The generally low bioavailability of iron in aerobic soil systems forced plants to evolve sophisticated genetic strategies to improve the acquisition of iron from sparingly soluble and immobile iron ...pools. To distinguish between conserved and species-dependent components of such strategies, we analyzed iron deficiency-induced changes in the transcriptome of two model species, Arabidopsis (Arabidopsis thaliana) and Medicago truncatula. Transcriptional profiling by RNA sequencing revealed a massive upregulation of genes coding for enzymes involved in riboflavin biosynthesis in M. truncatula and phenylpropanoid synthesis in Arabidopsis upon iron deficiency. Coexpression and promoter analysis indicated that the synthesis of flavins and phenylpropanoids is tightly linked to and putatively coregulated with other genes encoding proteins involved in iron uptake. We further provide evidence that the production and secretion of phenolic compounds is critical for the uptake of iron from sources with low bioavailability but dispensable under conditions where iron is readily available. In Arabidopsis, homozygous mutations in the Fe(II)- and 2-oxoglutarate-dependent dioxygenase family gene F6'H1 and defects in the expression of PLEIOTROPIC DRUG RESISTANCE9, encoding a putative efflux transporter for products from the phenylpropanoid pathway, compromised iron uptake from an iron source of low bioavailability. Both mutants were partially rescued when grown alongside wild-type Arabidopsis or M. truncatula seedlings, presumably by secreted phenolics and flavins. We concluded that production and secretion of compounds that facilitate the uptake of iron is an essential but poorly understood aspect of the reduction-based iron acquisition strategy, which is likely to contribute substantially to the efficiency of iron uptake in natural conditions.
Respiratory syncytial virus (RSV) is a major cause of childhood medically attended respiratory infection (MARI).
We conducted a randomized, double-blind, placebo-controlled phase 3 trial in 1154 ...preterm infants of 1 or 2 doses of suptavumab, a human monoclonal antibody that can bind and block a conserved epitope on RSV A and B subtypes, for the prevention of RSV MARI. The primary endpoint was proportion of subjects with RSV-confirmed hospitalizations or outpatient lower respiratory tract infection (LRTI).
There were no significant differences between primary endpoint rates (8.1%, placebo; 7.7%, 1-dose; 9.3%, 2-dose). Suptavumab prevented RSV A infections (relative risks, .38; 95% confidence interval CI, .14-1.05 in the 1-dose group and .39 95% CI, .14-1.07 in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .0499), while increasing the rate of RSV B infections (relative risk 1.36 95% CI, .73-2.56 in the 1-dose group and 1.69 95% CI, .92-3.08 in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .12). Sequenced RSV isolates demonstrated no suptavumab epitope changes in RSV A isolates, while all RSV B isolates had 2-amino acid substitution in the suptavumab epitope that led to loss of neutralization activity. Treatment emergent adverse events were balanced across treatment groups.
Suptavumab did not reduce overall RSV hospitalizations or outpatient LRTI because of a newly circulating mutant strain of RSV B. Genetic variation in circulating RSV strains will continue to challenge prevention efforts.
NCT02325791.
Respiratory syncytial virus (RSV) causes lower respiratory tract illness frequently. No effective antivirals or vaccines for RSV are approved for use in the United States; however, there are at least ...50 vaccines and monoclonal antibody products in development, with those targeting older adults and pregnant women (to protect young infants) in phase 2 and 3 clinical trials. Unanswered questions regarding RSV epidemiology need to be identified and addressed prior to RSV vaccine introduction to guide the measurement of impact and future recommendations. The Centers for Disease Control and Prevention (CDC) convened a technical consultation to gather input from external subject matter experts on their individual perspectives regarding evidence gaps in current RSV epidemiology in the United States, potential studies and surveillance platforms needed to fill these gaps, and prioritizing efforts. Participants articulated their individual views, and CDC staff synthesized individuals' input into this report.
Any organization is routinely faced with the need to make decisions regarding the selection and scheduling of project portfolios from a set of candidate projects. We propose a multiobjective binary ...programming model that facilitates both obtaining efficient portfolios in line with the set of objectives pursued by the organization, as well as their scheduling regarding the optimum time to launch each project within the portfolio without the need for a priori information on the decision-maker's preferences. Resource constraints, the possibility of transferring resources not consumed in a given a period to the following one, and project interdependence have also been taken into account. Given that the complexity of this problem increases as the number of projects and the number of objectives increase, we solve it using a metaheuristic procedure based on Scatter Search that we call SS-PPS (Scatter Search for Project Portfolio Selection). The characteristics and effectiveness of this method are compared with other heuristic approaches (SPEA and a fully random procedure) using computational experiments on randomly generated instances.
