to manage peritoneal carcinomatosis.

The hepatoprotective effect of sodium butyrate on hepatic inflammatory injury mediated by the NLRP3 inflammatory pathway in subchronic fluoride-exposed mice.

BACKGROUND: Excessive subchronic fluoride exposure can cause severe damage to detoxification organs, including the liver. Sodium butyrate has anti-inflammatory, antitumor, antioxidant and immunomodulatory properties. However, relatively few studies have investigated the effects of sodium butyrate on liver injury caused by subchronic fluoride exposure. The purpose of this research was to investigate the effect and mechanism of sodium butyrate on fluoride-induced hepatic inflammatory injury via the expression of nod-like receptor protein 3 (NLRP3). METHODS: Mice were subjected to randomization into four groups, control group (C), fluorosis group (F), sodium butyrate alone group (S), and treatment group (Y). The mice in groups F and F + S drank 100 mg/L sodium fluoride-containing distilled water freely every day. After fluoride exposure lasted for 3 months, the mice in group S and F + S were gavaged with sodium butyrate daily at a concentration of 1000 mg/kg. Following the treatment regimen, liver specimens were collected for analysis. The mRNA and protein expression levels of inflammatory factors and NLRP3 and its downstream gene were measured by RT-qPCR and western blotting. RESULTS: The histological hematoxylin and eosin (H&E) staining of liver showed that the subchronic fluoride-exposed group were chronic inflammation. The liver of treatment group were less vacuolar degeneration and inflammatory infiltration. The results of the biochemical assay showed that the subchronic fluoride-exposed group were liver injury. In addition, the detection of oxidative stress indicators showed that chronic subchronic fluoride exposure could lead to an increase in the level of oxidative stress in the liver, and the treatment alleviated this increase. RT-qPCR results showed that compared with those in the control group, the mRNA levels of the inflammatory factors TNF-α, IL-6 and IL-1ß, the NLRP3 inflammasome and its downstream factors NLRP3, caspase-1, gasdermin D (GSDMD) and IL-18 increased in the liver tissue of mice in the subchronic fluoride-exposed group. Sodium butyrate released inflammatory factors during subchronic fluoride exposure and inhibited the protein expression of activated NLRP3 to a certain extent. CONCLUSIONS: Sodium butyrate may play a protective role by antagonizing the production of activated inflammasomes and their downstream inflammatory factors in the livers of subchronic fluoride-exposed mice.

Distant metastasis patterns among lung cancer subtypes and impact of primary tumor resection on survival in metastatic lung cancer using SEER database.

This research aimed to systematically uncover the metastatic characteristics and survival rates of lung cancer subtypes and to evaluate the impact of surgery at the primary tumor site on cancer-specific survival in DM lung cancer. We used the Surveillance, Epidemiology, and End Results (SEER) database (2010-2019) to identify primary lung cancers with DM at presentation (M1). Kaplan-Meier (KM) survival curves were generated and compared utilizing log-rank tests. Cox regression methods were employed to determine hazard ratios (HR) and 95% confidence intervals related to CSS factors. Inverse probability of treatment weighting (IPTW) was applied to reduce bias. We analyzed 77,827 M1 lung cancer cases, with 41.22% having DM at presentation. Bone metastasis was most common in ADC, ASC, SCC, LCC; brain in LCNEC; liver in SCLC. Lung was common in TC + AC and SCC. Long-term survival was best in TC + AC and worst in SCLC (p < 0.001). Male gender, age < 50, primary tumor site (main bronchus, lower lobe), large tumor diameter, ADC/SCLC/SCC pathology, and regional lymph node involvement were significant risk factors for multiorgan metastasis. Age ≥ 50, male, large tumor diameter, positive lymph nodes, and multiorgan metastases were associated with lower CSS. In contrast, radiotherapy, chemotherapy, systemic therapy, and surgery were associated with higher CSS rates. Primary tumor resection improved survival in lung cancer patients (excluding small cell lung cancer, SCLC) with single organ metastases (KM log rank p < 0.001, HR = 0.6165; 95% CI (0.5468-0.6951)), especially in brain (p < 0.001, HR = 0.6467; 95% CI (0.5505-0.7596)) and bone (p = 0.182, HR = 0.6289; p < 0.01), but not in liver or intrapulmonary metastases after IPTW. Significant differences in DM patterns and corresponding survival rates exist among lung cancer subtypes. Primary tumor resection improves survival in lung cancer patients (excluding small cell lung cancer, SCLC) with single organ metastases, with better outcomes in patients with brain and bone metastases, while no significant benefit was seen in patients with liver and intrapulmonary metastases.

