Quantitative risk assessment of radiocesium associated with Japanese foods imported into the United Kingdom.

Damage to a nuclear power station resulted in radioactive contamination of certain areas of Japan in 2011. Legislation was put in place in Europe to establish controls on the import of certain types of food and feed, including a limit of 100 radioactive decays (becquerel, Bq) per second of radiocesium per kg. This legislation was retained in the United Kingdom after leaving the EU and then reviewed in 2021. A quantitative risk assessment was developed to estimate the radiological risk to public health from consuming Japanese food imported into the United Kingdom should the maximum level on radiocesium be removed. Although Japanese monitoring data indicated occurrences when products exceeded the 100 Bq per kg limit, these were found to be rare; a total of 1485 occurrences (0.0013%) of all measured foodstuff samples (>1 million) within the scope of this assessment had radiocesium activity concentrations that exceeded 100 Bq per kg. Using the recorded occurrence and level of radiocesium measured, and the current pattern and volume of food imported from Japan, there was an estimated excess risk of fatal cancer of around one in a million per year, categorized as negligible compared to the baseline 2018-2020 UK cancer fatality rate of around 1 in 4. On the basis of the described assessment and the estimated small additional risk, Great Britain lifted import controls related to radioactivity present in food from Japan. A number of recommendations to address data gaps and approaches in this assessment are made, particularly how we can improve modeling UK dietary habits for specialist foods.

Mechanisms for controlling Dorsal nuclear levels.

Formation of the Dorsal nuclear-cytoplasmic gradient is important for the proper establishment of gene expression patterns along the dorsal-ventral (DV) axis during embryogenesis in Drosophila melanogaster. Correct patterning of the DV axis leads to formation of the presumptive mesoderm, neurogenic ectoderm, dorsal ectoderm, and amnioserosa, which are tissues necessary for embryo viability. While Toll signaling is necessary for Dorsal gradient formation, a gradient still forms in the absence of Toll, suggesting there are additional mechanisms required to achieve correct nuclear Dorsal levels. Potential mechanisms include post-translational modification, shuttling, and nuclear spacing. Post-translational modification could affect import and export rates either directly through modification of a nuclear localization sequence or nuclear export sequence, or indirectly by affecting interactions with binding partners that alter import and export rates. Shuttling, which refers to the facilitated diffusion of Dorsal through its interaction with its cytoplasmic inhibitor Cactus, could regulate nuclear levels by delivering more Dorsal ventrally. Finally, nuclear spacing could result in higher nuclear levels by leaving fewer nuclei in the ventral domain to uptake Dorsal. This review details how each of these mechanisms may help establish Dorsal nuclear levels in the early fly embryo, which serves as a paradigm for understanding how the dynamics of graded inputs can influence patterning and target gene expression. Furthermore, careful analysis of nuclear Dorsal levels is likely to provide general insights as recent studies have suggested that the regulation of nuclear import affects the timing of gene expression at the maternal-to-zygotic transition.

The ATP-driven extractor ATAD1/Msp1 proof-reads protein translocation into mitochondria.

The accumulation of translocation intermediates in the mitochondrial import machinery threatens cellular fitness and is associated with cancer and neurodegeneration. A recent study by Weidberg and colleagues identifies ATAD1 as an ATP-driven extraction machine on the mitochondrial surface that pulls precursors into the cytosol to prevent clogging of mitochondrial import pores.

Assessment of genetically modified maize MON 95275 (application GMFF-2022-5890).

