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Cervical cancer is one of the most common causes of cancer-related deaths in women worldwide. Despite advances in current therapies, women with advanced or recurrent disease present poor prognosis. Photodynamic therapy (PDT) has emerged as an effective therapeutic alternative to treat oncological diseases such as cervical cancer. Phthalocyanines (Pcs) are considered good photosensitizers (PS) for PDT, although most of them present high levels of aggregation and are lipophilic. Despite many investigations and encouraging results, Pcs have not been approved as PS for PDT of invasive cervical cancer yet. This review presents an overview on the pathophysiology of cervical cancer and summarizes the most recent developments on the physicochemical properties of Pcs and biological results obtained both in vitro in tumor-bearing mice and in clinical tests reported in the last five years. Current evidence indicates that Pcs have potential as pharmaceutical agents for anti-cervical cancer therapy. The authors firmly believe that Pc-based formulations could emerge as a privileged scaffold for the establishment of lead compounds for PDT against different types of cervical cancer.

Several studies examined the fine-scale structure of human genetic variation in Europe. However, the European sets analyzed represent mainly northern, western, central, and southern Europe. Here, we report an analysis of approximately 166,000 single nucleotide polymorphisms in populations from eastern (northeastern) Europe: four Russian populations from European Russia, and three populations from the northernmost Finno-Ugric ethnicities (Veps and two contrast groups of Komi people). These were compared with several reference European samples, including Finns, Estonians, Latvians, Poles, Czechs, Germans, and Italians. The results obtained demonstrated genetic heterogeneity of populations living in the region studied. Russians from the central part of European Russia (Tver, Murom, and Kursk) exhibited similarities with populations from central-eastern Europe, and were distant from Russian sample from the northern Russia (Mezen district, Archangelsk region). Komi samples, especially Izhemski Komi, were significantly different from all other populations studied. These can be considered as a second pole of genetic diversity in northern Europe (in addition to the pole, occupied by Finns), as they had a distinct ancestry component. Russians from Mezen and the Finnic-speaking Veps were positioned between the two poles, but differed from each other in the proportions of Komi and Finnic ancestries. In general, our data provides a more complete genetic map of Europe accounting for the diversity in its most eastern (northeastern) populations.

Flavodiiron proteins are known to have crucial and specific roles in photoprotection of photosystems I and II in cyanobacteria. The filamentous, heterocyst-forming cyanobacterium Anabaena sp. strain PCC 7120 contains, besides the four flavodiiron proteins Flv1A, Flv2, Flv3A, and Flv4 present in vegetative cells, two heterocyst-specific flavodiiron proteins, Flv1B and Flv3B. Here, we demonstrate that Flv3B is responsible for light-induced O ₂ uptake in heterocysts, and that the absence of the Flv3B protein severely compromises the growth of filaments in oxic, but not in microoxic, conditions. It is further demonstrated that Flv3B-mediated photosynthetic O ₂ uptake has a distinct role in heterocysts which cannot be substituted by respiratory O ₂ uptake in the protection of nitrogenase from oxidative damage and, thus, in an efficient provision of nitrogen to filaments. In line with this conclusion, the Δ flv3B strain has reduced amounts of nitrogenase NifHDK subunits and shows multiple symptoms of nitrogen deficiency in the filaments. The apparent imbalance of cytosolic redox state in Δ flv3B heterocysts also has a pronounced influence on the amounts of different transcripts and proteins. Therefore, an O ₂-related mechanism for control of gene expression is suggested to take place in heterocysts.

Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals 1 , 2 , but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose female individuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion. A large-scale meta-analysis across eight biobank datasets identifies common genetic variants associated with mosaic loss of the X chromosome in female participants.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities. The genetic basis of atopic dermatitis is not fully understood. Here, the authors find 91 genetic loci associated with atopic dermatitis in a GWAS of >1million individuals, which highlight the importance of systemic immune regulation.

We compare simulations from three high-top (with upper lid above 120 km) and five medium-top (with upper lid around 80 km) atmospheric models with observations of odd nitrogen (NOx  =  NO + NO2), temperature, and carbon monoxide from seven satellite instruments (ACE-FTS on SciSat, GOMOS, MIPAS, and SCIAMACHY on Envisat, MLS on Aura, SABER on TIMED, and SMR on Odin) during the Northern Hemisphere (NH) polar winter 2008/2009. The models included in the comparison are the 3-D chemistry transport model 3dCTM, the ECHAM5/MESSy Atmospheric Chemistry (EMAC) model, FinROSE, the Hamburg Model of the Neutral and Ionized Atmosphere (HAMMONIA), the Karlsruhe Simulation Model of the Middle Atmosphere (KASIMA), the modelling tools for SOlar Climate Ozone Links studies (SOCOL and CAO-SOCOL), and the Whole Atmosphere Community Climate Model (WACCM4). The comparison focuses on the energetic particle precipitation (EPP) indirect effect, that is, the polar winter descent of NOx largely produced by EPP in the mesosphere and lower thermosphere. A particular emphasis is given to the impact of the sudden stratospheric warming (SSW) in January 2009 and the subsequent elevated stratopause (ES) event associated with enhanced descent of mesospheric air. The chemistry climate model simulations have been nudged toward reanalysis data in the troposphere and stratosphere while being unconstrained above. An odd nitrogen upper boundary condition obtained from MIPAS observations has further been applied to medium-top models. Most models provide a good representation of the mesospheric tracer descent in general, and the EPP indirect effect in particular, during the unperturbed (pre-SSW) period of the NH winter 2008/2009. The observed NOx descent into the lower mesosphere and stratosphere is generally reproduced within 20 %. Larger discrepancies of a few model simulations could be traced back either to the impact of the models' gravity wave drag scheme on the polar wintertime meridional circulation or to a combination of prescribed NOx mixing ratio at the uppermost model layer and low vertical resolution. In March–April, after the ES event, however, modelled mesospheric and stratospheric NOx distributions deviate significantly from the observations. The too-fast and early downward propagation of the NOx tongue, encountered in most simulations, coincides with a temperature high bias in the lower mesosphere (0.2–0.05 hPa), likely caused by an overestimation of descent velocities. In contrast, upper-mesospheric temperatures (at 0.05–0.001 hPa) are generally underestimated by the high-top models after the onset of the ES event, being indicative for too-slow descent and hence too-low NOx fluxes. As a consequence, the magnitude of the simulated NOx tongue is generally underestimated by these models. Descending NOx amounts simulated with medium-top models are on average closer to the observations but show a large spread of up to several hundred percent. This is primarily attributed to the different vertical model domains in which the NOx upper boundary condition is applied. In general, the intercomparison demonstrates the ability of state-of-the-art atmospheric models to reproduce the EPP indirect effect in dynamically and geomagnetically quiescent NH winter conditions. The encountered differences between observed and simulated NOx, CO, and temperature distributions during the perturbed phase of the 2009 NH winter, however, emphasize the need for model improvements in the dynamical representation of elevated stratopause events in order to allow for a better description of the EPP indirect effect under these particular conditions.

