bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping the endothelial cell S-Sulfhydrome highlights the crucial role of integrin sulfhydration in vascular function
Authors: Bibli D R , Hu D R , Looso D R , Weigert D R , Wittig D R , Papapetropoulos D R , Sigala D R , Fleming D R ,   IVS
Published: October 2021

Background

In vascular endothelial cells, cysteine metabolism by the cystathionine-γ lyase (CSE), generates hydrogen sulfide-related sulfane sulfur compounds (H2Sn), that exert their biological actions via cysteine S-sulfhydration of target proteins. This study set out to map the “S-sulfhydrome” i.e. the spectrum of proteins targeted by H2Sn in human endothelial cells.

Methods

LC-MS/MS was used to identify S-sulfhydrated cysteines in endothelial cell proteins and β3 integrin intra-protein disulfide bond rearrangement. Functional studies included endothelial cell adhesion, shear stress-induced cell alignment, blood pressure measurements and flow-induced vasodilatation in endothelial cell-specific CSE knock out mice and a small collective of patients with endothelial dysfunction.

Results

Three paired sample sets were compared: (1) native human endothelial cells isolated from plaque-free mesenteric arteries (CSE activity high) and plaque-containing carotid arteries (CSE activity low), (2) cultured human endothelial cells kept under static conditions or exposed to fluid shear stress to decrease CSE expression, and (3) cultured endothelial cells exposed to shear stress to decrease CSE expression and treated with solvent or the slow-releasing H2Sn donor, SG1002. The endothelial cell “S-sulfhydrome” consisted of 3446 individual cysteine residues in 1591 proteins. The most altered family of proteins were the integrins and focusing on β3 integrin in detail we found that S-sulfhydration affected intra-protein disulfide bond formation and was required for the maintenance of an extended-open conformation of the β leg. β3 integrin S-sulfhydration was required for endothelial cell mechanotransduction in vitro as well as flow-induced dilatation in murine mesenteric arteries. In cultured cells, the loss of S-sulfhydration impaired interactions between β3 integrin and Gα13, resulting in the constitutive activation of RhoA and impaired flow-induced endothelial cell realignment. In humans with atherosclerosis, endothelial function correlated with low H2Sn generation, impaired flow-induced dilatation and a failure to detect β3 integrin S-sulfhydration, all of which were rescued following the administration of an H2S supplement.

Conclusions

Vascular disease is associated with marked changes in the S-sulfhydration of endothelial cell proteins involved in mediating responses to flow. Short term H2Sn supplementation improved vascular reactivity in humans highlighting the potential of interfering with this pathway to treat vascular disease.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft
Is the TCF21 gene protection or risk for coronary artery disease?
Authors: Santos M , Mendonca M I , Temtem M , Sousa J A , Mendonca F , Monteiro J , Sousa A C , Freitas S , Henriques E , Guerra G , Drumond A , Palma Dos Reis R ,   GENEMACOR study
Published: October 2021

Introduction

TCF21 is expressed in cells that migrate into the developing plaque facilitating the repair of the vessel wall. However, the rs12190287 risk allele (C) of TCF21 can lead to reduced TCF21 expression being a risk factor for CAD.

Purpose

Investigate whether the variant rs12190287 G>C of TCF21 gene represents a risk factor for CAD in a Southern European population.

Methods

Case-control with 3139 individuals, 1723 CAD patients and 1416 controls, adjusted for age and gender. Genotyping of TCF21 rs12190287 G>C was performed by TaqMan Real-Time PCR. CAD association of each genetic model was evaluated.

Multivariate logistic regression analysis adjusted for confound variables: smoking status, dyslipidemia, diabetes, physical inactivity, and hypertension, was made.

Results

TCF21 rs12190287 G>C has shown significant genotypic differences between cases and controls: GG 9.5% vs 11.9%; GC 43.2% vs 46.5% and CC 47.3% vs 41.6%. CAD risk was significant in all models: dominant (OR 1.28; 95% CI: 1.02–1.61; p=0.033); recessive (OR 1.26; 95% CI: 1.09–1.45; p=0.001); additive (OR 1.20; 95% CI: 1.08–1.34; p=0.001). After multivariate analysis, TCF21 variant was independently associated with CAD.

Conclusion

TCF21 variant rs12190287 G>C may be a risk factor for CAD. It is plausible that TCF21 loci exert its protective effect by promoting infiltration of fibromyocytes in the coronary wall lesion and fibrous layer and loss of TCF21 expression can result in fewer fibromyocytes to fibrous cap increasing vulnerability of the plaque.

Funding Acknowledgement

Type of funding sources: None. Variables associated with CAD risk
Omega-3 fatty acids differentially alter the expression of detoxification enzymes and nitric oxide bioavailability in endothelial cells during IL-6 exposure
Authors: Sherratt S C R , Libby P , Bhatt D L , Dawoud H , Malinski T , Mason R P
Published: October 2021

Background

Atherosclerotic plaques can elaborate reactive oxygen species (ROS) that reduce nitric oxide (NO) bioavailability. Cellular detoxification enzymes including various peroxiredoxin (PRDX) and superoxide dismutase (SOD) isoforms can inactivate ROS. The omega-3 fatty acid (n3-FA) eicosapentaenoic acid (EPA) reduced cardiovascular (CV) events in high-risk patients (REDUCE-IT), a benefit not observed with mixed n3-FAs containing docosahexaenoic acid (DHA).

Purpose

The purpose of this study was to compare the effects of EPA and DHA on NO bioavailability and expression of detoxification enzymes in the vascular endothelium in vitro.

Methods

Human umbilical vein endothelial cells (HUVECs) were pretreated with EPA or DHA at equimolar levels (10 μM) for 2 h, then challenged with IL-6 at 12 ng/ml for 24 h. Proteomic analysis was performed using LC/MS to measure relative protein expression. Only significant (p<0.05) changes between treatment groups >1-fold were analyzed. Cells were stimulated with calcium ionophore to measure NO and peroxynitrite (ONOO-) release using a porphyrinic nanosensor.

Results

EPA, but not DHA, augmented PRDX-2 and SOD1 expression in HUVECs relative to IL-6 alone (1.2-fold and 1.6-fold, respectively, p=0.03). EPA also significantly lowered other isoforms unlike DHA. Either EPA or DHA increased thioredoxin expression by 1.5-fold (p=0.001) and 1.3-fold (p=0.02), respectively and decreased SOD2 expression by 1.5-fold (p=8.75E-11) and 1.6-fold (p=6.03E-9), respectively. IL-6 alone only increased expression of 6 detoxification enzymes by at least 1.2-fold, relative to vehicle. Unlike DHA, EPA also increased the NO to ONOO- release ratio by 36% (p<0.05) relative to IL-6 alone, without changes in NO synthase (eNOS) expression.

Conclusions

n3-FAs differentially influenced NO bioavailability and expression of ROS detoxification proteins, including peroxiredoxin and SOD isoforms. The net benefits of EPA on eNOS function and ROS detoxification may contribute to reduced atherothrombotic risk compared to DHA.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): Amarin Pharma Inc., Elucida Research
Contributions of small dense LDL and oxidized LDL on the formation of neoatherosclerosis in patients under statin treatment
Authors: Sakai R , Sekimoto T , Arai T , Tanaka H , Ogura K , Oishi Y , Nomura K , Sakai K , Arai K , Tsujita H , Kondo S , Tsukamoto S , Mori H , Koba S , Shinke T
Published: October 2021

Aim

In-stent neoatherosclerosis (NA) has emerged as an important contributing factor to late stent failure and cardiovascular events. The aim of this study was to investigate whether lipid markers are associated with NA using optical coherence tomography (OCT) after percutaneous coronary intervention (PCI) in patients with coronary artery disease under well-controlled low density lipoprotein cholesterol (LDL-c) on statin treatment.

Methods

We enrolled consecutive 115 patients under statin treatment who underwent PCI with current-generation drug-eluting stent for acute and chronic coronary syndrome. OCT image and various lipid markers were obtained at 1-year for scheduled research assessment. NA was defined as a lipid laden neointima or calcified neointima. Both small dense LDL-c (sd-LDL-c) and remnant lipoprotein cholesterol (RL-c) were measured using direct homogenous assay.

Results

During an average follow-up of 13 months, NA was observed in 14 (13.6%) patients. Not LDL-c but sd-LDL-c, Malondialdehyde-modified LDL (MDA-LDL) as oxidized LDL and (RL-c) were significantly higher in patients with NA. The optimal threshold values of sd-LDL-c, MDA-LDL and RL-c for predicting NA according to receiver operating characteristics analysis were 32.3 mg/dl, 91.0 U/L, and 3.3 mg/dL, respectively. On multivariate logistic regression analysis, sd-LDL-c (≥32.3 mg/dL) and MDA (≥91.0 U/L) were significantly associated with NA (odds ratio [OR]:13.62, p=0.016, OR: 12.68, p=0.01, respectively).

Conclusions

In statin-treated patients, sd-LDL-c and MDA-LDL but not LDL-c might be useful biomarkers to identify the formation of NA at 1 years after PCI. Aggressive reduction of these atherogenic LDL may have a potential to prevent the formation of NA.

Funding Acknowledgement

Type of funding sources: None.
Phage display and other peptide display technologies
Authors: Jaroszewicz Weronika , Morcinek-Orłowska Joanna , Pierzynowska Karolina , Gaffke Lidia , Węgrzyn Grzegorz
Published: October 2021

Phage display technology, which is based on the presentation of peptide sequences on the surface of bacteriophage virions, was developed over 30 years ago. Improvements in phage display systems have allowed us to employ this method in numerous fields of biotechnology, as diverse as immunological and biomedical applications, the formation of novel materials and many others. The importance of phage display platforms was recognized by awarding the Nobel Prize in 2018 ‘for the phage display of peptides and antibodies’. In contrast to many review articles concerning specific applications of phage display systems published in recent years, we present an overview of this technology, including a comparison of various display systems, their advantages and disadvantages, and examples of applications in various fields of science, medicine and the broad sense of biotechnology. Other peptide display technologies, which employ bacterial, yeast and mammalian cells, as well as eukaryotic viruses and cell-free systems, are also discussed. These powerful methods are still being developed and improved; thus, novel sophisticated tools based on phage display and other peptide display systems are constantly emerging, and new opportunities to solve various scientific, medical and technological problems can be expected to become available in the near future.
Experiencing and Forecasting COVID-19 Daily Stress on Mental Health Reactivity Across Age and Race
Authors: Pearman Ann , Hughes MacKenzie L , Coblenz Clara W , Smith Emily L , Neupert Shevaun D
Published: October 2021

Objectives

This study systematically evaluates age and race differences in mental health symptoms as they unfold microlongitudinally during the coronavirus disease 2019 (COVID-19) pandemic with a focus on within-person reactivity to forecasting and experiencing COVID-19 stress.