Genomic analysis of hypoxia-tolerant population of the Chinese mitten crab (Eriocheir sinensis).

Hypoxic stress, triggered by a multitude of factors, has inflicted significant economic repercussions on the aquaculture of Eriocheir sinensis. In this research, we sequenced a collective of 60 samples from both hypoxia-sensitive and hypoxia-resistant groups utilizing streamlined genome sequencing techniques. Subsequently, we delved into population evolution, scrutinized the selective sweep within these populations, and performed a genome-wide association study (GWAS) focused on the hypoxia tolerance traits within the population, all through the lens of SNPs molecular markers. This comprehensive analysis aimed to uncover the SNPs and pinpoint the pertinent candidate genes that influence the hypoxia tolerance capabilities of E. sinensis. The selective sweep analysis revealed that genes harboring potential genetic variations within the two populations were predominantly enriched in areas such as signaling molecules and interactions, energy metabolism, glycolipid metabolism, and immune response. In the genome-wide association study focusing on hypoxia tolerance traits, we identified four SNPs significantly associated with hypoxia resistance. Furthermore, one potential candidate gene, Dscam2, which is believed to influence hypoxia tolerance, was discovered within a 50 kb vicinity of these SNPs. These identified SNPs can serve as molecular markers for screening hypoxia tolerance, offering valuable insights for the genetic improvement of E. sinensis.

Bmal1 upregulates ATG5 expression to promote autophagy in skin cutaneous melanoma.

BACKGROUND: Skin cutaneous melanoma (SKCM) is a highly aggressive and malignant tumor that arises from the malignant transformation of melanocytes. In light of the limitations of existing treatment modalities, there is a pressing need to identify new drug targets for SKCM. Aryl-hydrocarbon receptor nuclear translocator-like (ARNTL), also known as Bmal1, is a gene that has been linked to the onset and progression of cancer. However, its role in SKCM remains understudied. METHODS: The expression of Bmal1 mRNA and protein was detected using TCGA, GTEx, CCLE, and ULCAN databases. Moreover, survival analysis was performed to investigate the association between Bmal1 and immune invasion and gene expression in immune infiltrating cells via CIBERSORT, R programming, TIMER, Sangerbox, Kaplan-Meier. The study also explored the role of proteins associated with Bmal1 by using R programming and databases (STRING and GSEA). Both in vitro and in vivo studies were conducted to examine the potential role of Bmal1 in SKCM. RESULTS: Compared to normal tissues, the expression level of Bmal1 was significantly reduced in SKCM. Which has been associated with its poor prognosis. Similarly, its expression in SKCM was substantially correlated with immune infiltration, while biogenic analysis indicated that it could potentially influence the tumor immune microenvironment (TME) by influencing tumor-associated neutrophils (TANs). Moreover, Bmal1 overexpression suppressed the proliferation and invasion of melanoma cells and enhanced apoptosis, migration, and cell colony formation. CONCLUSION: This study concluded that Bmal1 is a novel biomarker that functions as both a diagnostic and prognostic indicator for the progression of SKCM.

Recent advances in AIE-based platforms for cancer immunotherapy.

Aggregation-induced emission luminogens (AIEgens) possess the unique property of enhanced fluorescence and photostability in aggregated states, making them exceptional materials for the convergence of imaging and phototherapy. With their inherent advantages, AIEgens are propelling the field of nanomedicine into a vibrant frontier in the phototheranostics of a spectrum of diseases, particularly in the realm of cancer immunotherapy. AIEgens-based therapeutics enhance the cancer immune response through a variety of approaches, including real-time image-guided precise therapy, induction of programmed cell death, metabolic reprogramming, and modulation of the tumor microenvironment. Additionally, they contribute to the synergistic effect of immune checkpoint inhibition, a pivotal aspect of modern cancer immunotherapy strategies. This review offers a comprehensive overview of the integration of AIEgens in nanomedicine and their role in immune adaptation, highlighting the advantages, basic action mechanisms, and recent advancement of AIEgens as promising therapeutic platform for cancer immunotherapy.

The Microstructure and Properties of Ni60/60% WC Wear-Resistant Coatings Prepared by Laser-Directed Energy Deposition.

