Soluble histone H2AX is induced by DNA replication stress and sensitizes cells to undergo apoptosis

<p>Abstract</p> <p>Background</p> <p>Chromatin-associated histone H2AX is a key regulator of the cellular responses to DNA damage. However, non-nucleosomal functions of histone H2AX are poorly characterized. We have recently shown that soluble H2AX can trigger apoptosis but the mechanisms leading to non-chromatin-associated H2AX are unclear. Here, we tested whether stalling of DNA replication, a common event in cancer cells and the underlying mechanism of various chemotherapeutic agents, can trigger increased soluble H2AX.</p> <p>Results</p> <p>Transient overexpression of H2AX was found to lead to a detectable fraction of soluble H2AX and was associated with increased apoptosis. This effect was enhanced by the induction of DNA replication stress using the DNA polymerase α inhibitor aphidicolin. Cells manipulated to stably express H2AX did not contain soluble H2AX, however, short-term treatment with aphidicolin (1 h) resulted in detectable amounts of H2AX in the soluble nuclear fraction and enhanced apoptosis. Similarly, soluble endogenous H2AX was detected under these conditions. We found that excessive soluble H2AX causes chromatin aggregation and inhibition of ongoing gene transcription as evidenced by the redistribution and/or loss of active RNA polymerase II as well as the transcriptional co-activators CBP and p300.</p> <p>Conclusion</p> <p>Taken together, these results show that DNA replication stress rapidly leads to increased soluble H2AX and that non-chromatin-associated H2AX can sensitize cells to undergo apoptosis. Our findings encourage further studies to explore H2AX and the cellular pathways that control its expression as anti-cancer drug targets.</p

Constraints and solutions for development and uptake of integrated pest management in the UK

Agricultural improvements that reduce conventional pesticide use and support environmental aims are a priority. Current approaches develop promising alternative products but meet significant challenges in bringing them to market. This article reports findings of an Association of Applied Biologists event at which delegates from relevant industry sectors discussed the establishment of an effective integrated pest management innovation system linking multiple stakeholders. Interrelated recommendations were agreed upon, focused on structured gap analysis, co‐design processes reflecting the complete innovation system, the approval process, application equipment, enhancing grower confidence, integrating knowledge exchange activities, promulgation of public good information and the need for an overarching national action plan and supporting legislation

Standard practice in the treatment of unstable pelvic ring injuries: an international survey

PURPOSE Unstable pelvic ring injury can result in a life-threatening situation and lead to long-term disability. Established classification systems, recently emerged resuscitative and treatment options as well as techniques, have facilitated expansion in how these injuries can be studied and managed. This study aims to access practice variation in the management of unstable pelvic injuries around the globe. METHODS A standardized questionnaire including 15 questions was developed by experts from the SICOT trauma committee (Société Internationale de Chirurgie Orthopédique et de Traumatologie) and then distributed among members. The survey was conducted online for one month in 2022 with 358 trauma surgeons, encompassing responses from 80 countries (experience > 5 years = 79%). Topics in the questionnaire included surgical and interventional treatment strategies, classification, staging/reconstruction procedures, and preoperative imaging. Answer options for treatment strategies were ranked on a 4-point rating scale with following options: (1) always (A), (2) often (O), (3) seldom (S), and (4) never (N). Stratification was performed according to geographic regions (continents). RESULTS The Young and Burgess (52%) and Tile/AO (47%) classification systems were commonly used. Preoperative three-dimensional (3D) computed tomography (CT) scans were utilized by 93% of respondents. Rescue screws (RS), C-clamps (CC), angioembolization (AE), and pelvic packing (PP) were observed to be rarely implemented in practice (A + O: RS = 24%, CC = 25%, AE = 21%, PP = 25%). External fixation was the most common method temporized fixation (A + O = 71%). Percutaneous screw fixation was the most common definitive fixation technique (A + O = 57%). In contrast, 3D navigation techniques were rarely utilized (A + O = 15%). Most standards in treatment of unstable pelvic ring injuries are implemented equally across the globe. The greatest differences were observed in augmented techniques to bleeding control, such as angioembolization and REBOA, more commonly used in Europe (both), North America (both), and Oceania (only angioembolization). CONCLUSION The Young-Burgess and Tile/AO classifications are used approximately equally across the world. Initial non-invasive stabilization with binders and temporary external fixation are commonly utilized, while specific haemorrhage control techniques such as pelvic packing and angioembolization are rarely and REBOA almost never considered. The substantial regional differences' impact on outcomes needs to be further explored