Method

A daily diary approach was used to examine predictors of daily anxiety and depressive symptoms among 526 adults (White [54%] and Black American [46%]) aged 21–79. A total of 3,605 online diaries were collected for 21 consecutive days between October and November, 2020. In addition to mental health symptoms, participants reported forecasted (next 24 h) stress as well as experienced (past 24 h) stress related to COVID-19.

Results

Patterns of reactivity to forecasted and experienced COVID-19 stress depended on age and race. White older adults displayed greater reactivity to COVID-19-related stress than White younger adults, but the effects of COVID-19-related stress were consistently detrimental for the daily anxiety of Black Americans, regardless of age. For Black Americans, age was less negatively associated with depressive symptoms than for White Americans. Increases in experienced COVID-19 stress were also more strongly associated with increases in depressive symptoms for Black Americans relative to White participants.

Discussion

This study moves beyond cross-sectional, descriptive work within the context of the COVID-19 pandemic and emphasizes the dynamic nature of within-person reactivity patterns that differ by age and race. Although White older adults experienced an increase in daily anxiety when forecasting COVID-19 stress, the co-occurring pandemic of systemic racism may be more powerful than age-related vulnerabilities for Black adults.
Autoridad y disenso en la Corte Interamericana de Derechos HumanosAuthority and dissent in the Inter-American Court of Human Rights
Authors: Contesse Jorge
Published: October 2021

Legal scholars have paid significant attention to backlash and resistance against international tribunals. In general, the phenomenon is examined as coming from the outside, that is, from states dissatisfied with certain judgments. Resistance, however, may also come “from within,” when members of the tribunal themselves not only have interpretive disagreements, but challenge the way in which the Court shapes its authority. In this short work, I briefly examine two areas in which this interaction occurs and connect it to the more recent context of resistance against the Inter-American human rights system in order to begin a discussion about how the Court’s expansive interpretations may expand its jurisprudence, but ultimately at the cost of exposing the Court’s authority.
The Effect of Gain-versus-Loss Framing of Economic and Health Prospects of Different COVID-19 Interventions: An Experiment Integrating Equivalence and Emphasis Framing
Authors: Hameleers Michael , Boukes Mark
Published: October 2021

A survey experiment was conducted that exposed Dutch citizens to different scenarios that either emphasized the gains or the losses regarding the number of victims or the economic damage caused by SARS-CoV-2. Replicating prospect theory in an ecologically valid crisis context, we found that gain frames promoted risk-aversive preferences, whereas loss frames increased support for risk-seeking alternatives. We further demonstrate the effect’s conditionality: Framing effects are strongest for health compared to economic scenarios and most pronounced when the type of intervention entails the highest risk associated with the respective domain. Theoretically, we show that the strongest media effects occur as an interplay between emphasis and equivalence framing effects, which underlines the need for media effects research to integrate both framing elements rather than studying them separately.
Almost Sure Large Fluctuations of Random Multiplicative Functions
Authors: Harper Adam J
Published: October 2021

We prove that if $f(n)$ is a Steinhaus or Rademacher random multiplicative function, there almost surely exist arbitrarily large values of $x$ for which $|\sum _{n \leq x} f(n)| \geq \sqrt{x} (\log \log x)^{1/4+o(1)}$. This is the first such bound that grows faster than $\sqrt{x}$, answering a question of Halász and proving a conjecture of Erd̋s. It is plausible that the exponent $1/4$ is sharp in this problem. The proofs work by establishing a multivariate Gaussian approximation for the sums $\sum _{n \leq x} f(n)$ at a sequence of $x$, conditional on the behaviour of $f(p)$ for all except the largest primes $p$. The most difficult aspect is showing that the conditional covariances of the sums are usually small, so the corresponding Gaussians are usually roughly independent. These covariances are related to a Euler product (or multiplicative chaos) type integral twisted by additive characters, which we study using various tools including mean value estimates for Dirichlet polynomials, high mixed moment estimates for random Euler products, and barrier arguments with random walks.
Public Debt Accumulation in SSA: A Looming Debt Crisis
Authors: Atingi-Ego Michael , Timuno Sayed , Makuve Tiviniton
Published: October 2021

