The properties of synthetic peptides, including potency, stability, and bioavailability, are strongly influenced by modification of the peptide chain termini. Unfortunately, generally applicable ...methods for selective and mild C-terminal peptide functionalization are lacking. In this work, we explored the peptide amidase from Stenotrophomonas maltophilia as a versatile catalyst for diverse carboxy-terminal peptide modification reactions. Because the scope of application of the enzyme is hampered by its mediocre stability, we used computational protein engineering supported by energy calculations and molecular dynamics simulations to discover a number of stabilizing mutations. Twelve mutations were combined to yield a highly thermostable (Δ T m = 23 °C) and solvent-compatible enzyme. Protein crystallography and molecular dynamics simulations revealed the biophysical effects of mutations contributing to the enhanced robustness. The resulting enzyme catalyzed the selective C-terminal modification of synthetic peptides with small nucleophiles such as ammonia, methylamine, and hydroxylamine in various organic (co)solvents. The use of a nonaqueous environment allowed modification of peptide free acids with >85% product yield under thermodynamic control. On the basis of the crystal structure, further mutagenesis gave a biocatalyst that favors introduction of larger functional groups. Thus, the use of computational and rational protein design provided a tool for diverse enzymatic peptide modification.
Lifting is to use lifting equipment to lift components and install them to the designated position. On the main structure, lifting equipment is used to transport the flue and transport the sectional ...flue to the designated position. Certain deformation will occur during the lifting operation of the flue due to its force condition, but it is not known whether it is elastic deformation or plastic deformation. Therefore, this paper analyzes the stress and strain of the flue during operation by finite element method, and observes and analyzes the influence of plastic deformation on the whole flue.
Epidermal growth factor (EGF) is a recently described biomarker of acute GvHD (aGvHD). Whether low plasma EGF prior to hematopoietic cell transplantation (HCT) predisposes to the development of ...aGvHD, or whether EGF levels fall because of severe aGvHD, is unknown. To evaluate this, we tested plasma samples collected at pre-HCT baseline, day +28 and day +100 during the course of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402. We found that baseline EGF plasma concentrations were three-fold lower in HCT recipients compared to donors (24.3 vs 76.0 pg/mL, P<0.01). Ninety-one patients (43%) had a markedly low plasma EGF at pre-HCT baseline, defined as <2.7 pg/mL-an optimal cutpoint associated with development of grade III-IV aGvHD. Patients with these low EGF levels at pre-HCT baseline had a 2.9-fold increased risk of grade III-IV aGvHD by day +100. Patients with low EGF at day +28 after HCT had an increased risk of death (relative risk 2.3, P=0.02) by 1 year due to transplant-related toxicities, especially aGvHD. Our results suggest that very low plasma EGF early in the HCT process may predispose patients to an increased risk of death, potentially due to epithelial damage and limited repair capacity.
This study evaluated an expressive arts intervention program (“Colorful Life”) for adolescents with addicted parents and parents with addiction in Hong Kong. Different evaluation strategies were ...employed. Objective outcome evaluation adopting a one group pretest-posttest design showed positive changes in adolescents’ (
N
= 43) beliefs about addiction. Both adolescents’ and parents’ (
N
= 21) psychosocial competencies were enhanced post-intervention. Subjective outcome evaluation from both adolescent (
N
= 47) and parent (
N
= 22) groups showed positive perceptions of the program content, implementers, and achievement of program objectives. Findings provided preliminary evidence to support and yielded practical implications for the adoption of the multi-addiction syndrome model, positive youth development, and expressive arts approaches in the development of interventions for high-risk adolescents and addictive parents.
