Multi-rendezvous Spacecraft Trajectory Optimization with Beam P-ACO

The design of spacecraft trajectories for missions visiting multiple celestial bodies is here framed as a multi-objective bilevel optimization problem. A comparative study is performed to assess the performance of different Beam Search algorithms at tackling the combinatorial problem of finding the ideal sequence of bodies. Special focus is placed on the development of a new hybridization between Beam Search and the Population-based Ant Colony Optimization algorithm. An experimental evaluation shows all algorithms achieving exceptional performance on a hard benchmark problem. It is found that a properly tuned deterministic Beam Search always outperforms the remaining variants. Beam P-ACO, however, demonstrates lower parameter sensitivity, while offering superior worst-case performance. Being an anytime algorithm, it is then found to be the preferable choice for certain practical applications.Comment: Code available at https://github.com/lfsimoes/beam_paco__gtoc

Comprehensive Cell Surface Protein Profiling Identifies Specific Markers of Human Naive and Primed Pluripotent States

Human pluripotent stem cells (PSCs) exist in naive and primed states and provide important models to investigate the earliest stages of human development. Naive cells can be obtained through primed-to-naive resetting, but there are no reliable methods to prospectively isolate unmodified naive cells during this process. Here we report comprehensive profiling of cell surface proteins by flow cytometry in naive and primed human PSCs. Several naive-specific, but not primed-specific, proteins were also expressed by pluripotent cells in the human preimplantation embryo. The upregulation of naive-specific cell surface proteins during primed-to-naive resetting enabled the isolation and characterization of live naive cells and intermediate cell populations. This analysis revealed distinct transcriptional and X chromosome inactivation changes associated with the early and late stages of naive cell formation. Thus, identification of state-specific proteins provides a robust set of molecular markers to define the human PSC state and allows new insights into the molecular events leading to naive cell resetting.Imaging was performed at the Live Cell Imaging Facility/Nikon Center of Excellence, Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden, supported by grants from the Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Centre for Innovative Medicine, and the Jonasson donation to the School of Technology and Health, Royal Institute of Technology, Sweden. We would like to acknowledge the MedH Flow Cytometry facility at Karolinska Institutet, supported by grants from Karolinska Institutet and the Stockholm County Council. We thank Céline Vallot and Claire Rougeulle at the Université Paris Diderot for providing X chromosome SNP coordinates. We are grateful to Rudolph Jaenisch at the Whitehead Institute for Biomedical Research for providing WIBR3 cells and Austin Smith at the WT–MRC Cambridge Stem Cell Institute for providing H9 NK2 and FiPS cells. We thank all couples who donated embryos to this study. S.P., A.P.R., J.P.S., and F.L. are supported by grants from the Swedish Research Council (2013-2570), Ragnar Söderberg Foundation (M67/13), Swedish Foundation for Strategic Research (ICA-5), Knut and Alice Wallenberg Foundation (4-1205/2016 and 4-148/2017), and Centre for Innovative Medicine and by a Lau fellowship. R.W. is an ISAC Shared Resource Laboratory Emerging Leader. A.J.C. is supported by an MRC DTG Studentship (MR/J003808/1). P.J.R.G. is supported by the Wellcome Trust (WT093736) and BBSRC (BBS/ E/B/000C0402)

Prevalence and management of diabetic neuropathy in secondary care in Qatar

Aims Diabetic neuropathy (DN) is a “Cinderella” complication, particularly in the Middle East. A high prevalence of undiagnosed DN and those at risk of diabetic foot ulceration (DFU) is a major concern. We have determined the prevalence of DN and its risk factors, DFU and those at risk of (DFU) in patients with T2DM in secondary care in Qatar. Materials and methods Adults with T2DM were randomly selected from the two National Diabetes Centers in Qatar. DN was defined by the presence of neuropathic symptoms and a vibration perception threshold (VPT) ≥ 15 V. Participants with a VPT≥25 V were categorized as high risk for DFU. Painful DN was defined by a DN4 score ≥ 4. Logistic regression analysis was used to identify predictors of DN. Results In 1082 adults with T2DM (age 54 ± 11 years, duration of diabetes 10.0 ± 7.7 years, 60.6% males) the prevalence of DN was 23.0% (95% CI: 20.5%‐25.5%), of whom 33.7% (95% CI: 27.9%‐39.6%) were at high risk of DFU and 6.3% had DFU. 82.0% of the patients with DN were previously undiagnosed. The prevalence of DN increased with age and duration of diabetes and was associated with poor glycemic control (HbA1c ≥ 9%) AOR = 2.1 (95%CI: 1.3‐3.2), hyperlipidemia AOR = 2.7 (95%CI: 1.5‐5.0) and hypertension AOR = 2.0 (95%CI: 1.2‐3.4). Conclusions Despite, DN affecting 23% of adults with T2DM, 82% had not been previously diagnosed with 1/3 at high risk for DFU. This argues for annual screening and identification of patients with DN. Furthermore, we identify hyperglycemia, hyperlipidemia and hypertension as predictors of DN

Prevalence and risk factors for painful diabetic neuropathy in secondary health care in Qatar.