This paper discusses recent debt trends and evaluates performance of debt sustainability analysis (DSA) conducted in a sample of Sub-Saharan African (SSA) countries over the period 2008–16. Based on qualitative and quantitative analyses, the findings suggest the existence of systematic optimism bias in past DSA vintages resulting from optimistic macro-economic projections that underpin the DSAs. As a result, the DSAs for the sample countries analysed projected higher debt carrying capacities, which in most cases led to a faster pace of debt accumulation during this period. Moreover, this was not helped by the fact that average interest rates on new debt commitments were rising faster relative to gross domestic product growth rates, while the necessary fiscal adjustment to counter this development remained insufficient. Countercyclical policies supported by fiscal buffers that were used to address the impact of the 2008 global financial crisis have largely not been reversed despite the erosion of the buffers and a pick-up in growth in some countries. As a result, the overall risk of debt distress in the region has deteriorated in the past decade. Going forward, strengthening analytical/research work on country macroeconomic projections underlying their DSAs, relationship between investment and growth, impact of natural disasters on DSA frameworks and quantifying and monitoring fiscal risks would be important pieces of work in leveraging DSA results for financing and policy decisions. Other supporting issues to embrace include capacity building to enhance quality of policies, transparency and accountability at institutional level; managing roll over risk; developing and implementing sound debt management strategies.
Outpatient portal use in prenatal care: differential use by race, risk, and area social determinants of health
Authors: Singh Priti , Jonnalagadda Pallavi , Morgan Evan , Fareed Naleef
Published: October 2021

To report the relationship of outpatient portal (OPP) use with clinical risk, area social determinants of health (SDoH), and race/ethnicity among pregnant women. Regression models predicting overall and individual portal feature use (main effects and interactions) based on key variables were specified using log files and clinical data. Overall OPP use among non-Hispanic Black women or patients who lived in lower SDoH neighborhoods were significantly less. High-risk pregnancy patients were likely to use the OPP more than those with normal-risk pregnancy. We found similar associations with individual OPP features, like Visit (scheduling) and My Record (test results). We also found significant interactive associations between race/ethnicity, clinical risk, and SDoH. Non-Hispanic Black women and those living in lower SDoH areas used OPP less than non-Hispanic White women from similar or affluent areas. More research must be conducted to learn of OPP use implications for pregnant women with specific clinical diagnoses.
Growth performance, visceral organ weights, and gut health of weaned pigs fed diets with different dietary fiber solubility and lipid sources
Authors: Hong Jinsu , Ndou Saymore Petros , Adams Seidu , Scaria Joy , Woyengo Tofuko Awori
Published: October 2021

The objective of this study was to determine the interactive effects of dietary fiber solubility and lipid source on growth performance, visceral organ weights, gut histology, and gut microbiota composition of weaned pigs. A total of 280 nursery pigs [initial body weight (BW) = 6.84 kg] weaned at 21 d were housed in 40 pens (7 pigs/pen). The pigs were fed four diets (10 pens/diet) in a randomized complete block design in two phases: Phase 1 from 0 to 2 wk and Phase 2 from 2 to 5 wk. The diets were corn-soybean meal-based with either sugar beet pulp (SBP) or soybean hulls (SBH) as a fiber source and either soybean oil (SBO) or choice white grease (CWG) as a lipid source in a 2 × 2 factorial arrangement. The BW and feed intake were determined by phase, whereas visceral organ weights, intestinal histology, and gut microbial composition were determined at the end of the trial. Dietary fiber solubility and lipid source did not interact (P > 0.05) on average daily feed intake and average daily gain across all phases. However, the gain to feed ratio (G:F) for CWG-containing diets was lower (P < 0.05) than that for SBO-containing diets for Phase 1. Also, G:F for SBP-containing diets was lower (P < 0.05) than that for SBH-containing diets for Phase 1 and for the entire study period. Pigs fed SBP-containing diets had greater (P < 0.05) stomach weight, and tended to have greater (P < 0.10) small and large intestine weights relative to BW than those fed SBH-containing diets. Duodenal villous height to crypt depth ratio for CWG-based diets tended to be greater (P = 0.09) than that for SBO-based diets. Fiber solubility and lipid source interacted (P < 0.05) on relative abundance of Bacteroides in the colon such that the relative abundance of the Bacteroides for CWG was greater (P < 0.05) than that for the SBO in SBP-based diet, but not in SBH-based diet. Relative abundance of Butyricicoccus in the colon for SBH-based diet was greater (P < 0.05) than that for SBP-based diet. In conclusion, inclusion of SBH instead of SBP in corn-soybean meal-based diets for weaned pigs can result in increased feed efficiency and relative abundance of Butyricicoccus in the colon, which is associated with improved gut health. Also, inclusion of SBO instead of CWG in the diets for weaned pigs can result in improved feed efficiency during Phase 1 feeding; however, the pigs may recover from the low feed efficiency induced by dietary inclusion of CWG instead of SBO after Phase 1 feeding.
Different Depths May Not Determine the Fluid Resuscitation Volume in Early-stage Management of Severe Burns: A Model-comparison Retrospective Analysis of Fluid Volume Determining Factors
Authors: Ning Fanggang , Jiang Huihao , Qiu Jiaming , Wang Lifang
Published: October 2021

