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Oncogenic human papillomavirus (HPV) infection is the cause of nearly all cervical cancers and a proportion of other anogenital and oropharyngeal cancers. A bivalent vaccine containing HPV 16 and 18 and a quadrivalent vaccine containing HPV 6, 11, 16, and 18 antigens are in use in vaccination programmes around the world. In clinical trials, three vaccine doses provided 90–100% protection against cervical infection and pre-cancer related to HPV 16 and 18 in women aged 15–26 years who were not infected at vaccination. Partial cross-protection against other HPV types has been reported but its duration is unknown. The vaccines were also efficacious at the prevention of HPV 16 and 18 infections at other anatomical sites in both sexes. Immunobridging studies allowed licensing of the vaccines for use starting at age 9 years for both sexes. Two-dose schedules elicit high antibody concentrations, leading to the recommendation of two-dose schedules for girls aged 9–14 years. Pre-licensure and post-licensure studies have provided data supporting vaccine safety. In 2014, a nonavalent vaccine containing HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 antigens was licensed by the US Food and Drug Administration. HPV vaccination was first introduced in high-income countries owing to vaccine cost, logistic challenges, and competing health priorities. Since 2011, vaccine prices have lowered, allowing the introduction of the vaccine in some middle-income countries. Funding of the vaccine by the GAVI Alliance in 2012 led to demonstration projects in some low-income countries. By 2014, more than 57 countries had included the HPV vaccine in their national health programmes. Data from several countries have shown the effect of vaccination on HPV infection and associated disease, and provided evidence of herd immunity. Expansion of programmes to countries with the highest burden of disease is beginning, but further efforts are needed to realise the potential of HPV vaccines.

Extreme weather events have devastating impacts on human health, economic activities, ecosystems, and infrastructure. It is therefore crucial to anticipate extremes and their impacts to allow for preparedness and emergency measures. There is indeed potential for probabilistic subseasonal prediction on time scales of several weeks for many extreme events. Here we provide an overview of subseasonal predictability for case studies of some of the most prominent extreme events across the globe using the ECMWF S2S prediction system: heatwaves, cold spells, heavy precipitation events, and tropical and extratropical cyclones. The considered heatwaves exhibit predictability on time scales of 3–4 weeks, while this time scale is 2–3 weeks for cold spells. Precipitation extremes are the least predictable among the considered case studies. Tropical cyclones, on the other hand, can exhibit probabilistic predictability on time scales of up to 3 weeks, which in the presented cases was aided by remote precursors such as the Madden–Julian oscillation. For extratropical cyclones, lead times are found to be shorter. These case studies clearly illustrate the potential for event-dependent advance warnings for a wide range of extreme events. The subseasonal predictability of extreme events demonstrated here allows for an extension of warning horizons, provides advance information to impact modelers, and informs communities and stakeholders affected by the impacts of extreme weather events.

Tuberculosis (TB), caused by Mycobacterium tuberculosis , is one of the deadliest infectious diseases worldwide. Multidrug and extensively drug-resistant strains are making disease control difficult, and exhausting treatment options. New anti-TB drugs bedaquiline (BDQ), delamanid (DLM) and pretomanid (PTM) have been approved for the treatment of multi-drug resistant TB, but there is increasing resistance to them. Nine genetic loci strongly linked to resistance have been identified ( mmpR5 , atpE , and pepQ for BDQ; ddn , fgd1 , fbiA , fbiB , fbiC , and fbiD for DLM/PTM). Here we investigated the genetic diversity of these loci across >33,000  M . tuberculosis isolates. In addition, epistatic mutations in mmpL5-mmpS5 as well as variants in ndh , implicated for DLM/PTM resistance in M. smegmatis , were explored . Our analysis revealed 1,227 variants across the nine genes, with the majority (78%) present in isolates collected prior to the roll-out of BDQ and DLM/PTM. We identified phylogenetically-related mutations, which are unlikely to be resistance associated, but also high-impact variants such as frameshifts (e.g. in mmpR5 , ddn ) with likely functional effects, as well as non-synonymous mutations predominantly in MDR-/XDR-TB strains with predicted protein destabilising effects. Overall, our work provides a comprehensive mutational catalogue for BDQ and DLM/PTM associated genes, which will assist with establishing associations with phenotypic resistance; thereby, improving the understanding of the causative mechanisms of resistance for these drugs, leading to better treatment outcomes.

Late-onset Alzheimer’s disease (LOAD) is a high-occurrence neurological disorder but the difficulty in identifying precise and early biomarkers has complicated the understanding of the disease and the development of new treatments. In this sense, important knowledge is emerging regarding novel molecular and biological candidates with diagnostic potential, including microRNAs (miRNAs), which have a key role in gene repression. The aim of this systematic review was to define the role of miRNAs’ expression as biomarkers for LOAD both in brain tissues, which could help understand the biology of the disease, and circulating tissues, which could serve as non-invasive markers of the pathology. A systematic search was performed in Web of Science and PubMed using the keywords ((Alzheimer or Alzheimer’s) and (microRNA or microRNAs or miRNA or miRNAs or miR)) until August 2018 to retrieve all articles that presented independent original data evaluating the impact of miRNA expression on the development of LOAD in human population. A total of 90 studies investigating the role of miRNAs’ expression in the development of LOAD were identified. While other widely studied miRNAs such as hsa-miR-146a presented contradictory results among studies, deregulation in brain tissue of seven miRNAs, hsa-miR-16-5p, hsa-miR-34a-5p, hsa-miR-107, hsa-miR-125-5p, hsa-miR-132-3p, hsa-miR-181-3p, and hsa-miR-212-3p, was consistently identified in LOAD patients. Their role in the disease could be mediated through the regulation of key pathways, such as axon guidance, longevity, insulin, and MAPK signaling pathway. However, regarding their role as non-invasive biomarkers of LOAD in fluids, although the limited results available are promising, further studies are required.

Out of all the metal additive manufacturing (AM) techniques, the directed energy deposition (DED) technique, and particularly the wire-based one, are of great interest due to their rapid production. In addition, they are recognized as being the fastest technique capable of producing fully functional structural parts, near-net-shape products with complex geometry and almost unlimited size. There are several wire-based systems, such as plasma arc welding and laser melting deposition, depending on the heat source. The main drawback is the lack of commercially available wire; for instance, the absence of high-strength aluminum alloy wires. Therefore, this review covers conventional and innovative processes of wire production and includes a summary of the Al-Cu-Li alloys with the most industrial interest in order to foment and promote the selection of the most suitable wire compositions. The role of each alloying element is key for specific wire design in WAAM; this review describes the role of each element (typically strengthening by age hardening, solid solution and grain size reduction) with special attention to lithium. At the same time, the defects in the WAAM part limit its applicability. For this reason, all the defects related to the WAAM process, together with those related to the chemical composition of the alloy, are mentioned. Finally, future developments are summarized, encompassing the most suitable techniques for Al-Cu-Li alloys, such as PMC (pulse multicontrol) and CMT (cold metal transfer).

Cellular senescence is an antiproliferative response with a critical role in the control of cellular balance in diverse physiological and pathological settings. Here, we set to study the impact of senescence on the regulation of cell plasticity, focusing on the regulation of the myofibroblastic phenotype in primary fibroblasts. Myofibroblasts are contractile, highly fibrogenic cells with key roles in wound healing and fibrosis. Using cellular models of fibroblast senescence, we find a consistent loss of myofibroblastic markers and functional features upon senescence implementation. This phenotype can be transmitted in a paracrine manner, most likely through soluble secreted factors. A dynamic transcriptomic analysis during paracrine senescence confirmed the non‐cell‐autonomous transmission of this phenotype. Moreover, gene expression data combined with pharmacological and genetic manipulations of the major SASP signaling pathways suggest that the changes in myofibroblast phenotype are mainly mediated by the Notch/TGF‐β axis, involving a dynamic switch in the TGF‐β pathway. Our results reveal a novel link between senescence and myofibroblastic differentiation with potential implications in the physiological and pathological functions of myofibroblasts. Primary fibroblasts under standard tissue culture conditions acquire myofibroblastic features. Cellular senescence results in the loss of myofibroblastic features in these cells. This phenotype can be transmitted by the senescent secretome, and it is associated with a dynamic switch in the TGF‐beta pathway during senescence. These results reveal a link between senescence and myofibroblastic differentiation with potential implications in the physiological and pathological function of myofibroblasts.

Oxygen heterocycles are units that are abundant in a great number of marine natural products. Among them, marine polyketides containing tetrahydrofuran rings have attracted great attention within the scientific community due to their challenging structures and promising biological activities. An overview of the most important marine tetrahydrofuran polyketides, with a focused discussion on their isolation, structure determination, approaches to their total synthesis, and biological studies is provided.

Breast Cancer (BC) is the most common neoplasm in women worldwide, considered a global public health problem. Among BC women, some of the most common psychological symptoms in the adaptation to the disease are reduction in self-esteem and distorted body image (BI). Although there are numerous studies with the goal of promoting different psychological variables, BI and self-esteem are often separately observed despite their relationship and their importance in the process of the illness. Moreover, there have been no reviews that have synthesized the findings related to interventions aimed at enhancing both self-esteem and BI in BC women. Therefore, the objective of this review was to identify and examine the implemented interventions aimed at boosting both variables in this population. For this purpose, a systematic review was implemented following the PRISMA statement. A thorough search was performed on the following databases: Web of Science, PubMed, PsychInfo, PsychArticles, and Scopus. Among 287 records, only eight articles met the eligibility criteria. Interventions were grouped into three types according to their characteristics: Group therapies, Physical activity therapies, and Cosmetic and beauty treatments. The levels of effectiveness of the different interventions varied between them, and within each, in their impact on self-esteem and BI. More interventions focused on developing BI and self-esteem in this population are needed due to their ability to predict psychological functioning and quality of life of women with breast cancer.

Heterocycles are particularly common moieties within marine natural products. Specifically, tetrahydrofuranyl rings are present in a variety of compounds which present complex structures and interesting biological activities. Focusing on terpenoids, a high number of tetrahydrofuran-containing metabolites have been isolated during the last decades. They show promising biological activities, making them potential leads for novel antibiotics, antikinetoplastid drugs, amoebicidal substances, or anticancer drugs. Thus, they have attracted the attention of the synthetics community and numerous approaches to their total syntheses have appeared. Here, we offer the reader an overview of marine-derived terpenoids and related compounds, their isolation, structure determination, and a special focus on their total syntheses and biological profiles.

PurposeMergers and acquisition are a very common part of business strategy. However, it is not clear if and how these processes affect customers. This study aims to assess banking M&A from the marketing perspective, by analyzing its impact on the customer loyalty.Design/methodology/approachThe study employed a purposive sampling method for collecting data from 232 respondents using a self-administered questionnaire. Variance-based structural equation modelling (PLS-SEM) was used for testing the proposed structural model.FindingsResults show that M&A integration does influence customers' perception of key variables like customer–company relationship, and their loyalty after the M&A. Findings highlight the relative importance of these variables and the potential influence of some moderators (customer orientation, speed of integration and communication). The most important antecedent of loyalty in a M&A situation is service quality followed by company image, products and prices, sales channels and sales force.Originality/valueThis paper explores the impact of M&A on clients by using customer survey data, an area that is still an under-explored field, in relation with the total number of articles on M&A that are published each year.