Genetically modified maize MON 95275 was developed to confer protection to certain coleopteran species. These properties were achieved by introducing the mpp75Aa1.1, vpb4Da2 and DvSnf7 expression cassettes. The molecular characterisation data and bioinformatic analyses reveal similarity to known toxins, which was further assessed. None of the identified differences in the agronomic/phenotypic and compositional characteristics tested between maize MON 95275 and its conventional counterpart needs further assessment. The GMO Panel does not identify safety concerns regarding the toxicity and allergenicity of the Mpp75Aa1.1 and Vpb4Da2 proteins and the DvSnf7 dsRNA and derived siRNAs as expressed in maize MON 95275 and finds no evidence that the genetic modification would change the overall allergenicity of maize MON 95275. In the context of this application, the consumption of food and feed from maize MON 95275 does not represent a nutritional concern in humans and animals. The GMO Panel concludes that maize MON 95275 is as safe as the conventional counterpart and non-GM maize varieties tested, and no post-market monitoring of food/feed is considered necessary. In the case of accidental release of maize MON 95275 material into the environment, this would not raise environmental safety concerns. The post-market environmental monitoring plan and reporting intervals are in line with the intended uses of maize MON 95275. The GMO Panel concludes that maize MON 95275 is as safe as its conventional counterpart and the tested non-GM maize varieties with respect to potential effects on human and animal health and the environment.

Assessment of genetically modified maize DP910521 (application GMFF-2021-2473).

Genetically modified (GM) maize DP910521 was developed to confer resistance against certain lepidopteran insect pests as well as tolerance to glufosinate herbicide; these properties were achieved by introducing the mo-pat, pmi and cry1B.34 expression cassettes. The molecular characterisation data and bioinformatic analyses did not identify issues requiring food/feed safety assessment. None of the identified differences in the agronomic/phenotypic and compositional characteristics tested between maize DP910521 and its conventional counterpart needs further assessment except for the levels of iron in grain, which do not raise safety and nutritional concerns. The GMO Panel does not identify safety concerns regarding the toxicity and allergenicity of the Cry1B.34, PAT and PMI proteins as expressed in maize DP910521. The GMO panel finds no evidence that the genetic modification impacts the overall safety of maize DP910521. In the context of this application, the consumption of food and feed from maize DP910521 does not represent a nutritional concern in humans and animals. The GMO Panel concludes that maize DP910521 is as safe as its conventional counterpart and non-GM maize varieties tested, and no post-market monitoring of food/feed is considered necessary. In the case of accidental release of maize DP910521 material into the environment, this would not raise environmental safety concerns. The post-market environmental monitoring plan and reporting intervals are in line with the intended uses of maize DP910521. The GMO Panel concludes that maize DP910521 is as safe as its conventional counterpart and the tested non-GM maize varieties with respect to potential effects on human and animal health and the environment.

Reconstruction of artificial nuclei with nuclear import activity in living mouse oocytes.

In eukaryotes, DNA is housed within the cell nucleus. Molecules required for the formation of a nucleus have been identified using in vitro systems with frog egg extracts and in vivo imaging of somatic cells. However, little is known about the physicochemical factors and conditions required for nuclear formation in mouse oocytes. In this study, using a reconstitution approach with purified DNA, we aimed to determine factors, such as the amount and timing of DNA introduction, required for the formation of nuclei with nuclear transport activity in mouse oocytes. T4 phage DNA (~166 kbp) was microinjected into strontium-activated oocytes to evaluate the conditions appropriate for nuclear formation. Microinjection of 100-500 ng/µL of T4 DNA, but not 20 ng/µL, was sufficient for the formation of nucleus-like structures. Furthermore, microinjection of DNA during metaphase II to telophase II, but not during interphase, was sufficient. Electron and fluorescence microscopy showed that T4 DNA-induced nucleus-like structures had nuclear lamina and nuclear pore complex structures similar to those of natural nuclei, as well as nuclear import activity. These results suggest that exogenous DNA can form artificial nuclei with nuclear transport functions in mouse oocytes, regardless of the sequence or source of the DNA.

The N-region sequence context impacts the chloroplast import efficiency of multi-TMD protein.

Targeting heterologous multi-transmembrane domain (TMD) proteins to plant chloroplasts requires sequences in addition to the chloroplast transit peptide (cTP). The N-terminal domain (N-region), located C-terminal to the cTP in chloroplast inner envelope membrane proteins, is an essential region for import. However, it was unclear if the N-region functions solely as a spacer sequence to facilitate cTP access or if it plays an active role in the import process. This study addresses the N-region's role by using combinations of cTPs and N-regions from Arabidopsis chloroplast inner envelope membrane proteins to direct the cyanobacterial protein SbtA to the chloroplast. We find that the sequence context of the N-region affects the chloroplast import efficiency of SbtA, with particular sequences mis-targeting the protein to different cellular sub-compartments. Additionally, specific cTP and N-region pairs exhibit varying targeting efficiencies for different heterologous proteins. Substituting individual N-region motifs did not significantly alter the chloroplast targeting efficiency of a particular cTP and N-region pair. We conclude that the N-region exhibits contextual functioning and potentially functional redundancy in motifs.

The TOM complex from an evolutionary perspective and the functions of TOMM70.

In humans, up to 1,500 mitochondrial precursor proteins are synthesized at cytosolic ribosomes and must be imported into the organelle. This is not only essential for mitochondrial but also for many cytosolic functions. The majority of mitochondrial precursor proteins are imported over the translocase of the outer membrane (TOM). In recent years, high-resolution structure analyses from different organisms shed light on the composition and arrangement of the TOM complex. Although significant similarities have been found, differences were also observed, which have been favored during evolution and could reflect the manifold functions of TOM with cellular signaling and its response to altered metabolic situations. A key component within these regulatory mechanisms is TOMM70, which is involved in protein import, forms contacts to the ER and the nucleus, but is also involved in cellular defense mechanisms during infections.

The PB2 I714S mutation influenced mammalian adaptation of the H3N2 canine influenza virus by interfering with nuclear import efficiency and RNP complex assembly.

Avian influenza viruses (AIVs) are the origin of multiple mammal influenza viruses. The genetic determinants of AIVs adapted to humans have been widely elucidated, however, the molecular mechanism of cross-species transmission and adaptation of AIVs to canines are still poorly understood. In this study, two H3N2 influenza viruses isolated from a live poultry market (A/environment/Guangxi/13431/2018, GX13431) and a swab sample from a canine (A/canine/Guangdong/0601/2019, GD0601) were used to investigate the possible molecular basis that determined H3N2 AIV adapting to canine. We found that GD0601 exhibited more robust polymerase activity in cells and higher pathogenicity in mice compared with its evolution ancestor H3N2 AIV GX13431. A series of reassortments of the ribonucleoprotein (RNP) complex showed that the PB2 subunit was the crucial factor that conferred high polymerase activity of GD0601, and the substitution of I714S in the PB2 subunit of GD0601 attenuated the replication and pathogenicity in mammal cells and the mouse model. Mechanistically, the reverse mutation of I714S in the PB2 polymerase subunit which was identified in AIV GX13431 reduced the nuclear import efficiency of PB2 protein and interfered with the interactions of PB2-PA/NP that affected the assembly of the viral RNP complex. Our study reveals amino acid mutation at the position of 714 in the nuclear localization signal (NLS) area in PB2 plays an important role in overcoming the barrier from poultry to mammals of the H3N2 canine influenza virus and provides clues for further study of mammalian adaptation mechanism of AIVs.

Blooming markets: The economic dynamics of the Nepal rose trade.

Thanks to its excellent climate and varied agroecological zones, Nepal has been a significant player in the global rose market. The geographical variety of the nation makes it possible to grow roses all year long, making it a desirable location for rose export and cultivation. The production and export of roses have significantly increased in recent years. The rose trade has increased in Nepal for several reasons. Investment in the industry has been stimulated by government measures to support floriculture and offer incentives to rose farmers. Additionally, the effective distribution of roses to domestic and foreign markets has been made possible by better transportation infrastructure. The growth of the global market has greatly aided the development of Nepal's rose industry. The growth of rose cultivation in Nepal has significantly impacted the economy and employment. It is a good source of revenue through internal sales, export, and other activities that provide value addition. The sector creates direct farm jobs while local communities benefit from indirect employment in supporting industries. In addition, there is increased job opportunities due to seasonal spikes in demand. Rose exports have expanded due to a rise in demand for Nepali roses, particularly in European markets and nearby nations like India. The favorable trade agreements Nepal has with several nations have helped to increase its exports even more. But issues still exist in the rose trade sector. Since maintaining consistent quality is necessary to compete in the international market, quality control and standardization continue to be areas of concern. The rose business in Nepal is also vulnerable to changes in global demand and competition from other nations that grow roses. Further expansion of the industry will help it overcome problems like limited technology and training hence leading to its fast development; this calls for government support as well as market expansion. In conclusion, the rose trade environment in Nepal is a fluid and changing one. Due to favorable circumstances, government assistance, and global demand, the sector has seen significant expansion. Continuous efforts in quality control, market diversification, and innovation are necessary to maintain and grow this sector. The rose trade in Nepal has the potential to significantly boost the nation's agricultural exports while promoting economic growth in rural areas.