Large-volume fluid resuscitation remains irreplaceable in the early-stage management of severe burns. We aimed to explore the relationship between fluid volume and other indicators. Data of severe burn patients with successful resuscitation in the early stage was collected. Correlation and linear regression analyses were performed. Multiple linear regression models, related goodness-of-fit assessment (adjusted R-square and Akaike Information Criterion), scatter plots, and paired t-test for two models, and a likelihood ratio test were performed. 96 patients were included. The median of total burn area (TBA) was 70%TBSA, with full thickness burn area (FTBA)/TBA of 0.4, a resuscitation volume of 1.93 mL/kg/%TBSA. Among volume-correlated indicators, two linear regression models were established (Model 1: TBA × weight and tracheotomy; and Model 2: FTBA × weight, partial thickness burn area (PTBA) × weight, and tracheotomy). For these models, close values of Akaike Information Criterion, adjusted R-squares, outliers of the prediction range, and the result of paired t-test, all suggest similarity between two models estimations, while the likelihood ratio test for coefficients of FTBA × weight and PTBA × weight showed a statistical difference. Inhalational injury and decompression surgery only correlated with volume, while Tracheotomy, TBA × weight, FTBA × weight, and PTBA × weight correlated with and were accepted in linear models of volume. Although FTBA and PTBA differed statistically, there may be no need to distinguish them when estimating the resuscitation volume requirements in this patient set. Further study about different depths fluid should be conducted.
Malnutrition in Burns: A Prospective, Single-Center Study
Authors: Caldis-Coutris Nancy , Gawaziuk Justin P , Magnusson Saul , Logsetty Sarvesh
Published: October 2021

The hypermetabolic response from a burn injury is the highest of the critically ill patient population. When coupled with the hypermetabolic response, preexisting malnutrition may increase the hospital resources used. The goal of this study was to evaluate the rate of malnutrition in burn patients and the associated hospital resource utilization. We collected prospective data on burn patients 18 years or older with a burn at least 10% TBSA admitted to a regional burn center. Demographics, %TBSA, comorbidities, length of stay (LOS), and standardized LOS (LOS/%TBSA) were evaluated on 49 patients. A multivariable regression model was constructed. Nutrition assessment was completed within 24 to 48 hours of admission including an SGA (Subjective Global Assessment) classification. SGA A (well-nourished) was compared to SGA B and C (malnourished). Fourteen patients (28.6%) in this study were malnourished. Malnourished patients were not statistically different with respect to median age (50 vs 39; P = .08) and body mass index (22.9 vs 26.5; P = .08) compared to the well-nourished group. However, malnourished patients had significantly longer median LOS (21.0 vs 11.0 days, P = .01) and LOS/%TBSA (1.69 vs 0.83, P = .001) than the well-nourished group. Being malnourished was a significant independent predictor of above-median LOS/%TBSA (P = .027) with an odds ratio of 5.61 (95% CI 1.215–25.890). The rate of malnutrition is important given the high metabolic demands of these patients. Malnutrition increased the resource requirements via higher standardized LOS. This underscores the importance of completing SGA on admission to identify malnutrition early on to optimize nutrition intervention during the patients’ hospital stay.
Health-Care Professionals and Lethal Injection: An Ethical Inquiry
Authors: Sawicki Sarah K
Published: October 2021

The practice of health-care professional involvement in capital punishment has come under scrutiny since the implementation of lethal injection as a method of execution, raising questions of the goals of medicine and the ethics of medicalized procedures. The American Medical Association and other professional associations have issued statements prohibiting physician involvement in capital punishment because medicine is dedicated to preserving life. I address the three primary arguments against health-care professionals being involved in lethal injection (healing, trust, and nonmaleficence) and argue that they are not strong enough to prohibit physician involvement in the lethal injection process.
An application of p-sulfonatocalix[6]arenes to attenuate cardiotoxicity of mitoxantrone in vitro: preparation, characterization and evaluation
Authors: Yu Xuan , Wang Meng , Wang Huimin , Ren Xiaoliang , Jiang Miaomiao , Zhu Yan , Zhang Deqin
Published: October 2021

Objectives

In this study, p-sulfonatocalix[6]arenes (SCA6) was proposed to construct a host–guest complexation to carry mitoxantrone (MIT) to maintain its anti-proliferation effect on HepG2 cells as well as to attenuate cardiotoxicity on H9C2 cells as a nano-size drug delivery system.

Methods

SCA6 binding to MIT evidenced through competitive fluorescence titration method. The complex was characterized using UV–visible, Fourier transform infrared, and proton nuclear magnetic resonance (1H-NMR) spectroscopies and differential scanning calorimetry analysis. The cytotoxicity was examined by a cell counting kit-8 assay on six cells. High content analysis, cell apoptosis and cell cycle experiments were measured to investigate the mechanism of detoxification in H9C2.

Key findings

The host–guest complexation was formed with a stoichiometry ratio of 1:1. Cytotoxicity study demonstrated that MIT/SCA6 complex could improve the cell viability on H9C2, MCF-7, A549, Hek293 and L02 cells and remained cytotoxicity effect on HepG2 cells. High content analysis showed that MIT/SCA6 complex could enhance the cell viability, mitochondrial mass and mitochondrial membrane potential and ameliorate the nuclear swelling on H9C2 cells. Moreover, the complex were arrested in G0/G1 phase of the cell cycle and same with MIT, while the detoxication was attributed to reducing early apoptosis.

Conclusions

The host–guest complexation between SCA6 and MIT had the ability to attenuate cardiotoxicity and provided a potential strategy for the application of soluble calixarenes in chemotherapy.
The effect of free and encapsulated cisplatin into long-circulating and pH-sensitive liposomes on IEC-6 cells during wound healing in the presence of host–microbiota
Authors: Araújo Raquel Silva , Cristina Oliveira Mônica , Cardoso Valbert Nascimento , Keefe Dorothy M K , Stringer Andrea M
Published: October 2021

Objectives

To circumvent cisplatin (CDDP) toxic effects and improve the antitumoural effect, our research group developed long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP). This study aimed to evaluate whether SpHL-CDDP is associated with intestinal protection under in-vitro conditions in the presence of host–microbiota, compared with free CDDP.

Methods

The cytotoxicity of CDDP and SpHL-CDDP were evaluated by colorimetric MTT and sulforhodamine B (SRB) assays. Epithelial proliferation was assessed by using an in-vitro wounding model in the presence of host–microbiota with intestinal epithelial cell line 6 (IEC-6) monolayers. Cytokines were determined by ELISA.

Key findings

Reduced cytotoxicity of SpHL-CDDP in IEC-6 cells (minimum of 1.3-fold according to the IC50 values) was observed when compared with CDDP. The presence of microbiota or CDDP reduced the wound healing. The association of microbiota and SpHL-CDDP improved the wound healing and cell number in IEC-6 cells when compared with control. These beneficial results can be associated with increased IL-6 and IL-10 levels induced by SpHL-CDDP which were affected by the presence of microbiota.

Conclusions

These results indicate that the presence of microbiota associated with SpHL-CDDP provided less intestinal cellular damages compared with CDDP and constitutes a promising candidate for clinical use.
An in-vitro comparative study of the binding of caspofungin and micafungin to plasma proteins
Authors: Yamasaki Keishi , Sakurama Keiki , Nishi Koji , Tsukigawa Kenji , Seo Hakaru , Otagiri Masaki , Taguchi Kazuaki
Published: October 2021

Objectives

Echinocandins are widely used for the treatment of invasive fungal diseases. While they bind strongly to plasma proteins, our knowledge of this process is not sufficient to permit their pharmacokinetics and pharmacodynamics targets to be discussed. In this study, we characterized the binding of two echinocandins, caspofungin and micafungin, to plasma proteins, human serum albumin (HSA) and human α 1-acid glycoprotein (AAG).

Methods

The binding parameters, number of binding sites (n) and association constant (K) for caspofungin and micafungin to HSA and AAG were determined by equilibrium dialysis. The binding site on HSA for these echinocandins was identified by conducting inhibition experiments.

Key findings

Caspofungin was found to bind strongly to a single site on HSA (n = 1.26, K = 0.45 × 106 M−1) and AAG (n = 0.99, K = 0.29 × 106 M−1). Micafungin was found to bind more strongly to HSA (n = 1.35, K = 1.44 × 106 M−1) and AAG (n = 1.32, K = 1.16 × 106 M−1). The binding site for these drugs on HSA appears to be within subdomain IA.

Conclusions

Free fraction of caspofungin and micafungin in patients may not be substantially affected due to the contribution of AAG to the overall protein binding and the binding to subdomain IA on HSA, which is different from the major drug-binding sites within subdomains IB, IIA and IIIA.
Commission on Human Rights Drafting Committee
Authors: Clooney Amal , Webb Philippa , Nelson Matthew
Published: October 2021

This section presents the Drafting Committee (CHR) Meeting Summary, 12 June 1947.
Commission on Human Rights Drafting Committee Second
Session
Authors: Clooney Amal , Webb Philippa , Nelson Matthew
Published: October 2021

This section presents the Drafting Committee (CHR) Meeting Summary, 12 May 1948.
Commission on Human Rights Drafting Committee Second
Session
Authors: Clooney Amal , Webb Philippa , Nelson Matthew
Published: October 2021

This section presents the Drafting Committee (CHR) Meeting Summary, 13 May 1948.
Commission on Human Rights
Authors: Clooney Amal , Webb Philippa , Nelson Matthew
Published: October 2021

This section presents the CHR United States proposals, 6 May 1949.
Agenda Item 58
Authors: Clooney Amal , Webb Philippa , Nelson Matthew
Published: October 2021

This section presents the Third Committee (GA) Meeting Summary, 28 October 1954.
Tenth session
Authors: Clooney Amal , Webb Philippa , Nelson Matthew
Published: October 2021

This section presents the Third Committee (GA) Government Observations, 13 September 1955.
Tenth session
Authors: Clooney Amal , Webb Philippa , Nelson Matthew
Published: October 2021

This section presents the Third Committee (GA) Annotated Draft International Covenants on Human Rights, 1 July 1955.
Fourteenth sessionThird CommitteeAgenda item 34
Authors: Clooney Amal , Webb Philippa , Nelson Matthew
Published: October 2021

This section presents the Third Committee (GA) Netherlands amendment, 6 November 1959.
Fourteenth sessionThird CommitteeAgenda item 34
Authors: Clooney Amal , Webb Philippa , Nelson Matthew
Published: October 2021

This section presents the Third Committee (GA) Israel amendment, 23 November 1959.
Fourteenth sessionThird CommitteeAgenda item 34
Authors: Clooney Amal , Webb Philippa , Nelson Matthew
Published: October 2021

This section presents the Third Committee (GA) Amendments, 24 November 1959.
Fourteenth sessionThird CommitteeAgenda item 34
Authors: Clooney Amal , Webb Philippa , Nelson Matthew
Published: October 2021

This section presents the Third Committee (GA) Draft text, 26 November 1959.
Fourteenth sessionThird CommitteeAgenda item 34
Authors: Clooney Amal , Webb Philippa , Nelson Matthew
Published: October 2021

This section presents the Third Committee (GA) Corrigendum to Draft text, 27 November 1959.
Contract Law in Practice
Authors: Andrews Neil
Published: October 2021

