Sferična kristalizacija zdravilnih učinkovin

Spherical crystallization of drugs is the process of obtaining larger particles by agglomeration during crystallization. The most common techniques used to obtain such particles are spherical agglomeration and quasi-emulsion solvent diffusion. Ammonia diffusion systems and crystallo-co-agglomeration are extensions of these techniques. By controlling process parameters during crystallization, such as temperature, stirring rate, type and amount of solvents, or excipient selection, it is possible to control the formation of agglomerates and obtain spherical particles of the desired size, porosity, or hardness. Researchers have reported that the particles produced have improved micromeritic, physical, and mechanical properties, which make them suitable for direct compression. In some cases, when additional excipients are incorporated during spherical crystallization, biopharmaceutical parameters including the bioavailability of drugs can also be tailored.Sferična kristalizacija je postopek izdelave večjih delcev z aglomeracijo manjših med samo kristalizacijo. Najpogosteje uporabljeni tehniki za izdelavo takšnih delcev sta sferična aglomeracija in kvaziemulzija z difuzijo topila. Sistem z difuzijo amoniaka in kristalo-ko-aglomeracija sta razširitvi teh dveh metod. Z nadzorovanjem procesnih parametrov med kristalizacijo, kot sta temperatura in hitrost mešanja, z izbiro lastnosti in množine topil ter z izbiro pomožnih snovi, lahko vplivamo na nastanek aglomeratov in izdelamo sferične delce želenih velikosti, primerne poroznosti ali trdote. Raziskovalci poročajo, da imajo izdelani delci izboljšane pretočne lastnosti, izboljšane druge fizikalne in mehanske lastnosti zaradi česar so primerni za direktno tabletiranje. V nekaterih primerih lahko ob vgradnji ustreznih pomožnih snovi, ki jih dodamo med procesom sferične kristalizacije, izboljšamo tudi biofarmacevtske lastnosti zdravilnih učinkovin vključno s povečanjem biološke uporabnosti

A global observational analysis to understand changes in air quality during exceptionally low anthropogenic emission conditions