This paper describes a model to aid in the selection and scheduling of project portfolios within an organization. The model was designed assuming strong interdependence between projects, which therefore have to be assessed in groups, while allowing individual projects to start at different times depending on resource availability or any other strategic or political requirements, which involves timing issues. The simultaneous combination of project portfolio selection and scheduling under general conditions involves known drawbacks that we attempt to remedy. Finally, the model takes into account multiple objectives without requiring a priori specifications regarding the decision-maker's preferences.
The resolution of the problem was approached using a metaheuristic procedure, which showed by computational experiments good performance compared with other heuristics.
Purpose
We describe our series of 4 patients with megalencephaly-capillary malformation syndrome (MCAP) and review the literature in order to assess the optimal treatment for the associated ...hydrocephalus.
Methods
We review our institutional series of hydrocephalus associated with MCAP and review the literature, analyzing the causes that could originate the hydrocephalus and the different types of treatments proposed for them.
Results
Of our patients treated with ventriculoperitoneal (VP) shunt, one suffered a surgical revision of the shunt and died due to a cranial trauma unrelated to her syndrome or the previous shunt surgery, and the other did not undergo surgical revisions until the end of her follow-up. Our patients treated with endoscopic third ventriculostomy (ETV) have improved their symptomatology and have not suffered of any complications related to the hydrocephalus after the ETV surgery.
Conclusions
We update the treatment of MCAP-associated hydrocephalus and propose ETV as a valid treatment, as it seems a safe procedure with a low rate of complications.
The identification of the two most prevalent susceptibility genes in breast cancer, BRCA1 and BRCA2, was the beginning of a sustained effort to uncover new genes explaining the missing heritability ...in this disease. Today, additional high, moderate and low penetrance genes have been identified in breast cancer, such as P53, PTEN, STK11, PALB2 or ATM, globally accounting for around 35 percent of the familial cases. In the present study we used massively parallel sequencing to analyze 7 BRCA1/BRCA2 negative families, each having at least 6 affected women with breast cancer (between 6 and 10) diagnosed under the age of 60 across generations. After extensive filtering, Sanger sequencing validation and co-segregation studies, variants were prioritized through either control-population studies, including up to 750 healthy individuals, or case-control assays comprising approximately 5300 samples. As a result, a known moderate susceptibility indel variant (CHEK2 1100delC) and a catalogue of 11 rare variants presenting signs of association with breast cancer were identified. All the affected genes are involved in important cellular mechanisms like DNA repair, cell proliferation and survival or cell cycle regulation. This study highlights the need to investigate the role of rare variants in familial cancer development by means of novel high throughput analysis strategies optimized for genetically heterogeneous scenarios. Even considering the intrinsic limitations of exome resequencing studies, our findings support the hypothesis that the majority of non-BRCA1/BRCA2 breast cancer families might be explained by the action of moderate and/or low penetrance susceptibility alleles.
The effects of iron deficiency on the composition of the xylem sap and leaf apoplastic fluid have been characterized in sugar beet (Beta vulgaris Monohil hybrid). pH was estimated from direct ...measurements in apoplastic fluid and xylem sap obtained by centrifugation and by fluorescence of leaves incubated with 5-carboxyfluorescein and fluorescein isothiocyanate-dextran. Iron deficiency caused a slight decrease in the pH of the leaf apoplast (from 6.3 down to 5.9) and xylem sap (from 6.0 down to 5.7) of sugar beet. Major organic acids found in leaf apoplastic fluid and xylem sap were malate and citrate. Total organic acid concentration in control plants was 4.3 mM in apoplastic fluid and 9.4 mM in xylem sap and increased to 12.2 and 50.4 mM, respectively, in iron-deficient plants. Inorganic cation and anion concentrations also changed with iron deficiency both in apoplastic fluid and xylem sap. Iron decreased with iron deficiency from 5.5 to 2.5 μM in apoplastic fluid and xylem sap. Major predicted iron species in both compartments were $\text{FeCitOH}^{-1}$ in the controls and $\text{FeCit}_{2}^{-3}$ in the iron-deficient plants. Data suggest the existence of an influx of organic acids from the roots to the leaves via xylem, probably associated to an anaplerotic carbon dioxide fixation by roots.
