The Dimensional Synthesis of Planar Parallel Cable-Driven Mechanisms Through Convex Relaxations

The wrench-closure workspace (WCW) of parallel cable-driven mechanisms is the set of poses for which any wrench can be produced at the end-effector by a set of positive cable tensions. In this paper, we tackle the dimensional synthesis problem, namely, that of finding a geometry for a planar parallel cable-driven mechanism (PPCDM) whose WCW contains a prescribed workspace. To this end, we first recall a linear program to determine whether a given pose is inside or outside the WCW of a given PPCDM. The relaxation of this linear program over a box leads to a nonlinear feasibility problem that can only be satisfied when this box is completely inside the WCW. We extend this feasibility problem to find a PPCDM geometry whose WCW includes a given set of boxes. These boxes represent the prescribed workspace or an estimate thereof, which may be obtained through interval analysis. Finally, we introduce a nonlinear program through which the PPCDM geometry is changed while maximizing the scaling factor of the prescribed set of boxes. When the optimum scaling factor is greater or equal to one, the WCW of the resulting PPCDM contains the set of boxes

Selective Labeling and Identification of the Tumor Cell Proteome of Pancreatic Cancer In Vivo

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers. Dissecting the tumor cell proteome from that of the non-tumor cells in the PDAC tumor bulk is critical for tumorigenesis studies, biomarker discovery, and development of therapeutics. However, investigating the tumor cell proteome has proven evasive due to the tumor’s extremely complex cellular composition. To circumvent this technical barrier, we have combined bioorthogonal noncanonical amino acid tagging (BONCAT) and data-independent acquisition mass spectrometry (DIA-MS) in an orthotopic PDAC model to specifically identify the tumor cell proteome in vivo. Utilizing the tumor cell-specific expression of a mutant tRNA synthetase transgene, this approach provides tumor cells with the exclusive ability to incorporate an azide-bearing methionine analogue into newly synthesized proteins. The azide-tagged tumor cell proteome is subsequently enriched and purified via a bioorthogonal reaction and then identified and quantified using DIA-MS. Applying this workflow to the orthotopic PDAC model, we have identified thousands of proteins expressed by the tumor cells. Furthermore, by comparing the tumor cell and tumor bulk proteomes, we showed that the approach can distinctly differentiate proteins produced by tumor cells from those of non-tumor cells within the tumor microenvironment. Our study, for the first time, reveals the tumor cell proteome of PDAC under physiological conditions, providing broad applications for tumorigenesis, therapeutics, and biomarker studies in various human cancers

Caon serum iron level, ferritin and total iron binding capacity level among nonpregnant women with and without melasma

Background: Melasma is a common acquired disorder characterized by symmetric, hyperpigmented patches with an irregular outline, occurring most commonly on the face. It is most prevalent among young to middle-aged women. Although iron overload affects skin pigmentation, effect of iron deficiency on skin is not clear. So, we evaluated serum iron level, ferritin and total iron binding capacity (TIBC) level among nonpregnant women with and without melasma. Materials and Methods: A cross-sectional case study was conducted in 2012 at university dermatologic department on 33 nonpregnant women with melasma (case) and 33 nonpregnant women without melasma (control). Serum iron level, TIBC and ferritin in the two groups was measured and compared. Results: Serum iron level was lower in the case group (85 ± 11) in comparison with control group (102 ± 9), but the difference was not significant (P: 0.9). Mean TIBC and Ferritin were higher in the case group (TIBC: 329.4 ± 29, ferritin: 6 ± 18) than the control group (TIBC: 329.3 ± 29, ferritin: 33 ± 6) without significant difference. Conclusion: Although the serum iron level was lower in nonpregnant women with mealsma, it was not significant compared with those without melasma. © 2015, Isfahan University of Medical Sciences(IUMS). All rights reserved

Sinteza, antitumorsko i citostatsko djelovanje derivata 6H-indolo[2,3-b]kinoksalina

Various 6-aralkyl-9-substituted-6H-indolo[2,3-b]quinoxalines were synthesized by reaction of 1,5-disubstituted 2,3-dioxo-2,3-dihydroindole with orthophenylene diamine. Appreciable anticancer activity of compounds 5b, 5d, 5g and 5l at various cell lines among 59 human tumor cell panels was observed. All the synthesized compounds were evaluated for cytostatic activity against human Molt 4/C8 and CEM T-lymphocytes as well as for murine L1210 leukemia cells. Compound 5h exhibited an IC50 of 71 μmol mL1 against Molt 4/C8 and 117 μmol mL1 against CEM compared to melphalan 3.2 μmol mL1 and 2.5 μmol mL1, respectively. The IC50 for compound 7i against L1210 was 7.2 μmol mL1 compared to melphalan 2.1 μmol mL1.Reakcijom 1,5-disupstituiranih 2,3-diokso-2,3-dihidroindola s ortofenilen diaminom sintetizirani su različiti 6-aralkil-9-supstituirani-6H-indolo[2,3-b]kinoksalini. Spojevi 5b, 5d, 5g i 5l pokazali su značajno antitumorsko djelovanje na 59 humanih tumorskih stanica. Svi sintetizirani spojevi ispitani su na citostatsko djelovanje na stanične linije Molt 4/C8 i CEM T-limfocite, te na murin L1210 stanice leukemije. IC50 za spoj 5h je 71 μmol mL1 na staničnu liniju Molt 4/C8 i 117 μmol mL1 na CEM, dok su vrijednosti za melfalan 3,2, odnosno 2,5 μmol mL1. IC50 spoja 7i na stanice L1210 je 7,2 μmol mL1, dok je za melfalan 2,1 μmol mL1