Conservation and specialization of the Ycf2-FtsHi chloroplast protein import motor in green algae.

The protein import motor in chloroplasts plays a pivotal role in their biogenesis and homeostasis by driving the translocation of preproteins into chloroplasts. While the Ycf2-FtsHi complex serves as the import motor in land plants, its evolutionary conservation, specialization, and mechanisms across photosynthetic organisms are largely unexplored. Here, we isolated and determined the cryogenic electron microscopy (cryo-EM) structures of the native Ycf2-FtsHi complex from Chlamydomonas reinhardtii, uncovering a complex composed of up to 19 subunits, including multiple green-algae-specific components. The heterohexameric AAA+ ATPase motor module is tilted, potentially facilitating preprotein handover from the translocon at the inner chloroplast membrane (TIC) complex. Preprotein interacts with Ycf2-FtsHi and enhances its ATPase activity in vitro. Integrating Ycf2-FtsHi and translocon at the outer chloroplast membrane (TOC)-TIC supercomplex structures reveals insights into their physical and functional interplay during preprotein translocation. By comparing these findings with those from land plants, our study establishes a structural foundation for understanding the assembly, function, evolutionary conservation, and diversity of chloroplast protein import motors.

Structural insights into the chloroplast protein import in land plants.

Chloroplast proteins are imported via the translocon at the outer chloroplast membrane (TOC)-translocon at the inner chloroplast membrane (TIC) supercomplex, driven by an ATPase motor. The Ycf2-FtsHi complex has been identified as the chloroplast import motor. However, its assembly and cooperation with the TIC complex during preprotein translocation remain unclear. Here, we present the structures of the Ycf2-FtsHi and TIC complexes from Arabidopsis and an ultracomplex formed between them from Pisum. The Ycf2-FtsHi structure reveals a heterohexameric AAA+ ATPase motor module with characteristic features. Four previously uncharacterized components of Ycf2-FtsHi were identified, which aid in complex assembly and anchoring of the motor module at a tilted angle relative to the membrane. When considering the structures of the TIC complex and the TIC-Ycf2-FtsHi ultracomplex together, it becomes evident that the tilted motor module of Ycf2-FtsHi enables its close contact with the TIC complex, thereby facilitating efficient preprotein translocation. Our study provides valuable structural insights into the chloroplast protein import process in land plants.

Iron starvation results in up-regulation of a probable Haloferax volcanii siderophore transporter.

The response of the haloarchaeal model organism Haloferax volcanii to iron starvation was analyzed at the proteome level by data-independent acquisition mass spectrometry. Cells grown in minimal medium with normal iron levels were compared to those grown under low iron conditions, with samples being separated into membrane and cytoplasmic fractions in order to focus on import/export processes which are frequently associated with metal homeostasis. Iron starvation not only caused a severe retardation of growth but also altered the levels of many proteins. Using a comprehensive annotated spectral library and data-independent acquisition mass spectrometry (DIA-MS), we found that iron starvation resulted in significant changes to both the membrane and the soluble proteomes of Hfx. volcanii. The most affected protein is the RND family permease HVO_A0467, which is 44-fold enriched in cells grown under iron starvation. The gene HVO_A0467 can be deleted suggesting that it is not essential under standard conditions. Compared to wild type cells the deletion strain shows only slight changes in growth and cell morphologies show no differences. Molecular docking predictions indicated that HVO_A0467 may be an exporter of the siderophore schizokinen for which a potential biosynthesis cluster is encoded in the Hfx. volcanii genome. Together, these findings confirm the importance of iron for archaeal cells and suggest HVO_0467 as a siderophore exporter.

