In vivo consequences of deleting EGF repeats 8–12 including the ligand binding domain of mouse Notch1

<p>Abstract</p> <p>Background</p> <p>Notch signaling is highly conserved in the metazoa and is critical for many cell fate decisions. Notch activation occurs following ligand binding to Notch extracellular domain. <it>In vitro </it>binding assays have identified epidermal growth factor (EGF) repeats 11 and 12 as the ligand binding domain of Drosophila Notch. Here we show that an internal deletion in mouse Notch1 of EGF repeats 8–12, including the putative ligand binding domain (lbd), is an inactivating mutation <it>in vivo</it>. We also show that maternal and zygotic <it>Notch1</it>^{<it>lbd</it>/<it>lbd </it>}mutant embryos develop through gastrulation to mid-gestation.</p> <p>Results</p> <p><it>Notch1</it>^{<it>lbd</it>/<it>lbd </it>}embryos died at mid-gestation with a phenotype indistinguishable from <it>Notch1 </it>null mutants. In embryonic stem (ES) cells, Notch1^lbdwas expressed on the cell surface at levels equivalent to wild type Notch1, but Delta1 binding was reduced to the same level as in <it>Notch1 </it>null cells. In an ES cell co-culture assay, Notch signaling induced by Jagged1 or Delta1 was reduced to a similar level in <it>Notch1</it>^{<it>lbd</it><it/>}and <it>Notch1 </it>null cells. However, the <it>Notch1</it>^{<it>lbd</it>/<it>lbd </it>}allele was expressed similarly to wild type Notch1 in <it>Notch1</it>^{<it>lbd</it>/<it>lbd </it>}ES cells and embryos at E8.75, indicating that Notch1 signaling is not essential for the <it>Notch1 </it>gene to be expressed. In addition, maternal and zygotic <it>Notch1 </it>mutant blastocysts developed through gastrulation.</p> <p>Conclusion</p> <p>Mouse Notch1 lacking the ligand binding domain is expressed at the cell surface but does not signal in response to the canonical Notch ligands Delta1 and Jagged1. Homozygous <it>Notch1</it>^{<it>lbd</it>/<it>lbd </it>}mutant embryos die at ~E10 similar to <it>Notch1 </it>null embryos. While Notch1 is expressed in oocytes and blastocysts, Notch1 signaling via canonical ligands is dispensable during oogenesis, blastogenesis, implantation and gastrulation.</p

Effect of combined vitamin D and microwave ablation of parathyroid glands on blood pressure and cardiac function in maintenance-hemodialysis patients with uremic secondary hyperparathyroidism

Purpose: To investigate the effect of microwave ablation of parathyroid glands in combination with active vitamin D on blood pressure and cardiac function in maintenance-hemodialysis patients with uremic secondary hyperparathyroidism. Methods: One hundred and twenty maintenance-hemodialysis patients with uremic secondary hyperparathyroidism admitted to Meizhou People’s Hospital were assigned to 2 groups (A and B) in the order of their admission. Each group had 60 patients. Both groups were treated with active vitamin D, while patients in group A were, in addition, subjected to microwave ablation of parathyroid glands. Blood pressure, and indices for cardiac function, thyroid function s and anemia were determined. Results: After treatment, the blood pressure of group A was significantly lower than that of group B (p &lt; 0.05). Moreover, after treatment, there were significant improvements in indices of cardiac function, thyroid function and anemia in group A patients, relative to group B patients. Conclusion: Microwave ablation of parathyroid glands, when combined with active vitamin D, improves blood pressure, cardiac function and anemia status. Furthermore, the combined therapy enhances recovery of thyroid function in maintenance-hemodialysis patients with uremic secondary hyperparathyroidism. However, the combined therapy should be subjected to further clinical trials prior to application in clinical practice. Keywords: Microwave ablation; Parathyroid glands; Active vitamin D; Hyperparathyroidis

Disability transitions and health expectancies among elderly people aged 65 years and over in China: A nationwide longitudinal study

Disability has become a critical issue among elderly populations, yet limited large-scale research related to this issue has been conducted in China, an aging society. This study explored sex and urban-rural differences in disability transitions and life expectancies among older adults in China. Data were collected from the Chinese Longitudinal Health Longevity Survey (CLHLS), which enrolled people aged 65 and older and was conducted in randomly selected counties and cities across 22 provinces in China. Disability was diagnosed based on basic activities of daily living (BADLs) and instrumental activities of daily living (IADLs). Several individual characteristics were assessed, including sociodemographic factors (age, sex and region, etc.) and health behaviors (currently smoking, currently drinking, etc.). Multistate models were applied to analyze the transition rates among 4 states: no disability, mild disability, severe disability and death. The transition rates from disabled states to the no-disability state were found to decrease markedly with age. The rates of recovery from mild disability in rural areas were higher than those in urban areas. Rural elderly individuals lived shorter lives than their urban counterparts, but they tended to live with better functional status, spending a larger fraction of their remaining life with less severe disability. Based on these findings, devoting more attention and resources to rural areas may help less severely disabled people recuperate and prevent severe disability. The study provides insights into health plan strategies to help guide the allocation of limited resources

Sm3+-Mn4+ activated Sr2GdTaO6 red phosphor for plant growth lighting and optical temperature sensing

