פרסומים

BACKGROUNDCytomegalovirus (CMV) is the most common intrauterine infection, leading to infant brain damage. Prognostic assessment of CMV-infected fetuses has remained an ongoing challenge in prenatal care, in the absence of established prenatal biomarkers of congenital CMV (cCMV) infection severity. We aimed to identify prognostic biomarkers of cCMV-related fetal brain injury.METHODSWe performed global proteome analysis of mid-gestation amniotic fluid samples, comparing amniotic fluid of fetuses with severe cCMV with that of asymptomatic CMV-infected fetuses. The levels of selected differentially excreted proteins were further determined by specific immunoassays.RESULTSUsing unbiased proteome analysis in a discovery cohort, we identified amniotic fluid proteins related to inflammation and neurological disease pathways, which demonstrated distinct abundance in fetuses with severe cCMV. Amniotic fluid levels of 2 of these proteins - the immunomodulatory proteins retinoic acid receptor responder 2 (chemerin) and galectin-3-binding protein (Gal-3BP) - were highly predictive of the severity of cCMV in an independent validation cohort, differentiating between fetuses with severe (n = 17) and asymptomatic (n = 26) cCMV, with 100%-93.8% positive predictive value, and 92.9%-92.6% negative predictive value (for chemerin and Gal-3BP, respectively). CONCLUSIONAnalysis of chemerin and Gal-3BP levels in mid-gestation amniotic fluids could be used in the clinical setting to profoundly improve the prognostic assessment of CMV-infected fetuses.FUNDINGIsrael Science Foundation (530/18 and IPMP 3432/19); Research Fund - Hadassah Medical Organization.

In this paper, Artificial Intelligence assisted rule-based confidence metric (AI-CRBM) framework has been introduced for analyzing environmental governance expense prediction reform. A metric method is to assess a level of collective environmental governance representing general, government, and corporate aspects. The equilibrium approach is used to calculate improvements in the source of environmental management based on cost, and it is tailored to test the public sector-corporation for environmental shared governance. The overall concept of cost prediction or estimation of environmental governance is achieved by the rule-based confidence method. The framework compares the expected cost to the environment of governance to determine the efficiency of the cost prediction process.

The utilization of the wasted energy from power plants in power generation becomes a great challenge in recent times. This investigates the feasibility of using Organic Rankine Cycle (ORC) bottoming turbine to recover the energy generated from Al Zour South Power station in Kuwait. Both of qualitative and quantitative methods of data collection were used to collect the required data for this investigation. A block diagram was built for the new proposed model in which the location of the added ORC bottoming turbine is presented. The model includes four modules and each of them has different number of turbines. The amount of power generated per month by applying the new model with using two different extraction line capacities of 10% and 20% in addition to the produced power (1000 Mw) per month for each unit were measured and plotted. As a result, the four modules generated more power as the extraction line capacity increased to 20%. More profit was gained by module four at 10% extraction and it has the lowest rate of return which was 9 years. Based on these results, module 4 is the most suitable to be installed in Al Zour South Power station in Kuwait.

The spread of antibiotic resistance is attracting increased attention to combination-based treatments. Although drug combinations have been studied extensively for their effects on bacterial growth1–11, much less is known about their effects on bacterial long-term clearance, especially at cidal, clinically relevant concentrations12–14. Here, using en masse microplating and automated image analysis, we systematically quantify Staphylococcus aureus survival during prolonged exposure to pairwise and higher-order cidal drug combinations. By quantifying growth inhibition, early killing and longer-term population clearance by all pairs of 14 antibiotics, we find that clearance interactions are qualitatively different, often showing reciprocal suppression whereby the efficacy of the drug mixture is weaker than any of the individual drugs alone. Furthermore, in contrast to growth inhibition6–10 and early killing, clearance efficacy decreases rather than increases as more drugs are added. However, specific drugs targeting non-growing persisters15–17 circumvent these suppressive effects. Competition experiments show that reciprocal suppressive drug combinations select against resistance to any of the individual drugs, even counteracting methicillin-resistant Staphylococcus aureus both in vitro and in a Galleria mellonella larva model. As a consequence, adding a β-lactamase inhibitor that is commonly used to potentiate treatment against β-lactam-resistant strains can reduce rather than increase treatment efficacy. Together, these results underscore the importance of systematic mapping the long-term clearance efficacy of drug combinations for designing more-effective, resistance-proof multidrug regimes.