This global study, which has been coordinated by the World Meteorological Organization Global Atmospheric Watch (WMO/GAW) programme, aims to understand the behaviour of key air pollutant species during the COVID-19 pandemic period of exceptionally low emissions across the globe. We investigated the effects of the differences in both emissions and regional and local meteorology in 2020 compared with the period 2015–2019. By adopting a globally consistent approach, this comprehensive observational analysis focuses on changes in air quality in and around cities across the globe for the following air pollutants PM2.5, PM10, PMC (coarse fraction of PM), NO2, SO2, NOx, CO, O3 and the total gaseous oxidant (OX = NO2 + O3) during the pre-lockdown, partial lockdown, full lockdown and two relaxation periods spanning from January to September 2020. The analysis is based on in situ ground-based air quality observations at over 540 traffic, background and rural stations, from 63 cities and covering 25 countries over seven geographical regions of the world. Anomalies in the air pollutant concentrations (increases or decreases during 2020 periods compared to equivalent 2015–2019 periods) were calculated and the possible effects of meteorological conditions were analysed by computing anomalies from ERA5 reanalyses and local observations for these periods. We observed a positive correlation between the reductions in NO2 and NOx concentrations and peoples’ mobility for most cities. A correlation between PMC and mobility changes was also seen for some Asian and South American cities. A clear signal was not observed for other pollutants, suggesting that sources besides vehicular emissions also substantially contributed to the change in air quality. As a global and regional overview of the changes in ambient concentrations of key air quality species, we observed decreases of up to about 70% in mean NO2 and between 30% and 40% in mean PM2.5 concentrations over 2020 full lockdown compared to the same period in 2015–2019. However, PM2.5 exhibited complex signals, even within the same region, with increases in some Spanish cities, attributed mainly to the long-range transport of African dust and/or biomass burning (corroborated with the analysis of NO2/CO ratio). Some Chinese cities showed similar increases in PM2.5 during the lockdown periods, but in this case, it was likely due to secondary PM formation. Changes in O3 concentrations were highly heterogeneous, with no overall change or small increases (as in the case of Europe), and positive anomalies of 25% and 30% in East Asia and South America, respectively, with Colombia showing the largest positive anomaly of ~70%. The SO2 anomalies were negative for 2020 compared to 2015–2019 (between ~25 to 60%) for all regions. For CO, negative anomalies were observed for all regions with the largest decrease for South America of up to ~40%. The NO2/CO ratio indicated that specific sites (such as those in Spanish cities) were affected by biomass burning plumes, which outweighed the NO2 decrease due to the general reduction in mobility (ratio of ~60%). Analysis of the total oxidant (OX = NO2 + O3) showed that primary NO2 emissions at urban locations were greater than the O3 production, whereas at background sites, OX was mostly driven by the regional contributions rather than local NO2 and O3 concentrations. The present study clearly highlights the importance of meteorology and episodic contributions (e.g., from dust, domestic, agricultural biomass burning and crop fertilizing) when analysing air quality in and around cities even during large emissions reductions. There is still the need to better understand how the chemical responses of secondary pollutants to emission change under complex meteorological conditions, along with climate change and socio-economic drivers may affect future air quality. The implications for regional and global policies are also significant, as our study clearly indicates that PM2.5 concentrations would not likely meet the World Health Organization guidelines in many parts of the world, despite the drastic reductions in mobility. Consequently, revisions of air quality regulation (e.g., the Gothenburg Protocol) with more ambitious targets that are specific to the different regions of the world may well be required.World Meteorological Organization Global Atmospheric Watch programme is gratefully acknowledged for initiating and coordinating this study and for supporting this publication. We acknowledge the following projects for supporting the analysis contained in this article: Air Pollution and Human Health for an Indian Megacity project PROMOTE funded by UK NERC and the Indian MOES, Grant reference number NE/P016391/1; Regarding project funding from the European Commission, the sole responsibility of this publication lies with the authors. The European Commission is not responsible for any use that may be made of the information contained therein. This project has received funding from the European Commission’s Horizon 2020 research and innovation program under grant agreement No 874990 (EMERGE project). European Regional Development Fund (project MOBTT42) under the Mobilitas Pluss programme; Estonian Research Council (project PRG714); Estonian Research Infrastructures Roadmap project Estonian Environmental Observatory (KKOBS, project 2014-2020.4.01.20-0281). European network for observing our changing planet project (ERAPLANET, grant agreement no. 689443) under the European Union’s Horizon 2020 research and innovation program, Estonian Ministry of Sciences projects (grant nos. P180021, P180274), and the Estonian Research Infrastructures Roadmap project Estonian Environmental Observatory (3.2.0304.11-0395). Eastern Mediterranean and Middle East—Climate and Atmosphere Research (EMME-CARE) project, which has received funding from the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement no. 856612) and the Government of Cyprus. INAR acknowledges support by the Russian government (grant number 14.W03.31.0002), the Ministry of Science and Higher Education of the Russian Federation (agreement 14.W0331.0006), and the Russian Ministry of Education and Science (14.W03.31.0008). We are grateful to to the following agencies for providing access to data used in our analysis: A.M. Obukhov Institute of Atmospheric Physics Russian Academy of Sciences; Agenzia Regionale per la Protezione dell’Ambiente della Campania (ARPAC); Air Quality and Climate Change, Parks and Environment (MetroVancouver, Government of British Columbia); Air Quality Monitoring & Reporting, Nova Scotia Environment (Government of Nova Scotia); Air Quality Monitoring Network (SIMAT) and Emission Inventory, Mexico City Environment Secretariat (SEDEMA); Airparif (owner & provider of the Paris air pollution data); ARPA Lazio, Italy; ARPA Lombardia, Italy; Association Agr´e´ee de Surveillance de la Qualit´e de l’Air en ˆIle-de- France AIRPARIF / Atmo-France; Bavarian Environment Agency, Germany; Berlin Senatsverwaltung für Umwelt, Verkehr und Klimaschutz, Germany; California Air Resources Board; Central Pollution Control Board (CPCB), India; CETESB: Companhia Ambiental do Estado de S˜ao Paulo, Brazil. China National Environmental Monitoring Centre; Chandigarh Pollution Control Committee (CPCC), India. DCMR Rijnmond Environmental Service, the Netherlands. Department of Labour Inspection, Cyprus; Department of Natural Resources Management and Environmental Protection of Moscow. Environment and Climate Change Canada; Environmental Monitoring and Science Division Alberta Environment and Parks (Government of Alberta); Environmental Protection Authority Victoria (Melbourne, Victoria, Australia); Estonian Environmental Research Centre (EERC); Estonian University of Life Sciences, SMEAR Estonia; European Regional Development Fund (project MOBTT42) under the Mobilitas Pluss programme; Finnish Meteorological Institute; Helsinki Region Environmental Services Authority; Haryana Pollution Control Board (HSPCB), IndiaLondon Air Quality Network (LAQN) and the Automatic Urban and Rural Network (AURN) supported by the Department of Environment, Food and Rural Affairs, UK Government; Madrid Municipality; Met Office Integrated Data Archive System (MIDAS); Meteorological Service of Canada; Minist`ere de l’Environnement et de la Lutte contre les changements climatiques (Gouvernement du Qu´ebec); Ministry of Environment and Energy, Greece; Ministry of the Environment (Chile) and National Weather Service (DMC); Moscow State Budgetary Environmental Institution MOSECOMONITORING. Municipal Department of the Environment SMAC, Brazil; Municipality of Madrid public open data service; National institute of environmental research, Korea; National Meteorology and Hydrology Service (SENAMHI), Peru; New York State Department of Environmental Conservation; NSW Department of Planning, Industry and Environment; Ontario Ministry of the Environment, Conservation and Parks, Canada; Public Health Service of Amsterdam (GGD), the Netherlands. Punjab Pollution Control Board (PPCB), India. R´eseau de surveillance de la qualit´e de l’air (RSQA) (Montr´eal); Rosgydromet. Mosecomonitoring, Institute of Atmospheric Physics, Russia; Russian Foundation for Basic Research (project 20–05–00254) SAFAR-IITM-MoES, India; S˜ao Paulo State Environmental Protection Agency, CETESB; Secretaria de Ambiente, DMQ, Ecuador; Secretaría Distrital de Ambiente, Bogot´a, Colombia. Secretaria Municipal de Meio Ambiente Rio de Janeiro; Mexico City Atmospheric Monitoring System (SIMAT); Mexico City Secretariat of Environment, Secretaría del Medio Ambiente (SEDEMA); SLB-analys, Sweden; SMEAR Estonia station and Estonian University of Life Sciences (EULS); SMEAR stations data and Finnish Center of Excellence; South African Weather Service and Department of Environment, Forestry and Fisheries through SAAQIS; Spanish Ministry for the Ecological Transition and the Demographic Challenge (MITECO); University of Helsinki, Finland; University of Tartu, Tahkuse air monitoring station; Weather Station of the Institute of Astronomy, Geophysics and Atmospheric Science of the University of S˜ao Paulo; West Bengal Pollution Control Board (WBPCB).http://www.elsevier.com/locate/envintam2023Geography, Geoinformatics and Meteorolog