This book is a detailed examination of the general doctrines of English law of contract. Cases are analysed precisely, providing quick access to the major authoritative passages in the leading judgments. The coverage is comprehensive. It focuses on English law, but it also provides analysis of assistance throughout the Common Law family of legal systems. It provides up-to-date examination of case law developments. There are nearly fifty ‘evaluation’ sections which provide comment on controversial or unclear topics. Six major principles are identified: Freedom of Contract; Objectivity; the Contractual Bond Principle; Estoppel; Good Faith and Fair Dealing; the Compensation Principle.
Sources and General Features
Authors: Andrews Neil
Published: October 2021

This is an introductory chapter. The case law tradition of English contract law is explained, including the distinction between Common Law and Equity. The requirements of consensus are analysed. There is an overview of modern developments in the law. Doctrinal controversies are listed, with references to parts of the book where ‘Evaluation’ sections provide comment on difficult or uncertain developments or topics. There are forty-nine such ‘Evaluation’ sections, amongst which the author’s discussion of the following topics merits special attention: negotiation agreements [4.35] and [4.42]; the rule in Pinnel’s Case  [6.82]; the ‘fiction of fraud’ and the Misrepresentation Act 1967 [11.113]; duress as to person [13.27]; illegitimate (but not unlawful) pressure [13.38]; good faith [19.27]; the White & Carter case [27.66].
Certainty
Authors: Andrews Neil
Published: October 2021

A requirement in English law is that an agreement must have sufficient commercial certainty. The extensive case law is examined closely, with instances being cited of numerous cases where the courts have either concluded that the certainty requirement has been satisfied, or that the transaction is void for lack of fundamental clarity. An agreement to agree is not valid, nor an agreement to negotiate reasonably or in good faith. These restrictions are examined closely. An interesting exception has emerged, requiring a party to adhere to an undertaking to negotiate in an amicable and constructive way as a preliminary to commencing arbitration.
Intent to Create Legal Relations
Authors: Andrews Neil
Published: October 2021

The intent to create legal relations doctrine operates as a safety-net principle, supplementing the requirement of consideration. These two doctrines operate in tandem in English law. The chapter examines case law applications of the following two presumptions. (1) An agreement between spouses is presumed not to be legally enforceable, unless the marriage has already become seriously fractured. The same presumption probably extends to other close family relations. Pre-nuptial agreements are enforceable. (2) Conversely, commercial agreements are presumed to be legally enforceable. But a series of sales does not constitute a long-term supply agreement. And a ‘letter of comfort’, not intended to be a guarantee, lacks an intent to create legal relations.
Unconscionability
Authors: Andrews Neil
Published: October 2021

‘Unconscionability’ is a narrow equitable doctrine which protects a vulnerable party against reprehensible exploitation of his position of weakness. The doctrine of unconscionability comprises four factors: (i) the vulnerable party’s special or serious disadvantage; (ii) actual or constructive fraud, that is, conscious and reprehensible exploitation; (iii) highly disadvantageous terms; and (iv) lack of independent advice.
Illegality
Authors: Andrews Neil
Published: October 2021

This chapter examines the various heads of illegality, such as agreements contrary to statute or agreements to defraud the tax authorities. Neither party can sue on a contract if the contract is expressly or by necessary implication prohibited by statute or the common purpose was to commit a crime or other civil wrong. Nor can a claimant sue on a contract if the claimant became aware that the contract would involve illegally and then participated in, or was implicated in, that wrongdoing (it is otherwise if claimant was ignorant of, and not implicated in, the defendant’s decision to perform it in an illegal fashion, or the claimant was guilty of only incidental illegality during performance). The court must refuse to give effect to a transaction if its illegal nature emerges during the course of the case. In Patel v Mirza (2016) the Supreme Court radically tilted the law in favour of the restitution of money or property transferred under an illegal contract, unless there is a compelling contrary argument of legal policy.
Express Terms
Authors: Andrews Neil
Published: October 2021

This chapter examines the different types of express term. Terms can be express or implied, and they can be promissory (imposing primary duties) or non-promissory (regulating the contract without imposing primary duties, eg, dispute-resolution clauses, or exclusion clauses).
Good Faith
Authors: Andrews Neil
Published: October 2021

There is some judicial interest in recognizing a principle of good faith performance in English contract law (the topic was introduced at [2.69]). The idea is gaining, or at least might gain, momentum. But the traditional view, to which the appellate courts in England and Wales have remained loyal, is that there is no general doctrine that contracts must be performed in good faith. In other words, there is no general implied term that a contract must be performed in good faith.
Rectification
Authors: Andrews Neil
Published: October 2021

The Equitable remedy of rectification generally operates when the final text of the contract does not match exactly the final agreed draft version. The final document can be rectified to bring its contents into accordance with the final pre-formation agreed draft or version (‘common mistake rectification’).
Specific Performance and Other Equitable Remedies
Authors: Andrews Neil
Published: October 2021

The equitable remedy of specific performance to compel performance is a mandatory final injunction. This remedy takes the back-seat in English law when compared with the Common Law money remedies of debt and damages. But specific performance is the default remedy in the context of contracts for the transfer of interests in land or shares in a private company. Injunctions are primarily ordered when the contractual breach involves the commission of something which the wrongdoer has promised not to do (a ‘negative undertaking’).
The Electronic Bill of Exchange and Its Use in International Trade
Authors: Geva Benjamin
Published: October 2021