Different root parts with or without increased iron-reducing activities have been studied in iron-deficient and iron-sufficient control sugar beet (Beta vulgaris L. Monohil hybrid). The distal root ...parts of iron-deficient plants, 0 to 5 mm from the root apex, were capable to reduce Fe(III)-chelates and contained concentrations of flavins near 700 μM, two characteristics absent in the 5 to 10 mm sections of iron-deficient plants and the whole root of iron-sufficient plants. Flavin-containing root tips had large pools of carboxylic acids and high activities of enzymes involved in organic acid metabolism. In iron-deficient yellow root tips there was a large increase in carbon fixation associated to an increase in phosphoenolpyruvate carboxylase activity. Part of this carbon was used, through an increase in mitochondrial activity, to increase the capacity to produce reducing power, whereas another part was exported via xylem. Root respiration was increased by iron deficiency. In sugar beet iron-deficient roots flavins would provide a suitable link between the increased capacity to produce reduced nucleotides and the plasma membrane associated ferric chelate reductase enzyme(s). Iron-deficient roots had a large oxygen consumption rate in the presence of cyanide and hydroxisalycilic acid, suggesting that the ferric chelate reductase enzyme is able to reduce oxygen in the absence of Fe(III)-chelates.
Despite the recent advances in cancer therapeutics, highly aggressive cancer forms, such as glioblastoma (GBM), still have very low survival rates. The intracellular scaffold protein syntenin, ...comprising two postsynaptic density protein-95/discs-large/zona occludens-1 (PDZ) domains, has emerged as a novel therapeutic target in highly malignant phenotypes including GBM. Here, we report the development of a novel, highly potent, and metabolically stable peptide inhibitor of syntenin, KSL-128114, which binds the PDZ1 domain of syntenin with nanomolar affinity. KSL-128114 is resistant toward degradation in human plasma and mouse hepatic microsomes and displays a global PDZ domain selectivity for syntenin. An X-ray crystal structure reveals that KSL-128114 interacts with syntenin PDZ1 in an extended noncanonical binding mode. Treatment with KSL-128114 shows an inhibitory effect on primary GBM cell viability and significantly extends survival time in a patient-derived xenograft mouse model. Thus, KSL-128114 is a novel promising candidate with therapeutic potential for highly aggressive tumors, such as GBM.
Abstract Background With the future epidemiology and evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uncertain, the use of safe and effective coronavirus disease 2019 ...(COVID-19) vaccines in pediatric populations remains important. Methods We report data from two open-label substudies of an ongoing phase 1/2/3 master study (NCT05543616) investigating the safety and immunogenicity of a variant-adapted bivalent COVID-19 vaccine encoding ancestral and Omicron BA.4/BA.5 spike proteins (bivalent BNT162b2). The open-label groups presented here evaluate dose 4 with bivalent BNT162b2 in 6-month- to <12-year-olds who previously received three original (monovalent) BNT162b2 doses. In 6-month- to <5-year-olds, primary immunogenicity objectives were to demonstrate superiority (neutralizing titer) and noninferiority (seroresponse rate) to Omicron BA.4/BA.5 and noninferiority (neutralizing titer and seroresponse rate) to SARS-CoV-2 ancestral strains in participants who received bivalent BNT162b2 dose 4 compared with a matched group who received three doses of original BNT162b2 in the pivotal pediatric study (NCT04816643). In 5- to <12-year-olds, primary immunogenicity comparisons were descriptive. Reactogenicity and safety following vaccination were evaluated. Results In 6-month- to <5-year-olds, dose 4 with bivalent BNT162b2 met predefined immunogenicity superiority and noninferiority criteria against Omicron BA.4/BA.5 and ancestral strains when compared with dose 3 of original BNT162b2. In 5- to <12-year-olds, bivalent BNT162b2 induced robust Omicron BA.4/BA.5 and ancestral strain neutralizing titers comparable with dose 3 of original BNT162b2. The safety profile for dose 4 of bivalent BNT162b2 given as dose 4 was consistent with that of original BNT162b2 in 6-month- to <12-year-olds. Reactogenicity events were generally mild to moderate. No adverse events led to discontinuation. Conclusions These safety and immunogenicity data support a favorable benefit-risk profile for a variant-adapted BNT162b2 in children <12 years old.
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