Development of two reference materials for all trans-retinol, retinyl palmitate, α- and γ-tocopherol in milk powder and infant formula

AbstractVitamins are important food constituents that can be present in almost every foodstuff. Food quality and safety depends on food surveillance by reliable quantitative analysis enabled by appropriate quality control. Certified matrix reference materials are versatile tools to support quality assurance and control. However, in the case of vitamins, which are important in various foods, there is a lack of matrix reference materials. Two certified reference materials for the determination of all–trans-retinol, retinyl palmitate, and α- and γ-tocopherol in milk powder and infant formula have been developed by the National Institute of Standards, Egypt. This article presents the preparation, characterization, homogeneity, and stability testing as well as statistical treatment of data and certified value assignment. The assignment of the certified values and associated uncertainties in the prepared natural-matrix reference materials were based on the widely used approach of combining data from independent and reliable analytical methods

The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma

We performed a small interfering RNA screen to identify targets for cutaneous squamous cell carcinoma (cSCC) therapy in the ubiquitin/ubiquitin-like system. We provide evidence for selective anti-cSCC activity of knockdown of the E3 ubiquitin ligase MARCH4, the ATPase p97/VCP, the deubiquitinating enzyme USP8, the cullin-RING ligase (CRL) 4 substrate receptor CDT2/DTL, and components of the anaphase-promoting complex/cyclosome (APC/C). Specifically attenuating CRL4CDT2 by CDT2 knockdown can be more potent in killing cSCC cells than targeting CRLs or CRL4s in general by RBX1 or DDB1 depletion. Suppression of the APC/C or forced APC/C activation by targeting its repressor EMI1 are both potential therapeutic approaches. We observed that cSCC cells can be selectively killed by small-molecule inhibitors of USP8 (DUBs-IN-3/compound 22c) and the NEDD8 E1 activating enzyme/CRLs (MLN4924/pevonedistat). A substantial proportion of cSCC cell lines are very highly MLN4924-sensitive. Pathways that respond to defects in proteostasis are involved in the anti-cSCC activity of p97 suppression. Targeting USP8 can reduce the expression of growth factor receptors that participate in cSCC development. EMI1 and CDT2 depletion can selectively cause DNA re-replication and DNA damage in cSCC cells

B -> X_s gamma in Supersymmetry with Explicit CP Violation

We discuss B -> X_s gamma decay in both constrained and unconstrained supersymmetric models with explicit CP violation within the minimal flavor violation scheme by including tan(beta) -enhanced large contributions beyond the leading order. In this analysis, we take into account the relevant cosmological and collider bounds, as well as electric dipole moment constraints. In the unconstrained model, there are portions of the parameter space yielding a large CP asymmetry at leading order (LO). In these regions, we find that the CP phases satisfy certain sum rules, e.g., the sum of the phases of the \mu parameter and the stop trilinear coupling centralize around \pi with a width determined by the experimental bounds. In addition, at large values of tan(beta), the sign of the CP asymmetry tracks the sign of the gluino mass, and the CP asymmetry is significantly larger than the LO prediction. In the constrained minimal supersymmetric standard model based on minimal supergravity, we find that the decay rate is sensitive to the phase of the universal trilinear coupling. This sensitivity decreases at large values of the universal gauino mass. We also show that for a given set of the mass parameters, there exists a threshold value of the phase of the universal trilinear coupling which grows with tan(beta) and beyond which the experimental bounds are satisfied. In both supersymmetric scenarios, the allowed ranges of the CP phases are wide enough to have phenomenological consequences.Comment: 25 pages, 11 figures. Added references, made minor changes in the text; journal versio

The catalytic subunit of the system L1 amino acid transporter (S<i>lc7a5</i>) facilitates nutrient signalling in mouse skeletal muscle

The System L1-type amino acid transporter mediates transport of large neutral amino acids (LNAA) in many mammalian cell-types. LNAA such as leucine are required for full activation of the mTOR-S6K signalling pathway promoting protein synthesis and cell growth. The SLC7A5 (LAT1) catalytic subunit of high-affinity System L1 functions as a glycoprotein-associated heterodimer with the multifunctional protein SLC3A2 (CD98). We generated a floxed Slc7a5 mouse strain which, when crossed with mice expressing Cre driven by a global promoter, produced Slc7a5 heterozygous knockout (Slc7a5+/-) animals with no overt phenotype, although homozygous global knockout of Slc7a5 was embryonically lethal. Muscle-specific (MCK Cre-mediated) Slc7a5 knockout (MS-Slc7a5-KO) mice were used to study the role of intracellular LNAA delivery by the SLC7A5 transporter for mTOR-S6K pathway activation in skeletal muscle. Activation of muscle mTOR-S6K (Thr389 phosphorylation) in vivo by intraperitoneal leucine injection was blunted in homozygous MS-Slc7a5-KO mice relative to wild-type animals. Dietary intake and growth rate were similar for MS-Slc7a5-KO mice and wild-type littermates fed for 10 weeks (to age 120 days) with diets containing 10%, 20% or 30% of protein. In MS-Slc7a5-KO mice, Leu and Ile concentrations in gastrocnemius muscle were reduced by ∼40% as dietary protein content was reduced from 30 to 10%. These changes were associated with >50% decrease in S6K Thr389 phosphorylation in muscles from MS-Slc7a5-KO mice, indicating reduced mTOR-S6K pathway activation, despite no significant differences in lean tissue mass between groups on the same diet. MS-Slc7a5-KO mice on 30% protein diet exhibited mild insulin resistance (e.g. reduced glucose clearance, larger gonadal adipose depots) relative to control animals. Thus, SLC7A5 modulates LNAA-dependent muscle mTOR-S6K signalling in mice, although it appears non-essential (or is sufficiently compensated by e.g. SLC7A8 (LAT2)) for maintenance of normal muscle mass

Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation

In mammals, ∼100 deubiquitinases act on ∼20,000 intracellular ubiquitination sites. Deubiquitinases are commonly regarded as constitutively active, with limited regulatory and targeting capacity. The BRCA1-A and BRISC complexes serve in DNA double-strand break repair and immune signaling and contain the lysine-63 linkage-specific BRCC36 subunit that is functionalized by scaffold subunits ABRAXAS and ABRO1, respectively. The molecular basis underlying BRCA1-A and BRISC function is currently unknown. Here we show that in the BRCA1-A complex structure, ABRAXAS integrates the DNA repair protein RAP80 and provides a high-affinity binding site that sequesters the tumor suppressor BRCA1 away from the break site. In the BRISC structure, ABRO1 binds SHMT2α, a metabolic enzyme enabling cancer growth in hypoxic environments, which we find prevents BRCC36 from binding and cleaving ubiquitin chains. Our work explains modularity in the BRCC36 DUB family, with different adaptor subunits conferring diversified targeting and regulatory functions.ISSN:1097-2765ISSN:1097-416

Is quadratus lumborum block combined with low dose-spinal anesthesia an effective alternative to general anesthesia in patients undergoing percutaneous nephrolithotomy?

Background: General anesthesia in high-risk patients has many complications and needs long preoperative preparations and postoperative intensive care unit (ICU). Therefore the present study aimed to evaluate the efficacy of combined low-dose spinal anesthesia with quadratus lumborum block (QLB) as an alternative to general anesthesia for patients undergoing percutaneous nephrolithotomy. Patients and methods: A prospective study was conducted at the urology department of Al-Azhar University Hospitals in Cairo, Egypt, from January 2021 to January 2022. The study included 60 patients of ASA ll-lll scheduled for percutaneous nephrolithotomy. All patients received low-dose spinal anesthesia (5 mg bupivacaine) and QLB (QL1-QL2-QL3) approaches. The primary observation parameter was the efficacy of this technique as an alternative to general anesthesia. The secondary parameters measured were evaluation of need for intraoperative narcotics, postoperative pain score (VAS), and patients satisfaction as assessed using a 5-point Likert Scale. Results: None of the patients was given general anesthesia, and intraoperative sedation was given to nineteen patients (32.2%). No hemodynamic changes were observed in all patients. There was a significant correlation between the use of intraoperative sedation and stone site, intraoperative blood loss, and hospital stay. Pain intensity on VAS at rest and movement was low until the 24th postoperative hour. Patient satisfaction score was 3, 4, and 5 in 1 (1.7%), 4 (6.7%), and 55 (91.6%) patients, respectively. Conclusions: Combined low-dose spinal anesthesia with quadratus lumborum block is an effective alternative to general anesthesia in patients undergoing PCNL procedures with good postoperative analgesia. Patients with lower calyceal punctures have a lower incidence of intraoperative sedation requirements

Flavor changing neutral current processes in BB and KK decays in the supergravity model

Flavor changing neutral current processes such as $b \to s \gamma$, $b \to s l^+ l^-$, $b \to s \nu \bar{\nu}$, $\epsilon_K$, $\Delta m_B$, $K^+ \to \pi^+ \nu \bar{\nu}$ and \K_L \to \pi^0 \nu \bar{\nu} are calculated in the supersymmetric standard model based on supergravity. We consider two assumptions for the soft supersymmetry breaking terms. In the minimal case soft breaking terms for all scalar fields are taken to be universal at the GUT scale whereas those terms are different for the squark/slepton sector and the Higgs sector in the nonminimal case. In the calculation we have taken into account the next-to-leading order QCD correction to the $b \to s \gamma$ branching ratio, the results from the LEP II superparticles search, and the condition of the radiative electroweak symmetry breaking. We show that $\Delta m_B$ and $\epsilon_K$ can be enhanced up to 40% compared to the Standard Model values in the nonminimal case. In the same parameter region the $b \to s \nu \bar{\nu}$, $K^+ \to \pi^+ \nu \bar{\nu}$ and \K_L \to \pi^0 \nu \bar{\nu} branching ratios are reduced up to 10%. The corresponding deviation in the minimal case is 20% for $\Delta m_B$ and $\epsilon_K$ and within 3% for the $b \to s \nu \bar{\nu}$, $K^+ \to \pi^+ \nu \bar{\nu}$ and \K_L \to \pi^0 \nu \bar{\nu}. For the $b \to s l^+ l^-$ process the significant deviation from the Standard Model is realized only when the $b \to s \gamma$ amplitude has an opposite sign to the Standard Model prediction. Significance on these results from possible future improvements of the $b \to s \gamma$ branching ratio measurement and top squark search is discussed.Comment: 45 pages, 20 EPS figures included. Figures are corrected; references are added and updated (Jul 23, 1998

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Global economic burden of unmet surgical need for appendicitis

Background: There is a substantial gap in provision of adequate surgical care in many low-and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods: Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results: Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion: For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially