Reduced Prevalence of Oral Human Papillomavirus (HPV) 4 Years after Bivalent HPV Vaccination in a Randomized Clinical Trial in Costa Rica

Background

Human papillomavirus (HPV) infection, particularly with type 16, causes a growing fraction of oropharyngeal cancers, whose incidence is increasing, mainly in developed countries. In a double-blind controlled trial conducted to investigate vaccine efficacy (VE) of the bivalent HPV 16/18 vaccine against cervical infections and lesions, we estimated VE against prevalent oral HPV infections 4 years after vaccination.

Methods and Findings

A total of 7,466 women 18–25 years old were randomized (1∶1) to receive the HPV16/18 vaccine or hepatitis A vaccine as control. At the final blinded 4-year study visit, 5,840 participants provided oral specimens (91·9% of eligible women) to evaluate VE against oral infections. Our primary analysis evaluated prevalent oral HPV infection among all vaccinated women with oral and cervical HPV results. Corresponding VE against prevalent cervical HPV16/18 infection was calculated for comparison. Oral prevalence of identifiable mucosal HPV was relatively low (1·7%). Approximately four years after vaccination, there were 15 prevalent HPV16/18 infections in the control group and one in the vaccine group, for an estimated VE of 93·3% (95% CI = 63% to 100%). Corresponding efficacy against prevalent cervical HPV16/18 infection for the same cohort at the same visit was 72·0% (95% CI = 63% to 79%) (p versus oral VE = 0·04). There was no statistically significant protection against other oral HPV infections, though power was limited for these analyses.

Conclusions

HPV prevalence four years after vaccination with the ASO4-adjuvanted HPV16/18 vaccine was much lower among women in the vaccine arm compared to the control arm, suggesting that the vaccine affords strong protection against oral HPV16/18 infection, with potentially important implications for prevention of increasingly common HPV-associated oropharyngeal cancer.ClinicalTrials.gov, Registry number {"type":"clinical-trial","attrs":{"text":"NCT00128661","term_id":"NCT00128661"}}NCT00128661     

Low‐gluten,nontransgenic wheat engineered with CRISPR/Cas9

Coeliac disease is an autoimmune disorder triggered in genetically predisposed individuals by the ingestion of gluten proteins from wheat, barley and rye. The α‐gliadin gene family of wheat contains four highly stimulatory peptides, of which the 33‐mer is the main immunodominant peptide in patients with coeliac. We designed two sgRNAs to target a conserved region adjacent to the coding sequence for the 33‐mer in the α‐gliadin genes. Twenty‐one mutant lines were generated, all showing strong reduction in α‐gliadins. Up to 35 different genes were mutated in one of the lines of the 45 different genes identified in the wild type, while immunoreactivity was reduced by 85%. Transgene‐free lines were identified, and no off‐target mutations have been detected in any of the potential targets. The low‐gluten, transgene‐free wheat lines described here could be used to produce low‐gluten foodstuff and serve as source material to introgress this trait into elite wheat varieties.     

Wheat stem sawfly‐infested plants benefit from parasitism of the herbivorous larvae

1 Parasitoids Bracon cephi (Gahan) and Bracon lissogaster Muesebeck and their herbivorous host the wheat stem sawfly Cephus cinctus Norton, a pest of wheat Triticum aestivum, were investigated for yield in T. aestivum grown in the field. 2 Wheat stem sawfly‐infested stems had a higher yield potential than uninfested stems. However, final reproductive output was not significantly different between ears on infested stems that supported complete larval development compared with ears on uninfested stems. 3 Stems containing parasitized larvae and stems containing larvae that died before completing their development had a higher mean number of seeds and seed weight, when accounting for number of fertile spikelets of each ear, than either infested with live larvae and uninfested stems. 4 The results obtained suggest that larval feeding prevented infested stems from attaining their yield potential, and that the negative impact of the pest on wheat yield was reduced when late instar sawfly larvae were parasitized. Even though some feeding occurs before parasitism, this early damage has a comparatively low impact on yield. 5 This is the first study to show a yield benefit and enhanced plant fitness due to the wheat stem sawfly parasitoids B. cephi and B. lissogaster. This results from the maintenance of increased seed number and seed weight in the higher yielding stems that are preferentially infested by this pest.     

Thiodiacetato-copper(II) chelates with or without N-heterocyclic donor ligands: molecular and/or crystal structures of [Cu(tda)]n, [Cu(tda)(Him)2(H2O)] and [Cu(tda)(5Mphen)] · 2H2O (Him = imidazole, 5Mphen = 5-methyl-1,10-phenanthroline)

Three new thiodiacetato-Cu(II) chelates have been synthesized and studied by X-ray crystallography and by thermal, spectral and magnetic methods. [Cu(tda)]_n (1) is a 3D-polymer with a pentadentate tda, which acts with a fac-O₂ + S(apical)-tridentate chelating conformation and as a twofold anti, syn-μ-η¹:η¹ carboxylate bridge. In its square pyramidal Cu(II) coordination (type 4 + 1) four O(carboxylate) donors define a close regular square base, but the Cu-S(apical) bond deviates 27.4° from the perpendicular to the mean basal plane. Each anti,syn-bridging carboxylate group exhibits two C-O (average 1.26(1) Å) and two Cu-O bonds (average 1.958(7) Å), which are very similar in length to each other. In contrast, the mixed-ligand complexes of [Cu(tda)(Him)₂(H₂O)] (compound 2, distorted octahedral, type 4 + 1 + 1) and [Cu(tda)(5Mphen)] · 2H₂O (compound 3, distorted square pyramidal, type 4 + 1) have molecular structures and the tda ligand displays only a fac-O₂ + S(apical)-tridentate conformation. The Cu-S(apical) bond lengths (2.570(1), 2.623(1) or 2.573(1) Å for 1, 2 or 3, respectively) are shorter than those previously reported for closely related Cu(II)-tda derivatives. The different tda ligand roles in their Cu(II) derivatives are rationalized on the basis of crystal packing forces driving in the absence or presence of auxiliary ligands (with two or three N-donor atoms).     

Phylogenetic Signal,Congruence, and Uncertainty across Bacteria and Archaea

Reconstruction of the Tree of Life is a central goal in biology. Although numerous novel phyla of bacteria and archaea have recently been discovered, inconsistent phylogenetic relationships are routinely reported, and many inter-phylum and inter-domain evolutionary relationships remain unclear. Here, we benchmark different marker genes often used in constructing multidomain phylogenetic trees of bacteria and archaea and present a set of marker genes that perform best for multidomain trees constructed from concatenated alignments. We use recently-developed Tree Certainty metrics to assess the confidence of our results and to obviate the complications of traditional bootstrap-based metrics. Given the vastly disparate number of genomes available for different phyla of bacteria and archaea, we also assessed the impact of taxon sampling on multidomain tree construction. Our results demonstrate that biases between the representation of different taxonomic groups can dramatically impact the topology of resulting trees. Inspection of our highest-quality tree supports the division of most bacteria into Terrabacteria and Gracilicutes, with Thermatogota and Synergistota branching earlier from these superphyla. This tree also supports the inclusion of the Patescibacteria within the Terrabacteria as a sister group to the Chloroflexota instead of as a basal-branching lineage. For the Archaea, our tree supports three monophyletic lineages (DPANN, Euryarchaeota, and TACK/Asgard), although we note the basal placement of the DPANN may still represent an artifact caused by biased sequence composition. Our findings provide a robust and standardized framework for multidomain phylogenetic reconstruction that can be used to evaluate inter-phylum relationships and assess uncertainty in conflicting topologies of the Tree of Life.     

Early diagnosis of congenital toxoplasmosis in newborn infants using IgG subclasses against two Toxoplasma gondii recombinant proteins

The aim of this work was to evaluate the utility of ELISA-based testing of total IgG (IgGt) antibodies and its subclasses (IgG1, IgG2, IgG3 and IgG4) against soluble (STAg) and recombinant (rSAG1 and rMIC3) antigens of Toxoplasma gondii for diagnosing congenital toxoplasmosis. Sera from 217 newborns initially testing positive for specific IgM in filter paper dried blood spots were tested for specific IgM and IgG by ELFA-VIDAS. Congenital toxoplasmosis was confirmed in 175 and ruled out in 42 infants. The validity of the ELISA tests was determined using the persistence of IgG antibodies (ELFA-VIDAS kit) at the end of 12 months, which is considered the reference test for the diagnosis of congenital toxoplasmosis. The frequency of positivity with IgGt against STAg, rSAG1 and rMIC3 was found in 97.2%, 96.3% and 80.2%, respectively, of the newborns with confirmed congenital toxoplasmosis. IgG1 reacted with all three antigens, while IgG3 and IgG4 reacted preferentially with rMIC3. Higher mean values of reactivity (sample optical density/cut-off) were found for all subclasses when using rMIC3. All of the antigens showed high sensitivity and low specificity in detecting anti-T. gondii IgGt and IgG1 and low sensitivity and high specificity in detecting IgG3 and IgG4. In conclusion, the combined detection of IgG antibody subclasses against recombinant toxoplasmic antigens may be useful for the early diagnosis of congenital toxoplasmosis.     