Measles and Rubella Elimination in the Western Pacific Region in 2013-2022: Lessons Learned from Progress and Achievements Made during Regional and Global Measles Resurgences.

Measles is the most contagious communicable disease, causing an estimated 5.5 million cases and more than 30,000 deaths in the Western Pacific Region (WPR) during 2000. Rubella infection in a pregnant woman can be devastating for the foetus, resulting in congenital rubella syndrome (CRS) in 90% of rubella infections in early pregnancy. It was estimated that approximately 9000 CRS cases occurred in the WPR in 2010. World Health Organization (WHO) Member States in the WPR decided in 2003 to eliminate measles and in 2014 to eliminate rubella from the region. While the WPR successfully attained historically low measles incidence in 2012, it experienced a region-wide measles resurgence in 2013-2016. During the regional resurgence, WHO and Member States accumulated greater knowledge on the epidemiology of measles and rubella in the WPR and strategies to maintain gains. The implementation of the resulting new regional strategy and plan of action from 2018 has proven that measles and rubella elimination is achievable and sustainable under the pressure of multiple importations of measles virus during the world-wide measles resurgences in 2018-2019. This article discusses this progress and achievements towards achieving the global eradication of measles and rubella.

[THE ON-LINE TURNOVER OF BIOLOGICALLY ACTIVE ADDITIVES. PART 2. CUSTOMS CONTROL FOR THE TURNOVER OF IMPORTED DIETARY SUPPLEMENTS ON MARKETPLACES AS A MEASURE TO PROTECT THE LIFE AND HEALTH OF CITIZENS].

Various dietary supplements are used as prevention, and in some cases treatment, of a large number of pathological processes in the human body. The purchase of such dietary supplements on various online platforms, including marketplaces, as evidenced by the results of monitoring the Russian online market for 2021-2022, turned out to be the riskiest for human life and health: the components actually contained do not correspond to the declared ones, the presence of Dietary supplement of prohibited substances, lack of a state registration certificate, the presence of which confirms the safety of such dietary supplement for use. The listed violations in the conditions of complete lack of control during the sale of dietary supplements on marketplaces confirm the danger to health, and in some cases, to human life. Uncontrolled use of such products can lead to serious side effects and complications: allergic reactions, kidney failure, liver failure, complications from the gastrointestinal tract, nervous system and genitourinary tract. In this regard, issues related to ensuring the safety of human health and life in the event of their purchasing dietary supplements on marketplaces are relevant. The analysis carried out in the study confirmed the existence of a problem of unreliable declaration of imported dietary supplements on marketplaces by participants in foreign economic activity. In this regard, this article examines the requirements of technical regulations that must be observed when importing dietary supplements into the territory of the EAEU, studies in detail the issue of the possibility of selling imported dietary supplements on marketplaces, and formulates appropriate conclusions and recommendations for eliminating identified problems, which will eliminate possible sales of low-quality products on the marketplace. and prohibited products and identify sellers selling dietary supplements with violations.

[The problems and prospects of import substitution in medical industry].

The achievement of economic sustainability and assurance of national security through activation of production sectors, medical industry in particular, is the integral component of successful strategy of state development. The importance of achieving autonomy in production of medical technique is targeted to reducing dependence of external factors, ensuring continuity of supply of critically important equipment and increasing level of technical characteristics of production. Besides it, expansion of medical production positively impact on innovative development, organization of new work places and level of scientific research in this industry. The development of national medical industry contributes to improvement of quality of medical care that directly affect population health. The necessity to maintain stability of health care through import substitution of medical products is indisputable fact in modern conditions, determined by strategically important direction from national security point of view. The article considers measures within the framework of import substitution plan in medical industry of the Russian Federation for period up to 2024. The analysis of volume of national production of medical equipment in dynamics over 5 years was carried out. The main problems of production of medical devices at the present stage were considered. The measures of state support targeted to development of national production of medical equipment and innovative medical technologies were discussed.

Use of wastewater from passenger ships to assess the movement of COVID-19 and other pathogenic viruses across maritime international boundaries.