One species or two? Vicariance, lineage divergence and low mtDNA diversity in geographically isolated populations of South Asian river dolphin

Despite their endangered status, the taxonomic relationship between the two geographically isolated South Asian river dolphin populations has never been comprehensively assessed and remains contentious. Here we present the first dedicated evaluation of the molecular phylogenetic relationship between the Indus (Platanista gangetica minor) and Ganges (Platanista gangetica gangetica) River dolphins using mitochondrial DNA from the control region and cytochrome b, extracted from museum specimens. The 458 bp partial control region sequences from 26 Indus River dolphin samples exhibited no variation. Only six haplotypes were identified in the 31 (18 Indus; 13 Ganges) complete (856 bp) control region sequences obtained, none were shared between subspecies, and there were five fixed differences between them. Similarly low genetic diversity was found in a 541 bp section of the cytochrome b gene (n = 29). The lack of shared haplotypes and fixed differences resulted in ΦST for the partial control region sequences of 0.932 (p < 0.0001) and FST of 0.843 (p  < 0.0001), indicating the long-term absence of gene flow and clear genetic differentiation between the two geographically isolated populations. An externally calibrated molecular clock estimated that Indus and Ganges dolphins diverged around 550,000 years ago (95 % posterior probability 0.13–1.05 million years ago), possibly when dolphins from the Ganges dispersed into the Indus during drainage capture

Lost in translation: The biogenesis of non-LTR retrotransposon proteins.