AIMS/INTRODUCTION:Painful diabetic peripheral neuropathy (PDPN) has a significant impact on the patient's quality of life. The prevalence of PDPN in the Middle East and North Africa (MENA) region has been reported to be almost double that of populations in the UK. We sought to determine the prevalence of PDPN and its associated factors in T2DM patients attending secondary care in Qatar. MATERIALS AND METHODS:This is a cross-sectional study of 1095 participants with T2DM attending Qatar's two national diabetes centers. PDPN and impaired vibration perception on the pulp of the large toes were assessed using the DN4 questionnaire with a cut-off ≥4 and the Neurothesiometer with a cut-off ≥15V, respectively. RESULTS:The prevalence of PDPN was 34.5% (95% CI: 31.7%-37.3%), but 80% of these patients had not previously been diagnosed or treated for this condition. Arabs had a higher prevalence of PDPN compared to South Asians (P<0.05). PDPN was associated with impaired vibration perception AOR=4.42 (95%CI: 2.92-6.70), smoking AOR=2.43 (95%CI: 1.43-4.15), obesity AOR=1.74 (95%CI: 1.13-2.66), being female AOR=1.65 (95%CI: 1.03-2.64) and duration of diabetes AOR=1.08 (95%CI: 1.05-1.11). Age, poor glycemic control, hypertension, physical activity and proteinuria showed no association with PDPN. CONCLUSIONS:PDPN occurs in 1/3 of T2DM patients attending secondary care in Qatar, but the majority have not been diagnosed. Arabs are at higher risk for PDPN. Impaired vibration perception, obesity and smoking are associated with PDPN in Qatar. This article is protected by copyright. All rights reserved

Prevalence and risk factors for diabetic neuropathy and painful diabetic neuropathy in primary and secondary health care in Qatar.

AIMS/INTRODUCTION:This study determined the prevalence and risk factors for DPN and pDPN in patients with type 2 diabetes (T2D) in primary health care (PHC) and secondary health care (SHC) in Qatar. MATERIALS AND METHODS:This is a cross-sectional multi-center study. Adults with T2D were randomly enrolled from four PHC centres and two Diabetes Centres in SHC in Qatar. Subjects underwent assessment of clinical and metabolic parameters, DPN and pDPN. RESULTS:1,386 subjects with T2D (297 from PHC and 1,089 from SHC) were recruited. The prevalence of DPN (14.8% vs 23.9%, P=0.001) and pDPN (18.1% vs 37.5%, P<0.0001) was significantly lower in PHC compared to SHC, whilst those with DPN at high risk for DFU (31.8% vs 40.0%, P=0.3) was comparable. The prevalence of undiagnosed DPN (79.5% vs 82.3%, P=0.66) was comparably high but undiagnosed pDPN (24.1% vs 71.5%, P<0.0001) was lower in PHC compared to SHC. The odds of DPN and pDPN increased with age and diabetes duration and DPN increased with poor glycemic control, hyperlipidemia and hypertension, whilst pDPN increased with obesity and reduced physical activity. CONCLUSIONS:The prevalence of DPN and pDPN in T2D is lower in PHC compared to SHC and is attributed to overall better control of risk factors and referral bias due to patients with poorly managed complications being referred to SHC. However, ~80% of patients had not been previously diagnosed with DPN in PHC and SHC. Further, we identify a number of modifiable risk factors for PDN and pDPN

Synthesis and Evaluation of Chloramphenicol Homodimers: Molecular Target, Antimicrobial Activity, and Toxicity against Human Cells

As fight against antibiotic resistance must be strengthened, improving old drugs that have fallen in reduced clinical use because of toxic side effects and/or frequently reported resistance, like chloramphenicol (CAM), is of special interest. Chloramphenicol (CAM), a prototypical wide-spectrum antibiotic has been shown to obstruct protein synthesis via binding to the bacterial ribosome. In this study we sought to identify features intensifying the bacteriostatic action of CAM. Accordingly, we synthesized a series of CAM-dimers with various linker lengths and functionalities and compared their efficiency in inhibiting peptide-bond formation in an Escherichia coli cell-free system. Several CAM-dimers exhibited higher activity, when compared to CAM. The most potent of them, compound 5, containing two CAM bases conjugated via a dicarboxyl aromatic linker of six successive carbon-bonds, was found to simultaneously bind both the ribosomal catalytic center and the exit-tunnel, thus revealing a second, kinetically cryptic binding site for CAM. Compared to CAM, compound 5 exhibited comparable antibacterial activity against MRSA or wild-type strains of Staphylococcus aureus, Enterococcus faecium and E. coli, but intriguingly superior activity against some CAM-resistant E. coli and Pseudomonas aeruginosa strains. Furthermore, it was almost twice as active in inhibiting the growth of T-leukemic cells, without affecting the viability of normal human lymphocytes. The observed effects were rationalized by footprinting tests, crosslinking analysis, and MD-simulations