Senescence involves increased expression of proteases, which may participate in nitrogen recycling or cellular signalling. 2D zymograms detected two protein species with increased proteolytic activity in senescing leaves of Arabidopsis thaliana. A proteomic analysis revealed that both protein species correspond to a subtilisin protease encoded by At3g14067, termed Senescence-Associated Subtilisin Protease (SASP). SASP mRNA levels and enzyme activity increase during leaf senescence in leaves senescing during both the vegetative or the reproductive phase of the plant life cycle, but this increase is more pronounced in reproductive plants. SASP is expressed in all aboveground organs, but not in roots. Putative AtSASP orthologues were identified in dicot and monocot crop species. A phylogenetic analysis shows AtSASP and its putative orthologues clustering in one discrete group of subtilisin proteases in which no other Arabidospsis subtilisin protease is present. Phenotypic analysis of two knockout lines for SASP showed that mutant plants develop more inflorescence branches during reproductive development. Both AtSASP and its putative rice orthologue (OsSASP) were constitutively expressed in sasp-1 to complement the mutant phenotype. At maturity, sasp-1 plants produced 25% more inflorescence branches and siliques than either the wild-type or the rescued lines. These differences were mostly due to an increased number of second and third order branches. The increased number of siliques was compensated for by a small decrease (5.0%) in seed size. SASP downregulates branching and silique production during monocarpic senescence, and its function is at least partially conserved between Arabidopsis and rice.

Syndemics are a framework that documents health inequities and vulnerabilities in populations with rheumatic diseases. Compared with other approaches, syndemics are able to conjunctly consider epidemiological, biological, sociodemographic and economic factors, and their interactions.ObjectiveTo estimate health inequity and vulnerability among Indigenous and non-Indigenous populations with rheumatic and musculoskeletal diseases (RMD) in Latin America using the syndemic approach.DesignThis is a secondary analysis of a previously published large-scale study on the prevalence of RMD.SettingStudies carried out in five Latin American countries (Argentina, Colombia, Ecuador, Mexico and Venezuela). Health inequity and vulnerability in RMD were identified through a syndemic approach using network and cluster analysis.ParticipantsA total of 44 560 individuals were studied: 29.78% self-identified as Indigenous, 60.92% were female, the mean age was 43.25 years. Twenty clusters were identified in the Indigenous population and 17 in the non-Indigenous population.ResultsThe variables associated with RMD among Indigenous populations were rurality, public health system, high joint biomechanical stress, greater pain, disability and alcoholism; and among non-Indigenous people they were being a woman, urban origin, older age, private health system, joint biomechanical stress, greater pain and disability. We identified different health inequities among patients with RMD (ie, lower educational attainment, more comorbidities), associated with factors such as Indigenous self-identification and rural residence.ConclusionsA syndemic approach enables us to identify health inequities in RMD, as shown by higher prevalence of comorbidities, disability and socioeconomic factors like lower educational attainment. These inequities exist for the overall population of patients with RMD, although it is more evident in Indigenous groups with added layers of vulnerability.

Soil life supports the functioning and biodiversity of terrestrial ecosystems. Springtails (Collembola) are among the most abundant soil arthropods regulating soil fertility and flow of energy through above- and belowground food webs. However, the global distribution of springtail diversity and density, and how these relate to energy fluxes remains unknown. Here, using a global dataset representing 2470 sites, we estimate the total soil springtail biomass at 27.5 megatons carbon, which is threefold higher than wild terrestrial vertebrates, and record peak densities up to 2 million individuals per square meter in the tundra. Despite a 20-fold biomass difference between the tundra and the tropics, springtail energy use (community metabolism) remains similar across the latitudinal gradient, owing to the changes in temperature with latitude. Neither springtail density nor community metabolism is predicted by local species richness, which is high in the tropics, but comparably high in some temperate forests and even tundra. Changes in springtail activity may emerge from latitudinal gradients in temperature, predation and resource limitation in soil communities. Contrasting relationships of biomass, diversity and activity of springtail communities with temperature suggest that climate warming will alter fundamental soil biodiversity metrics in different directions, potentially restructuring terrestrial food webs and affecting soil functioning