Ni60/60% WC composite coatings with a good surface roughness and high mechanical properties were successfully prepared on 316L stainless steel substrate by laser-directed energy deposition (LDED) technology. The effects of laser power on the microstructural evolution and mechanical properties of the Ni60/60% WC composite coating were investigated. The relationships between the chemical composition, the microstructure, the hardness, and the friction wear resistance of the composite coatings were characterized and investigated. The results show that the laser power had a significant effect on the energy input, which determined the melting extent of the Ni60 phases around the WC particles and the bonding strength between the reinforcements and the matrix, as well as the bonding strength between the substrate and the coatings. With an increase in the laser power from 800 W to 1400 W, the average hardness of the coating surface increased due to the increased densification of the deposited coatings and then decreased due to grain coarsening under a high energy input. The average coefficient of friction of the coatings decreased gradually to 0.383 at 1000 W, showing a minimum wear of 0.00013 mm2 at 1200 W. The main wear mechanisms on the coated surfaces were adhesive wear and abrasive wear. Moreover, the coatings deposited at 1200 W exhibited better forming quality and wear resistance. This work suggests that the processing parameters during LDED can be optimized to prepare Ni60/60% WC wear-resistant coatings with excellent mechanical properties.

Design, synthesis, and activity evaluation of water-soluble propofol derivatives as anesthetic drugs.

In this work, two series of water-soluble derivatives were designed and synthesized based on the structure of propofol as the lead compound. Furthermore, the anesthetic activities of the synthesized compounds were evaluated in vivo against mice, and the in vitro propofol release rate from five target compounds was determined. The findings of this study have shown that series II compounds which possess the structure feature of propofol + Î³-hydroxybutyric acid + α-aminoacetate or γ-aminobutyrate have higher therapeutic index than that of series I compounds which possess the structure feature of propofol + α-aminoacetate or ß-aminopropionate. In addition, the rate of propofol released from series II compounds was significantly better than that of series I compounds. Among series II compounds, compound II-20 had a therapeutic index of 5.6 (propofol = 2.7), a duration time of 571 s (propofol = 57 s), and no significant toxicity was observed in vivo, which made it valuable for further development.

A genome-wide association study of occupational creativity and its relations with well-being and career success.

Creativity is one defining characteristic of human species. There have been mixed findings on how creativity relates to well-being, and little is known about its relationship with career success. We conduct a large-scale genome-wide association study to examine the genetic architecture of occupational creativity, and its genetic correlations with well-being and career success. The SNP-h2 estimates range from 0.08 (for managerial creativity) to 0.22 (for artistic creativity). We record positive genetic correlations between occupational creativity with autism, and positive traits and well-being variables (e.g., physical height, and low levels of neuroticism, BMI, and non-cancer illness). While creativity share positive genetic overlaps with indicators of high career success (i.e., income, occupational status, and job satisfaction), it also has a positive genetic correlation with age at first birth and a negative genetic correlation with number of children, indicating creativity-related genes may reduce reproductive success.

Source imaging method based on diagonal covariance bases and its applications to OPM-MEG.

Magnetoencephalography (MEG) is a noninvasive imaging technique used in neuroscience and clinical research. The source estimation of MEG involves solving a highly underdetermined inverse problem, which requires additional constraints to restrict the solution space. Traditional methods tend to obscure the extent of the sources. However, an accurate estimation of the source extent is important for studying brain activity or preoperatively estimating pathogenic regions. To improve the estimation accuracy of the extended source extent, the spatial constraint of sources is employed in the Bayesian framework. For example, the source is decomposed into a linear combination of validated spatial basis functions, which is proved to improve the source imaging accuracy. In this work, we further construct the spatial properties of the source using the diagonal covariance bases (DCB), which we summarize as the source imaging method SI-DCB. In this approach, specifically, the covariance matrix of the spatial coefficients is modeled as a weighted combination of diagonal covariance basis functions. The convex analysis is used to estimate noise and model parameters under the Bayesian framework. Extensive numerical simulations showed that SI-DCB outperformed five benchmark methods in accurately estimating the location and extent of patch sources. The effectiveness of SI-DCB was verified through somatosensory stimulation experiments performed on a 31-channel OPM-MEG system. The SI-DCB correctly identified the source area where each brain response occurred. The superior performance of SI-DCB suggests that it can provide a template approach for improving the accuracy of source extent estimations under a sparse Bayesian framework.

SIRT1 Regulates Mitochondrial Damage in N2a Cells Treated with the Prion Protein Fragment 106-126 via PGC-1α-TFAM-Mediated Mitochondrial Biogenesis.