Antibiotic resistance has become an increasing challenge in the treatment of various infectious diseases, especially those associated with biofilm formation on biotic and abiotic materials. There is an urgent need for new treatment protocols that can also target biofilm-embedded bacteria. Many secondary metabolites of plants possess anti-bacterial activities, and especially the phytocannabinoids of the Cannabis sativa L. varieties have reached a renaissance and attracted much attention for their anti-microbial and anti-biofilm activities at concentrations below the cytotoxic threshold on normal mammalian cells. Accordingly, many synthetic cannabinoids have been designed with the intention to increase the specificity and selectivity of the compounds. The structurally unrelated endocannabinoids have also been found to have anti-microbial and anti-biofilm activities. Recent data suggest for a mutual communication between the endocannabinoid system and the gut microbiota. The present review focuses on the anti-microbial activities of phytocannabinoids and endocannabinoids integrated with some selected issues of their many physiological and pharmacological activities.

BACKGROUND: Antisense oligonucleotide- based drugs for splicing modulation were recently approved for various genetic diseases with unmet need. Here we aimed to generate skipping over exon 23 of the CFTR transcript, to eliminate the W1282X nonsense mutation and avoid RNA degradation induced by the nonsense mediated mRNA decay mechanism, allowing production of partially active CFTR proteins lacking exon 23. METHODS: ∼80 ASOs were screened in 16HBEge W1282X cells. ASO candidates showing significant exon skipping were assessed for their W1282X allele selectivity and the increase of CFTR protein maturation and function. The effect of a highly potent ASO candidates was further analyzed in well differentiated primary human nasal epithelial cells, derived from a W1282X homozygous patient. RESULTS: ASO screening led to identification of several ASOs that significantly decrease the level of CFTR transcripts including exon 23. These ASOs resulted in significant levels of mature CFTR protein and together with modulators restore the channel function following free uptake into these cells. Importantly, a highly potent lead ASOs, efficiently delivered by free uptake, was able to increase the level of transcripts lacking exon 23 and restore the CFTR function in cells from a W1282X homozygote patient. CONCLUSION: The highly efficient exon 23 skipping induced by free uptake of the lead ASO and the resulting levels of mature CFTR protein exhibiting channel function in the presence of modulators, demonstrate the ASO therapeutic potential benefit for CF patients carrying the W1282X mutation with the objective to advance the lead candidate SPL23-2 to proof-of-concept clinical study.

Modulation of the endogenous cannabinoid system has been suggested as a potential anticancer strategy. In the search for novel and less toxic therapeutic options, structural modifications of the endocannabinoid anandamide and the synthetic derivative of oleic acid, Minerval (HU-600), were done to obtain 2-hydroxy oleic acid ethanolamide (HU-585), which is an HU-600 derivative with the anandamide side chain. We showed that treatment of SK-N-SH neuroblastoma cells with HU-585 induced a better anti-tumorigenic effect in comparison to HU-600 as evidenced by 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide assay, colony-forming assay, and migration assay. Moreover, HU-585 demonstrated pro-apoptotic properties shown by increased levels of activated caspase-3 following treatment and a better senescence induction effect in comparison to HU-600, as demonstrated by increased activity of lysosomal $\beta$-galactosidase. Finally, we observed that combined treatment of HU-585 with the senolytic drugs ABT-263 in vitro, and ABT-737 in vivo resulted in enhanced anti-proliferative effects and reduced neuroblastoma xenograft growth in comparison to treatment with HU-585 alone. Based on these results, we suggest that HU-585 is a pro-apoptotic and senescence-inducing compound, better than HU-600. Hence, it may be a beneficial option for the treatment of resistant neuroblastoma especially when combined with senolytic drugs that enhance its anti-tumorigenic effects.

The apiary discovered in Stratum V at Tel Reḥov in 2005–2007 remains unique in the archaeology of the ancient Near East. Here the authors briefly summarize the data previously published in this journal and add results of new studies, mainly concerning the identification of ancient charred bees trapped in burnt honeycombs found in the hives. Measurements of two wings and one leg, and statistical work based on existing database of modern subspecies, are inconsistent with the Syrian subspecies local to Israel (Apis meliferra syriaca), but were found to be similar to the Anatolian bee (Apis meliferra anatoliaca). We discuss the implications of this result, suggesting trade relations with southern Anatolia. The authors suggest that the beeswax was perhaps related to the copper-based metallurgical industry that entailed casting in the lost wax method, at a time when the copper trade based on the Arabah mines was at its peak.