Many studies examining genetic influences on physical activity (PA) have evaluated the impact of single nucleotide polymorphisms (SNPs) related to the development of lifestyle‐related chronic ...diseases, under the hypothesis that they would be associated with PA. However, PA is a multidetermined behavior and associated with a multitude of health consequences. Thus, examining a broader range of candidate genes associated with a broader range of PA correlates may provide new insights into the genetic underpinnings of PA. In this study, we focus on one such correlate – sensation‐seeking behavior. Participants (N = 1130 Mexican origin youth) provided a saliva sample and data on PA and sensation‐seeking tendencies in 2008–2009. Participants were genotyped for 630 functional and tagging variants in the dopamine, serotonin and cannabinoid pathways. Overall 30% of participants (males – 37.6% and females – 22.0%) reported ≥60 min of PA on 5 of 7 days. After adjusting for gender, age and population stratification, and applying the Bayesian False Discovery Probability approach for assessing noteworthiness, four gene variants were significantly associated with PA. In a multivariable model, being male, having higher sensation‐seeking tendencies and at least one copy of the minor allele for SNPs in angiotensin I‐converting enzyme gene ACE; rs8066276 odds ratio (OR) = 1.44; P = 0.012 and tryptophan hydroxylase 2 gene (TPH2; rs11615016 OR = 1.73; P = 0.021) were associated with increased likelihood of meeting PA recommendations. Participants with at least one copy of the minor allele for SNPs in synaptosomal‐associated protein 25 gene (SNAP25; rs363035 OR = 0.53; P = 0.005) and cannabinoid receptor 1 gene (CNR1; rs6454672 OR = 0.62; P = 0.022) have decreased likelihood of meeting PA recommendations. Our findings extend current knowledge of the complex relationship between PA and possible genetic underpinnings.
Being male, reporting higher levels of thrill and adventure seeking and subjective social status, as well as the minor alleles of the SNPs we identified in tryptophan hydroxylase 2 gene and angiotensin I‐converting enzyme gene were associated with increased likelihood of meeting PA recommendations, whereas the minor alleles of the SNPs we identified in synaptosomal‐associated protein 25 gene and in the cannabinoid receptor 1 gene were associated with decreased likelihood of meeting PA recommendations.
The study of children who experienced with febrile seizures(FS) as a result of COVID-19 infection to gain insight into the clinical characteristics and prognosis of neurological damage, with the aim ...of improving prevention, diagnosis, and the treatment of neurological complications. This study investigated the clinical features of 53 children with FS who were admitted to Sanya Women and Children's Hospital from December 1, 2022, to January 31, 2023. The results indicated that the duration of convulsion in the case and control group was 7.90±8.91 and 2.67±1.23 (minutes) respectively. The analysis reveals that convulsions occurred within 24 hours in 39 cases (95.12%) of the case group, and in 8 cases (66.7%) of the control group. The difference was statistically significant (P<0.05). Additionally, the case group presented lower counts of WBC and NEU compared to the control group (p<0.05). The findings indicate that convulsions manifest at earlier stages of COVID-19 in children and the last longer than in the control group. It is therefore crucial for healthcare workers to remain attentive to patients with COVID-19 who report fever within 24 hours, and act promptly to implement preventive measures, particularly in cases of prolonged fever. It is essential to integrate the clinical manifestation, particularly convulsions, and the continuous numerical changes of inflammatory factors to assess COVID-19 linked with febrile seizures. In addition, larger-scale multi-center and systematic research are necessary to aid clinicians in monitoring neuropathological signals and biological targets, enabling more equitable diagnosis and treatment plans.
Dietary factors may play an important role in periodontal health. However, current evidence from observational studies remains inconclusive.
This study aimed to investigate the causal relationships ...between dietary exposures and periodontal disease risks using Mendelian randomization analysis.
Large-scale genome-wide association study summary statistics for 20 dietary factors were obtained from the MRC-IEU consortium. Multivariable and univariable 2-sample Mendelian randomization analyses were performed to assess the causal effects of each dietary exposure on 6 periodontal outcomes, including gingivitis and periodontitis.
Genetically predicted higher dried fruit intake was significantly associated with reduced risks of acute gingivitis (odds ratio OR: 0.02; 95% confidence interval CI: 0.00-0.42;
= 0.01) and bleeding gums (OR: 0.96; 95% CI: 0.93-0.99;
= 0.01). Higher fresh fruit and water intake showed protective effects against chronic gingivitis (OR: 0.18; 95% CI: 0.04-0.91;
= 0.04 and OR: 0.15; 95% CI: 0.04-0.53;
= 0.00) and bleeding gums (OR: 0.95; 95% CI: 0.92-0.981;
= 0.00 and OR: 0.98; 95% CI: 0.96-0.99;
= 0.02). Alcohol intake frequency and processed meat intake were risk factors for bleeding gums (OR: 1.01; 95% CI: 1.00-1.02;
= 0.01 and OR: 1.05; 95% CI: 1.01-1.08;
= 0.00) and painful gums (OR: 1.01; 95% CI: 1.00-1.01;
= 0.00 and OR: 1.02; 95% CI: 1.01-1.03;
= 0.00). Most of the causal relationships between genetic predisposition to the specified dietary factors and periodontal diseases remained statistically significant (P < 0.05) after adjusting for genetic risks associated with dentures, smoking, and type 2 diabetes in multivariable Mendelian randomization models.