This chapter explores the ‘electronification’ of bills of exchange in connection with their use as credit and payment instruments in international trade. The chapter observes that the infinite number of international trade participants spread throughout the globe at different stages of technological development militates against the feasibility of a common, universal, and worldwide technological platform for handling electronic bills of exchange. Instead, particularly by reference to the extensive experience in the US in relation to the ‘electronification’ of cheques, the chapter proposes that a robust and flexible legal frameworkbe implanted in the Bills of Exchange Act, and used as agreed, to cover electronic presentment of bills of exchange and the exchange and negotiation of substitute bills, bills images, and electronic bills.
Digitalisation of Shipping and Insurance Documents
Authors: Goldby Miriam
Published: October 2021

The inefficiencies inherent in processing pieces of paper manually down a cross-border chain of sales have prompted the international trade community to attempt to replace bills of lading with digital alternatives. These efforts have been ongoing for thirty years, but the recent availability of new technologies, particularly distributed-ledger technology (‘DLT’), which can be used in combination with ‘smart contracts’, the internet of things (‘IoT’) and machine-learning, has given these efforts a new impetus. Digitalisation holds many promises, including the creation of a context wherein new and cheaper financing options may be developed that do not involve manual checking of large volumes of paper documents. However, doing away with the paper-based documents of title creates uncertainties in terms of the bank’s position as secured creditor. Similarly, while cargo insurance certificates have been issued over electronic platforms for many years now, their transfer by endorsement is still effected by printing the certificate out and endorsing the paper-based certificate. In order for the benefits of digitalisation to be reaped in full, cargo insurance certificates also need to be fully digitalised, which would in turn raise questions as to the bank’s position as assured under the insurance contract. This chapter will examine the options available for making the bank’s position more certain. These options include legislative intervention and the development of contractual frameworks governed by English law.
Will Blockchain Transform Trade Finance?
Authors: Winn Jane K
Published: October 2021

The administration of cross-border trade remains dominated by complex, old-fashioned, hybrid human-computer-paper systems long after disruptive innovations have transformed commerce in many other domains. Interest in blockchain is driven by the desire to cut through the ‘Gordian knot’ of complex, fragmented, anachronistic legacy trade-finance systems now in use. Blockchain advocates believe it is superior to the legacy database technologies currently in use in all important transaction-processing systems and designed to work within hierarchically networked computer systems controlled by large organisations. These advocates appear unaware, however, of the wide range of practical functions performed by different elements of existing trade finance systems, and are thus proposing alternatives that cannot perform all the functions of the systems they propose to replace. This kind of mismatch between real-world business requirements and the theoretical advantages of blockchain alternatives goes a long way to explain the failure of any blockchain projects to achieve widespread success in the market. Incremental efforts to transform trade finance in light of actual stakeholder requirements are both less vulnerable to speculative bubbles and more likely to meet the actual requirements of the many, diverse participants in global trade-finance systems today.
Islamic Trade Law and the Smart Contract Revolution
Authors: Ercanbrack Jonathan
Published: October 2021

The history of Islam is inextricably connected to a celebrated history of trade and commerce which distinguishes it amongst monotheistic faiths. The modern incarnation of Islamic trade finance, however, bears only rudimentary similarity to the trade practices of old. Modern Islamic trade finance is devised to replicate conventional trade practices so that the barter-like immediacy of the Islamic contract of sale has been replaced with promissory attributes (wa’d). Yet Islamic law (sharia) has shown itself to be fully capable of adapting to modern trade practices so long as its major principles remain intact. The introduction of blockchain and smart contracts for Islamic trade finance does not change this basic calculus and yet these technologies promise to revolutionise Islamic trade practices in a way that compels the industry to operate in closer keeping with its commercial principles. Paradoxically, these technologies require substantive changes in the way in which Islamic trade finance is practiced, helping the industry to overcome its attachment to legal artifice (hiyal). Using comparative law methodology, this chapter briefly examines a short history of trade and commerce in the Islamic tradition, followed by the development of modern Islamic finance. It addresses the principles of Islamic commercial law as the basis for understanding the murabaha contract for trade finance, followed by an analysis of the legal and sharia-related issues that English courts have dealt with in the practice of Islamic trade finance. Finally, the chapter considers the transformative capacity of blockchain and smart contracts for Islamic trade finance, highlighting prominent legal and sharia-related issues that compel the industry to transform its trade practices markedly.
Appointment of a Provisional Liquidator
Authors: French Derek
Published: October 2021

The chapter discusses various aspects of appointing a provisional liquidator. A provisional liquidator of a company may be appointed by the court under the Insolvency Act 1986 (IA 1986), s 135 at any time after the making of an application for a bank insolvency order. Provisional liquidators are independent persons operating under the direction of the court for a purpose that is one entirely of preservation during an interim period. He/she will take charge of the company’s affairs, maintain the status quo and prevent prejudice either to those supporting the winding-up petition or to those against it, pending the court’s decision on the petition. He/she terminates the powers of its directors as effectively as does the making of a winding-up order. The appointment terminates the actual authority of all the company’s agents, but the authority of an agent is not terminated until the agent has notice of the appointment of the provisional liquidator.