Antenatal diagnosis of fetal weight is challenging, and the detection rate of fetal growth restriction (FGR) is low. Neonates with FGR are known to have an increased rate of obstetric intervention during labor, but the association of antenatal fetal weight estimation with mode of delivery and neonatal outcomes among neonates who are small and appropriate for gestational age (SGA and AGA) has not been reported.To evaluate the association of antenatal fetal weight estimation with mode of delivery and neonatal outcomes among neonates who are SGA and AGA, applying psychological concepts of cognitive bias and prospect theory to a model of clinical behavior.This cohort study was conducted between 2019 and 2020 using data from 2006 to 2018 at a tertiary care center in Jerusalem, Israel. Participants were 100 198 term singleton neonates without anomalies who were categorized into 4 groups according to the presence of an antenatal suspicion of FGR and final birth weight. Neonates with false positives (FPs; ie, group 1-FP: those with suspected FGR who were AGA) and neonates with true positives (TPs; ie, group 2-TP: those with suspected FGR who were SGA) were compared with neonates with AGA antenatal fetal weight estimation, including neonates with false negatives (FNs; ie, group 3-FN: those not suspected to have FGR who were SGA) and neonates with true negatives (TNs; ie, group 4-TN: those not suspected to have FGR who were AGA). Data were analyzed from July 2019 to July 2020.Fetal weight estimation was performed according to sonographic and clinical evaluation at admission to labor, with FGR defined as a birth weight less than the 10th percentile for gestational age. Sonographic fetal weight estimation was performed according to Hadlock formula. Clinical weight estimation was performed by trained obstetricians.The primary outcomes were obstetric intervention and mode of delivery; the secondary outcomes were neonatal Apgar score (with low Apgar score defined as <7) and neonatal intensive care unit (NICU) admission rates.Among 100 198 neonates eligible for the study (50941 [50.8%] male neonates), there were 5671 neonates in group 1-FP, 3040 neonates in group 2-TP, 8508 neonates in group 3-FN, and 82 979 neonates in group 4-TN. Mean (SD) maternal age was 28.6 (5.7) years. Among 8711 neonates with suspected FGR, 34.9% were below the 10th percentile at birth, while 65.1% were AGA. Neonates with suspected FGR had a significantly increased rate of induction of labor (group 1-FP: 649 neonates [11.4%] and group 2-TP: 969 neonates [31.9%]) compared with neonates in group 3-FN (1055 neonates [12.4%]) and group 4-TN (7136 neonates [8.6%]) (P < .001) and a significantly increased rate of cesarean delivery (group 1-FP: 915 neonates [16.1%] and group 2-TP: 556 neonates [18.3%] vs group 3-FN: 1106 neonates [13.0%] and group 4-TN: 6588 neonates [7.9%]; P < .001). Increased NICU admission was found for neonates who were SGA compared with neonates who were AGA (group 2-TP: 182 neonates [6.0%] and group 3-FN: 328 neonates [3.9%] vs group 1-FP: 51 neonates [0.9%] and group 4-TN: 704 neonates [0.8%]; P <.001), as was increased rate of low Apgar score (eg, at 1 minute: group 2-TP: 149 neonates [4.9%] and group 3-FN: 384 neonates [4.5%] vs group 1-FP: 124 neonates [2.2%] and group 4-TN: 1595 neonates [1.9%]; P < .001). In a multivariable model comparing group 1-FP, group 2-TP, and group 3-FN with group 4-TN, suspicion of FGR was independently associated with increased risk of caesarean delivery among neonates in group 1-FP (odds ratio, 1.72; 95% CI, 1.56-1.88; P < .001).This study found that antenatal diagnosis of FGR was independently associated with an increase in risk of caesarean delivery by 70% in neonates who were AGA without improvement in neonatal outcomes. These findings suggest that such outcomes may be explained by application of prospect theory and may be associated with cognitive bias in clinical decision-making.