Mitochondrial damage is an early and key marker of neuronal damage in prion diseases. As a process involved in mitochondrial quality control, mitochondrial biogenesis regulates mitochondrial homeostasis in neurons and promotes neuron health by increasing the number of effective mitochondria in the cytoplasm. Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase that regulates neuronal mitochondrial biogenesis and quality control in neurodegenerative diseases via deacetylation of a variety of substrates. In a cellular model of prion diseases, we found that both SIRT1 protein levels and deacetylase activity decreased, and SIRT1 overexpression and activation significantly ameliorated mitochondrial morphological damage and dysfunction caused by the neurotoxic peptide PrP106-126. Moreover, we found that mitochondrial biogenesis was impaired, and SIRT1 overexpression and activation alleviated PrP106-126-induced impairment of mitochondrial biogenesis in N2a cells. Further studies in PrP106-126-treated N2a cells revealed that SIRT1 regulates mitochondrial biogenesis through the PGC-1α-TFAM pathway. Finally, we showed that resveratrol resolved PrP106-126-induced mitochondrial dysfunction and cell apoptosis by promoting mitochondrial biogenesis through activation of the SIRT1-dependent PGC-1α/TFAM signaling pathway in N2a cells. Taken together, our findings further describe SIRT1 regulation of mitochondrial biogenesis and improve our understanding of mitochondria-related pathogenesis in prion diseases. Our findings support further investigation of SIRT1 as a potential target for therapeutic intervention of prion diseases.

Human-in-the-Loop Trajectory Optimization Based on sEMG Biofeedback for Lower-Limb Exoskeleton.

Lower-limb exoskeletons (LLEs) can provide rehabilitation training and walking assistance for individuals with lower-limb dysfunction or those in need of functionality enhancement. Adapting and personalizing the LLEs is crucial for them to form an intelligent human-machine system (HMS). However, numerous LLEs lack thorough consideration of individual differences in motion planning, leading to subpar human performance. Prioritizing human physiological response is a critical objective of trajectory optimization for the HMS. This paper proposes a human-in-the-loop (HITL) motion planning method that utilizes surface electromyography signals as biofeedback for the HITL optimization. The proposed method combines offline trajectory optimization with HITL trajectory selection. Based on the derived hybrid dynamical model of the HMS, the offline trajectory is optimized using a direct collocation method, while HITL trajectory selection is based on Thompson sampling. The direct collocation method optimizes various gait trajectories and constructs a gait library according to the energy optimality law, taking into consideration dynamics and walking constraints. Subsequently, an optimal gait trajectory is selected for the wearer using Thompson sampling. The selected gait trajectory is then implemented on the LLE under a hybrid zero dynamics control strategy. Through the HITL optimization and control experiments, the effectiveness and superiority of the proposed method are verified.

Datopotamab-deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial.

Among the goals of patient-centric care are the advancement of effective personalized treatment, while minimizing toxicity. The phase 2 I-SPY2.2 trial uses a neoadjuvant sequential therapy approach in breast cancer to further these goals, testing promising new agents while optimizing individual outcomes. Here we tested datopotamab-deruxtecan (Dato-DXd) in the I-SPY2.2 trial for patients with high-risk stage 2/3 breast cancer. I-SPY2.2 uses a sequential multiple assignment randomization trial design that includes three sequential blocks of biologically targeted neoadjuvant treatment: the experimental agent(s) (block A), a taxane-based regimen tailored to the tumor subtype (block B) and doxorubicin-cyclophosphamide (block C). Patients are randomized into arms consisting of different investigational block A treatments. Algorithms based on magnetic resonance imaging and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathological complete response, the primary endpoint. There are two primary efficacy analyses: after block A and across all blocks for the six prespecified breast cancer subtypes (defined by clinical hormone receptor/human epidermal growth factor receptor 2 (HER2) status and/or the response-predictive subtypes). We report results of 103 patients treated with Dato-DXd. While Dato-DXd did not meet the prespecified threshold for success (graduation) after block A in any subtype, the treatment strategy across all blocks graduated in the hormone receptor-negative HER2-Immune-DNA repair deficiency- subtype with an estimated pathological complete response rate of 41%. No new toxicities were observed, with stomatitis and ocular events occurring at low grades. Dato-DXd was particularly active in the hormone receptor-negative/HER2-Immune-DNA repair deficiency- signature, warranting further investigation, and was safe in other subtypes in patients who followed the treatment strategy. ClinicalTrials.gov registration: NCT01042379 .