Objective: The worldwide spread of SARS-CoV-2 and the resulting COVID-19 pandemic has been driven by international travel. This has led to the desire to develop surveillance approaches which can estimate the rate of import of pathogenic organisms across international borders. The aim of this study was to investigate the use of wastewater-based approaches for the surveillance of viral pathogens on commercial short-haul (3.5 h transit time) roll-on/roll-off passenger/freight ferries operating between the UK and the Republic of Ireland. Methods: Samples of toilet-derived wastewater (blackwater) were collected from two commercial ships over a 4-week period and analysed for SARS-CoV-2, influenza, enterovirus, norovirus, the faecal-marker virus crAssphage and a range of physical and chemical indicators of wastewater quality. Results: A small proportion of the wastewater samples were positive for SARS-CoV-2 (8% of the total), consistent with theoretical predictions of detection frequency (4%-15% of the total) based on the national COVID-19 Infection Survey and defecation behaviour. In addition, norovirus was detected in wastewater at low frequency. No influenza A/B viruses, enterovirus or enterovirus D68 were detected throughout the study period. Conclusion: We conclude that testing of wastewater from ships that cross international maritime boundaries may provide a cost-effective and relatively unbiased method to estimate the flow of infected individuals between countries. The approach is also readily applicable for the surveillance of other disease-causing agents.

Importin subunit beta-1 mediates ERK5 nuclear translocation, and its inhibition synergizes with ERK5 kinase inhibitors in reducing cancer cell proliferation.

The mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 5 (ERK5) is emerging as a promising target in cancer. Indeed, alterations of the MEK5/ERK5 pathway are present in many types of cancer, including melanoma. One of the key events in MAPK signalling is MAPK nuclear translocation and its subsequent regulation of gene expression. Likewise, the effects of ERK5 in supporting cancer cell proliferation have been linked to its nuclear localization. Despite many processes regulating ERK5 nuclear translocation having been determined, the nuclear transporters involved have not yet been identified. Here, we investigated the role of importin subunit alpha (α importin) and importin subunit beta-1 (importin ß1) in ERK5 nuclear shuttling to identify additional targets for cancer treatment. Either importin ß1 knockdown or the α/ß1 importin inhibitor ivermectin reduced the nuclear amount of overexpressed and endogenous ERK5 in HEK293T and A375 melanoma cells, respectively. These results were confirmed in single-molecule microscopy in HeLa cells. Moreover, immunofluorescence analysis showed that ivermectin impairs epidermal growth factor (EGF)-induced ERK5 nuclear shuttling in HeLa cells. Both co-immunoprecipitation experiments and proximity ligation assay provided evidence that ERK5 and importin ß1 interact and that this interaction is further induced by EGF administration and prevented by ivermectin treatment. The combination of ivermectin and the ERK5 inhibitor AX15836 synergistically reduced cell viability and colony formation ability in A375 and HeLa cells and was more effective than single treatments in preventing the growth of A375 and HeLa spheroids. The increased reduction of cell viability upon the same combination was also observed in patient-derived metastatic melanoma cells. The combination of ivermectin and ERK5 inhibitors other than AX15836 provided similar effects on cell viability. The identification of importin ß1 as the nuclear transporter of ERK5 may be exploited for additional ERK5-inhibiting strategies for cancer therapy.

ATAD1 prevents clogging of TOM and damage caused by un-imported mitochondrial proteins.

Mitochondria require the constant import of nuclear-encoded proteins for proper functioning. Impaired protein import not only depletes mitochondria of essential factors but also leads to toxic accumulation of un-imported proteins outside the organelle. Here, we investigate the consequences of impaired mitochondrial protein import in human cells. We demonstrate that un-imported proteins can clog the mitochondrial translocase of the outer membrane (TOM). ATAD1, a mitochondrial ATPase, removes clogged proteins from TOM to clear the entry gate into the mitochondria. ATAD1 interacts with both TOM and stalled proteins, and its knockout results in extensive accumulation of mitochondrial precursors as well as decreased protein import. Increased ATAD1 expression contributes to improved fitness of cells with inefficient mitochondrial protein import. Overall, we demonstrate the importance of the ATAD1 quality control pathway in surveilling protein import and its contribution to cellular health.