"Young" APE-type non-LTR retrotransposons (non-LTRs) typically encode two open reading frames (ORFs 1 and 2). The shorter ORF1 translation product (ORF1p) comprises an RNA binding activity, thought to bind to non-LTR transcript RNA, protect against nuclease degradation and specify nuclear import of the ribonuclear protein complex (RNP). ORF2 encodes a multifunctional protein (ORF2p) comprising apurinic/apyrimidinic endonuclease (APE) and reverse-transcriptase (RT) activities, responsible for genome replication and re-integration into chromosomal DNA. However, some clades of APE-type non-LTRs only encode a single ORF-corresponding to the multifunctional ORF2p outlined above (and for simplicity referred-to as ORF2 below). The absence of an ORF1 correlates with the acquisition of a 2A oligopeptide translational recoding element (some 18-30 amino acids) into the N-terminal region of ORF2p. In the case of non-LTRs encoding two ORFs, the presence of ORF1 would necessarily downregulate the translation of ORF2. We argue that in the absence of an ORF1, 2A could provide the corresponding translational downregulation of ORF2. While multiple molecules of ORF1p are required to decorate the non-LTR transcript RNA in the cytoplasm, conceivably only a single molecule of ORF2p is required for target-primed reverse transcription/integration in the nucleus. Why would the translation of ORF2 need to be controlled by such mechanisms? An "excess" of ORF2p could result in disadvantageous levels of genome instability by, for example, enhancing short, interspersed, element (SINE) retrotransposition and the generation of processed pseudogenes. If so, the acquisition of mechanisms-such as 2A-to control ORF2p biogenesis would be advantageous

One Species or Two? Vicariance, Lineage Divergence and Low mtDNA Diversity in Geographically Isolated Populations of South Asian River Dolphin

Despite their endangered status, the taxonomic relationship between the two geographically isolated South Asian river dolphin populations has never been comprehensively assessed and remains contentious. Here we present the first dedicated evaluation of the molecular phylogenetic relationship between the Indus (Platanista gangetica minor) and Ganges (Platanista gangetica gangetica) River dolphins using mitochondrial DNA from the control region and cytochrome b, extracted from museum specimens. The 458 bp partial control region sequences from 26 Indus River dolphin samples exhibited no variation. Only six haplotypes were identified in the 31 (18 Indus; 13 Ganges) complete (856 bp) control region sequences obtained, none were shared between subspecies, and there were five fixed differences between them. Similarly low genetic diversity was found in a 541 bp section of the cytochrome b gene (n = 29). The lack of shared haplotypes and fixed differences resulted in ΦST for the partial control region sequences of 0.932 (p < 0.0001) and FST of 0.843 (p < 0.0001), indicating the long-term absence of gene flow and clear genetic differentiation between the two geographically isolated populations. An externally calibrated molecular clock estimated that Indus and Ganges dolphins diverged around 550,000 years ago (95 % posterior probability 0.13-1.05 million years ago), possibly when dolphins from the Ganges dispersed into the Indus during drainage capture. © 2014 Springer Science+Business Media New York

One Species or Two? Vicariance, Lineage Divergence and Low mtDNA Diversity in Geographically Isolated Populations of South Asian River Dolphin

Despite their endangered status, the taxonomic relationship between the two geographically isolated South Asian river dolphin populations has never been comprehensively assessed and remains contentious. Here we present the first dedicated evaluation of the molecular phylogenetic relationship between the Indus (Platanista gangetica minor) and Ganges (Platanista gangetica gangetica) River dolphins using mitochondrial DNA from the control region and cytochrome b, extracted from museum specimens. The 458 bp partial control region sequences from 26 Indus River dolphin samples exhibited no variation. Only six haplotypes were identified in the 31 (18 Indus; 13 Ganges) complete (856 bp) control region sequences obtained, none were shared between subspecies, and there were five fixed differences between them. Similarly low genetic diversity was found in a 541 bp section of the cytochrome b gene (n = 29). The lack of shared haplotypes and fixed differences resulted in ΦST for the partial control region sequences of 0.932 (p < 0.0001) and FST of 0.843 (p < 0.0001), indicating the long-term absence of gene flow and clear genetic differentiation between the two geographically isolated populations. An externally calibrated molecular clock estimated that Indus and Ganges dolphins diverged around 550,000 years ago (95 % posterior probability 0.13-1.05 million years ago), possibly when dolphins from the Ganges dispersed into the Indus during drainage capture. © 2014 Springer Science+Business Media New York