The findings suggest potential protective effects of higher fruit and water intake against gingivitis and other periodontal problems, while alcohol and processed meat intake may increase the risks of periodontal disease. Our study provides preliminary causal evidence on the effects of diet on periodontal health and could inform prevention strategies targeting dietary habits to improve oral health.
This study suggests that fruit and water intake may protect against periodontal disease, while alcohol and processed meats increase risk, informing dietary guidelines to improve oral health.
Long-term tracking of nanoparticles to resolve intracellular structures and motions is essential to elucidate fundamental parameters as well as transport processes within living cells. Fluorescent ...nanodiamond (ND) emitters provide cell compatibility and very high photostability. However, high stability, biocompatibility, and cellular uptake of these fluorescent NDs under physiological conditions are required for intracellular applications. Herein, highly stable NDs encapsulated with Cowpea chlorotic mottle virus capsid proteins (ND-CP) are prepared. A thin capsid protein layer is obtained around the NDs, which imparts reactive groups and high colloidal stability, while retaining the opto-magnetic properties of the coated NDs as well as the secondary structure of CPs adsorbed on the surface of NDs. In addition, the ND-CP shows excellent biocompatibility both in vitro and in vivo. Long-term 3D trajectories of the ND-CP with fine spatiotemporal resolutions are recorded; their intracellular motions are analyzed by different models, and the diffusion coefficients are calculated. The ND-CP with its brilliant optical properties and stability under physiological conditions provides us with a new tool to advance the understanding of cell biology, e.g., endocytosis, exocytosis, and active transport processes in living cells as well as intracellular dynamic parameters.
Amyotrophic lateral sclerosis (ALS) is a fatal movement disorder involving degeneration of motor neurons through dysfunction of the RNA-binding protein TDP-43. Pericytes, the perivascular cells of ...the blood-brain, blood-spinal cord, and blood-CSF barriers also degenerate in ALS. Indeed, pericytes are among the earliest cell types to show gene expression changes in pre-symptomatic animal models of ALS. This suggests that pericyte degeneration precedes neurodegeneration and may involve pericyte cell-autonomous TDP-43 dysfunction. Here we determined the effect of TDP-43 dysfunction in human brain pericytes on interleukin 6 (IL-6), a critical secreted inflammatory mediator reported to be regulated by TDP 43. Primary human brain pericytes were cultured from biopsy tissue from epilepsy surgeries and TDP-43 was silenced using siRNA. TDP-43 silencing of pericytes stimulated with pro-inflammatory cytokines, interleukin-1β or tumour necrosis factor alpha, robustly suppressed the induction of IL-6 transcript and protein. IL-6 regulation by TDP-43 did not involve the assembly of TDP-43 nuclear splicing bodies, and did not occur via altered splicing of IL6. Instead, transcriptome-wide analysis by RNA-Sequencing identified a poison exon in the IL6 destabilising factor HNRNPD (AUF1) as a splicing target of TDP-43. Our data support a model whereby TDP-43 silencing favours destabilisation of IL6 mRNA, via enhanced AU-rich element-mediated decay by HNRNP/AUF1. This suggests that cell-autonomous deficits in TDP-43 function in human brain pericytes would suppress their production of IL-6. Given the importance of the blood-brain and blood-spinal cord barriers in maintaining motor neuron health, TDP-43 in human brain pericytes may represent a cellular target for ALS therapeutics.
•Pericytes of the blood-brain and other barriers degenerate in ALS.•TDP-43 robustly regulates expression and secretion of the pericyte cytokine IL-6.•TDP-43 promotes poison exon inclusion in IL6 mRNA instability factor HNRNPD/AUF1.•TDP-43 dysfunction in pericytes in ALS may suppress IL-6 via HNRNPD/AUF1.
We present measurements of the cosmic microwave background (CMB) radiation temperature anisotropy in the multipole range 2000 < < 3000 from the QUaD telescope's second and third observing seasons. ...After masking the brightest point sources our results are consistent with the primary Lambda CDM expectation alone. We estimate the contribution of residual (un-masked) radio point sources using a model calibrated to our own bright source observations, and a full simulation of the source finding and masking procedure. Including this contribution slightly improves the xi 2. We also fit a standard Sunyaev-Zel'dovich (SZ) template to the bandpowers and see no strong evidence of an SZ contribution, which is as expected for sigma 8 0.8.
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