Arylmethylene hydrazine derivatives containing 1,3-dimethylbarbituric moiety as novel urease inhibitors

A new series of arylmethylene hydrazine derivatives bearing 1,3-dimethylbarbituric moiety 7a�o were designed, synthesized, and evaluated for their in vitro urease inhibitory activity. All the title compounds displayed high anti-urease activity, with IC50 values in the range of 0.61 ± 0.06�4.56 ± 0.18 µM as compared to the two standard inhibitors hydroxyurea (IC50 = 100 ± 0.15 μM) and thiourea (IC50 = 23 ± 1.7 μM). Among the synthesized compounds, compound 7h with 2-nitro benzylidene group was found to be the most potent compound. Kinetic study of this compound revealed that it is a mix-mode inhibitor against urease. Evaluation of the interaction modes of the synthesized compounds in urease active site by molecular modeling revealed that that compounds with higher urease inhibitor activity (7h, 7m, 7c, 7l, 7i, and 7o, with IC50 of 0.61, 0.86, 1.2, 1.34, 1.33, 1.94 μM, respectively) could interact with higher number of residues, specially Arg609, Cys592 (as part of urease active site flap) and showed higher computed free energy, while compounds with lower urease activity (7f, 7n, 7g, and 7a with IC50 of 3.56, 4.56, 3.62 and 4.43 μM, respectively) and could not provide the proper interaction with Arg609, and Cys592 as the key interacting residues along with lower free binding energy. MD investigation revealed compound 7h interacted with Arg609 and Cys592 which are of the key residues at the root part of mobile flap covering the active site. Interacting with the mentioned residue for a significant amount of time, affects the flexibility of the mobile flap covering the active site and causes inhibition of the ureolytic activity. Furthermore, in silico physico-chemical study of compounds 7a�o predicted that all these compounds are drug-likeness with considerable orally availability. © 2021, The Author(s)

Evaluation of sesamum gum as an excipient in matrix tablets

In developing countries modern medicines are often beyond the affordability of the majority of the population. This is due to the reliance on expensive imported raw materials despite the abundance of natural resources which could provide an equivalent or even an improved function. The aim of this study was to investigate the potential of sesamum gum (SG) extracted from the leaves of Sesamum radiatum (readily cultivated in sub-Saharan Africa) as a matrix former. Directly compressed matrix tablets were prepared from the extract and compared with similar matrices of HPMC (K4M) using theophylline as a model water soluble drug. The compaction, swelling, erosion and drug release from the matrices were studied in deionized water, 0.1 N HCl (pH 1.2) and phosphate buffer (pH 6.8) using USP apparatus II. The data from the swelling, erosion and drug release studies were also fitted into the respective mathematical models. Results showed that the matrices underwent a combination of swelling and erosion, with the swelling action being controlled by the rate of hydration in the medium. SG also controlled the release of theophylline similar to the HPMC and therefore may have use as an alternative excipient in regions where Sesamum radiatum can be easily cultivated

Global, regional, and national burden of meningitis and its aetiologies, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: Although meningitis is largely preventable, it still causes hundreds of thousands of deaths globally each year. WHO set ambitious goals to reduce meningitis cases by 2030, and assessing trends in the global meningitis burden can help track progress and identify gaps in achieving these goals. Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we aimed to assess incident cases and deaths due to acute infectious meningitis by aetiology and age from 1990 to 2019, for 204 countries and territories. Methods: We modelled meningitis mortality using vital registration, verbal autopsy, sample-based vital registration, and mortality surveillance data. Meningitis morbidity was modelled with a Bayesian compartmental model, using data from the published literature identified by a systematic review, as well as surveillance data, inpatient hospital admissions, health insurance claims, and cause-specific meningitis mortality estimates. For aetiology estimation, data from multiple causes of death, vital registration, hospital discharge, microbial laboratory, and literature studies were analysed by use of a network analysis model to estimate the proportion of meningitis deaths and cases attributable to the following aetiologies: Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, group B Streptococcus, Escherichia coli, Klebsiella pneumoniae, Listeria monocytogenes, Staphylococcus aureus, viruses, and a residual other pathogen category. Findings: In 2019, there were an estimated 236 000 deaths (95% uncertainty interval [UI] 204 000–277 000) and 2·51 million (2·11–2·99) incident cases due to meningitis globally. The burden was greatest in children younger than 5 years, with 112 000 deaths (87 400–145 000) and 1·28 million incident cases (0·947–1·71) in 2019. Age-standardised mortality rates decreased from 7·5 (6·6–8·4) per 100 000 population in 1990 to 3·3 (2·8–3·9) per 100 000 population in 2019. The highest proportion of total all-age meningitis deaths in 2019 was attributable to S pneumoniae (18·1% [17·1–19·2]), followed by N meningitidis (13·6% [12·7–14·4]) and K pneumoniae (12·2% [10·2–14·3]). Between 1990 and 2019, H influenzae showed the largest reduction in the number of deaths among children younger than 5 years (76·5% [69·5–81·8]), followed by N meningitidis (72·3% [64·4–78·5]) and viruses (58·2% [47·1–67·3]). Interpretation: Substantial progress has been made in reducing meningitis mortality over the past three decades. However, more meningitis-related deaths might be prevented by quickly scaling up immunisation and expanding access to health services. Further reduction in the global meningitis burden should be possible through low-cost multivalent vaccines, increased access to accurate and rapid diagnostic assays, enhanced surveillance, and early treatment. Funding: Bill & Melinda Gates Foundation