The role of ZAP and OAS3/RNAseL pathways in the attenuation of an RNA virus with elevated frequencies of CpG and UpA dinucleotides

Zinc finger antiviral protein (ZAP) is a powerful restriction factor for viruses with elevated CpG dinucleotide frequencies. We report that ZAP similarly mediates antiviral restriction against echovirus 7 (E7) mutants with elevated frequencies of UpA dinucleotides. Attenuation of both CpG- and UpA-high viruses and replicon mutants was reversed in ZAP k/o cell lines, and restored by plasmid-derived reconstitution of expression in k/o cells. In pull-down assays, ZAP bound to viral RNA transcripts with either CpG- and UpA-high sequences inserted in the R2 region. We found no evidence that attenuation of CpG- or UpA-high mutants was mediated through either translation inhibition or accelerated RNA degradation. Reversal of the attenuation of CpG-high, and UpA-high E7 viruses and replicons was also achieved through knockout of RNAseL and oligodenylate synthetase 3 (OAS3), but not OAS1. WT levels of replication of CpG- and UpA-high mutants were observed in OAS3 k/o cells despite abundant expression of ZAP, indicative of synergy or complementation of these hitherto unconnected pathways. The dependence on expression of ZAP, OAS3 and RNAseL for CpG/UpA-mediated attenuation and the variable and often low level expression of these pathway proteins in certain cell types, such as those of the central nervous system, has implications for the use of CpG-elevated mutants as attenuated live vaccines against neurotropic viruses

The role of ZAP and OAS3/RNAseL pathways in the attenuation of an RNA virus with elevated frequencies of CpG and UpA dinucleotides

Zinc finger antiviral protein (ZAP) is a powerful restriction factor for viruses with elevated CpG dinucleotide frequencies. We report that ZAP similarly mediates antiviral restriction against echovirus 7 (E7) mutants with elevated frequencies of UpA dinucleotides. Attenuation of both CpG- and UpA-high viruses and replicon mutants was reversed in ZAP k/o cell lines, and restored by plasmid-derived reconstitution of expression in k/o cells. In pull-down assays, ZAP bound to viral RNA transcripts with either CpG- and UpA-high sequences inserted in the R2 region. We found no evidence that attenuation of CpG- or UpA-high mutants was mediated through either translation inhibition or accelerated RNA degradation. Reversal of the attenuation of CpG-high, and UpA-high E7 viruses and replicons was also achieved through knockout of RNAseL and oligodenylate synthetase 3 (OAS3), but not OAS1. WT levels of replication of CpG- and UpA-high mutants were observed in OAS3 k/o cells despite abundant expression of ZAP, indicative of synergy or complementation of these hitherto unconnected pathways. The dependence on expression of ZAP, OAS3 and RNAseL for CpG/UpA-mediated attenuation and the variable and often low level expression of these pathway proteins in certain cell types, such as those of the central nervous system, has implications for the use of CpG-elevated mutants as attenuated live vaccines against neurotropic viruses

Effects of SARS-CoV-2 strain variation on virus neutralisation titres: therapeutic use of convalescent plasma

We compared neutralising antibody titres of convalescent samples collected before and after the emergence of novel strains of SARS-CoV-2, against the wild-type virus (WT), Alpha (B.1.1.7) and Beta (B.1.351) variants. Plasma collected in 2020 before emergence of variants showed reduced titres against the Alpha variants, and both sets of samples demonstrated significantly reduced titres against Beta. Comparison of microneutralisation titres to those obtained with pseudotype and HAT assays showed a good correlation of titres and effects of strain variation, supporting the use of these simpler assays for assessment of convalescent plasma potency against currently circulating and emerging strains of SARS-CoV-2