Optical temperature sensing and plant growth lighting multifunctional applications can be realized by red luminescent materials. In this paper, novel Sm3+ and Sm3+-Mn4+ activated Sr2GdTaO6 (SGTO) red phosphors for plant growth and optical temperature sensing were comprehensively analyzed. The phase, luminescence property and thermal stability of the material were tested. For PL performance, SGTO:0.075Sm3+ exhibits the maximum emission intensity in the range (560–670 nm). The emission range of SGTO:0.075Sm3+ after introducing Mn4+ is mainly dark red light emission in the range from 630 to 750 nm, and the optimum dopingconcentration of Mn4+ is determined to be 0.3 %. The emission band of SGTO:0.075Sm3+ and SGTO:0.075Sm3+, 0.003Mn4+ matches the absorption band of the plants. For optical temperature sensing properties, the relative sensitivity (Sr) and absolute sensitivity (Sa) of SGTO:0.075Sm3+, 0.003Mn4+ are 2.94

Cognitive impairment and risk of all-cause and cardiovascular disease mortality over 20-year follow-up: Results from the BLSA

Background-Cognitive impairment may increase the risk of all-cause and cardiovascular disease (CVD) mortality. This study examined the association between cognitive function and risk of all-cause and CVD mortality among the elderly in Beijing, China. Methods and Results-A total of 1996 participants aged ≥55 years at baseline were enrolled from the BLSA (Beijing Longitudinal Study of Aging). Cognitive function was assessed using the Mini-Mental State Examination (MMSE), and participants were categorized as

Correction: Multi-angle tracking synthetic kinetics of phase evolution in Li-rich Mn-based cathodes

Correction for ‘Multi-angle tracking synthetic kinetics of phase evolution in Li-rich Mn-based cathodes’ by Shenyang Xu et al., Energy Environ. Sci., 2024, https://doi.org/10.1039/d3ee04199a. The affiliation for the author Tianyi Li should have read as follows: X-Ray Science Division, Argonne National Laboratory, Lemont, IL 60439, USA. The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers

Identification of Parkinsons disease PACE subtypes and repurposing treatments through integrative analyses of multimodal data.

Parkinsons disease (PD) is a serious neurodegenerative disorder marked by significant clinical and progression heterogeneity. This study aimed at addressing heterogeneity of PD through integrative analysis of various data modalities. We analyzed clinical progression data (≥5 years) of individuals with de novo PD using machine learning and deep learning, to characterize individuals phenotypic progression trajectories for PD subtyping. We discovered three pace subtypes of PD exhibiting distinct progression patterns: the Inching Pace subtype (PD-I) with mild baseline severity and mild progression speed; the Moderate Pace subtype (PD-M) with mild baseline severity but advancing at a moderate progression rate; and the Rapid Pace subtype (PD-R) with the most rapid symptom progression rate. We found cerebrospinal fluid P-tau/α-synuclein ratio and atrophy in certain brain regions as potential markers of these subtypes. Analyses of genetic and transcriptomic profiles with network-based approaches identified molecular modules associated with each subtype. For instance, the PD-R-specific module suggested STAT3, FYN, BECN1, APOA1, NEDD4, and GATA2 as potential driver genes of PD-R. It also suggested neuroinflammation, oxidative stress, metabolism, PI3K/AKT, and angiogenesis pathways as potential drivers for rapid PD progression (i.e., PD-R). Moreover, we identified repurposable drug candidates by targeting these subtype-specific molecular modules using network-based approach and cell line drug-gene signature data. We further estimated their treatment effects using two large-scale real-world patient databases; the real-world evidence we gained highlighted the potential of metformin in ameliorating PD progression. In conclusion, this work helps better understand clinical and pathophysiological complexity of PD progression and accelerate precision medicine

J-shaped relationship between stress hyperglycemia ratio and 90-day and 180-day mortality in patients with a first diagnosis of acute myocardial infarction: analysis of the MIMIC-IV database

Abstract Aims The Stress Hyperglycemia Ratio (SHR) potently predicts adverse outcomes in patients with cardiovascular and cerebrovascular diseases. However, the relationship between SHR and short-term mortality risk in patients with a first diagnosis of acute myocardial infarction (AMI) remains contentious. This study sought to understand better the relationship between SHR and short-term mortality risk in patients with a first diagnosis of AMI. Methods We conducted a cohort study using data from 1961 patients with a first diagnosis of AMI from the MIMIC-IV (version 2.2) database. Patients were divided into three groups based on SHR tertiles. The Cox proportional hazards model and a two-segmented Cox proportional hazards model were used to elucidate the nonlinear relationship between SHR in patients with a first diagnosis of AMI and mortality. Results Of the surveyed population, 175 patients (8.92%) died within 90 days, and 210 patients (10.71%) died within 180 days. After multivariate adjustments, elevated SHR levels were significantly and non-linearly associated with a higher risk of 90-day and 180-day mortality in patients with a first diagnosis of AMI, showing a J-shaped correlation with an inflection point at 0.9. Compared to participants with SHR levels below the inflection point, those with higher SHR levels had a fivefold increased risk of 90-day mortality (hazard ratio [HR] 5.74; 95% confidence interval [CI] 3.19, 10.33) and a fourfold increased risk of 180-day mortality (HR 4.56; 95% CI 2.62, 7.95). In the subgroup analysis, patients with pre-diabetes mellitus (pre-DM) and higher SHR levels had increased 90-day (HR 6.90; 95% CI  1.98, 24.02) and 180-day mortality risks (HR 5.30; 95% CI  1.96, 14.27). Conclusion In patients with a first diagnosis of AMI, there is a J-shaped correlation between SHR and 90-day and 180-day mortality, with an adverse prognostic inflection point of SHR at 0.9