Hidden diversity in Antarctica: Molecular and morphological evidence of two different species within one of the most conspicuous ascidian species

The Southern Ocean is one of the most isolated marine ecosystems, characterized by high levels of endemism, diversity, and biomass. Ascidians are among the dominant groups in Antarctic benthic assemblages; thus, recording the evolutionary patterns of this group is crucial to improve our current understanding of the assembly of this polar ocean. We studied the genetic variation within Cnemidocarpa verrucosa sensu lato, one of the most widely distributed abundant and studied ascidian species in Antarctica. Using a mitochondrial and a nuclear gene (COI and 18S), the phylogeography of fifteen populations distributed along the West Antarctic Peninsula and Burdwood Bank/MPA Namuncurá (South American shelf) was characterized, where the distribution of the genetic distance suggested the existence of, at least, two species within nominal C. verrucosa. When reevaluating morphological traits to distinguish between genetically defined species, the presence of a basal disk in one of the genotypes could be a diagnostic morphological trait to differentiate the species. These results are surprising due to the large research that has been carried out with the conspicuous C. verrucosa with no differentiation between species. Furthermore, it provides important tools to distinguish species in the field and laboratory. But also, these results give new insights into patterns of differentiation between closely related species that are distributed in sympatry, where the permeability of species boundaries still needs to be well understood.     

Angiotensin and calcium signaling in the pituitary and hypothalamus

1) In the rat pituitary, angiotensin type 1B receptors (AT_1B) are located in lactotrophs and corticotrophs.2) Activation of AT_1B receptors are coupled to G_q/11 (Guanine protein coupled receptor, or GPCR); they increase phospholipase C (PLC) activity resulting in inositol 1,4,5 triphosphate (InsP₃) and diacylglycerol (DAG) formation. A biphasic increase in [Ca²⁺]_itriggered by InsP₃ and DAG ensues.3) As many GPCRs, AT_1B pituitary receptors rapidly desensitize.4) This was observed in the generation of InsP3, the mobilization of intracellular Ca²⁺, and in prolactin release. Both homologous and heterologous desensitization was evidenced.5) Desensitization of the angiotensin II type 1 (AT1) receptor in the pituitary shares similarities and differences with endogenously expressed or transfected AT1 receptors in different cell types.6) In the pituitary hyperplasia generated by chronic estrogen treatment there was desensitization or alteration in angiotensin II (Ang II) evoked intracellular Ca²⁺ increase, InsP3 generation, and prolactin release. This correlates with a downregulation of AT1 receptors.7) In particular, in hyperplastic cells Ang II failed to evoke a transient acute peak in [Ca²⁺]_i, which was replaced by a persistent plateau phase of [Ca²⁺]_i increase.8) Different calcium channels participate in Ang II induced [Ca²⁺]_i increase in control and hyperplastic cells. While spike phase in control cells is dependent on intracellular stores sensitive to thapsigargin, in hyperplastic cells plateau increase is dependent on extracellular calcium influx.9) Signal transduction of the AT1 pituitary receptor is greatly modified by hyperplasia, and it may be an important mechanism in the control of the hyperplastic process.10) In the hypothalamus and brain stem there is a predominant expression of AT_1A and AT₂ mRNA.11) Ang II acts at specific receptors located on neurons in the hypothalamus and brain stem to elicit alterations in blood pressure, fluid intake, and hormone secretion.12) Calcium channels play important roles in the Ang II induced behavioral and endocrine responses.13) Ang II, in physiological concentrations, can activate AT1 receptors to stimulate both Ca²⁺ release from intracellular stores and Ca²⁺ influx from the extracellular space to increase [Ca²⁺]_i in polygonal and stellate astroglia of the hypothalamus and brain stem.14) In primary cell culture of neurons from newborn rat hypothalamus and brain stem, it has also been determined that Ang II elicits an AT1 receptor mediated inhibition of delayed rectifier K(+) current and a stimulation of Ca²⁺ current.15) In primary cell cultures derived from the subfornical organ or the organum vasculosum laminae terminalis of newborn rat pups, Ang II produced a pronounced desensitization of the [Ca²⁺]_i response.16) Hypothalamic and pituitary Ang II systems are involved in different functions, some of which are related. At both levels Ang II signals through [Ca²⁺]_i in a characteristic way.