The spanish Blue Division in Y. Revista para la mujer (1941-1943)

Los cerca de 45.000 hombres que formaron parte de la División Azul estuvieron acompañados por un grupo de enfermeras españolas en el frente del Este. Los soldados, además, recibían desde España las cartas de las madrinas de guerra y la ayuda de la Sección Femenina. Estas acciones fueron altamente publicitadas por la propaganda del Régimen a través de las revistas para mujeres. El objetivo de este artículo es analizar cómo les fue contada a las mujeres la experiencia de la División Azul en Y. Revista para la mujer. Para ello, estudiamos los artículos sobre el tema en tres secciones específicas: las mujeres que viajaron a la Unión Soviética, las que colaboraron desde casa y la imagen del voluntario como héroe masculino.The about 45.000 men that were part of the Spanish Blue Division were accompanied by a group of Spanish nurses in the Eastern Front. The soldiers, moreover, received from Spain the letters of the godmothers of war and the aid of Falange Women’s Section. These actions were highly publicized by the regime’s propaganda through the women’s magazines. The aim of this paper is to analyze how the experience of the Spanish Blue Division was told to women in Y. Revista para la mujer. For it, we study the articles about the theme in three specific sections: the women who travelled to the Soviet Union, those who collaborated from Spain and the image of the volunteer as a male hero

Державне регулювання системи факторів оцінки та мінімізації ризиків легалізації коштів, одержаних злочинним шляхом в процесі фінансового моніторингу комерційних банків України

Основною ціллю данної статті є формулювання важливості впливу чітко визначених факторів, які впливають на процеси фінансового моніторингу в комерційних банків України. Виходячи з поставлених цілей, завданнями даної статті є розроблення моделі оцінки ризиків банківської установи щодо протидії легалізації коштів одержаних злочинним шляхом в системі внутрішньобанківського фінансового моніторингу, та використання в подальшому запропонованих стратегій управління наслідками даних ризиків

Enhanced bacterial cancer therapy delivering therapeutic RNA interference of c-Myc

Bacterial cancer therapy was first trialled in patients at the end of the nineteenth century. More recently, tumour-targeting bacteria have been harnessed to deliver plasmid-expressed therapeutic interfering RNA to a range of solid tumours. A major limitation to clinical translation of this is the short-term nature of RNA interference in vivo due to plasmid instability. To overcome this, we sought to develop tumour-targeting attenuated bacteria that stably express shRNA by virtue of integration of an expression cassette within the bacterial chromosome and demonstrate therapeutic efficacy in vitro and in vivo. Results The attenuated tumour targeting Salmonella typhimurium SL7207 strain was modified to carry chromosomally integrated shRNA expression cassettes at the xylA locus. The colorectal cancer cell lines SW480, HCT116 and breast cancer cell line MCF7 were used to demonstrate the ability of these modified strains to perform intracellular infection and deliver effective RNA and protein knockdown of the target gene c-Myc. In vivo therapeutic efficacy was demonstrated using the Lgr5creERT2Apcflx/flx and BlgCreBrca2flx/flp53flx/flx orthotopic immunocompetent mouse models of colorectal and breast cancer, respectively. In vitro co-cultures of breast and colorectal cancer cell lines with modified SL7207 demonstrated a significant 50–95% (P < 0.01) reduction in RNA and protein expression with SL7207/c-Myc targeted strains. In vivo, following establishment of tumour tissue, a single intra-peritoneal administration of 1 × 106 CFU of SL7207/c-Myc was sufficient to permit tumour colonisation and significantly extend survival with no overt toxicity in control animals. Conclusions In summary we have demonstrated that tumour tropic bacteria can be modified to safely deliver therapeutic levels of gene knockdown. This technology has the potential to specifically target primary and secondary solid tumours with personalised therapeutic payloads, providing new multi-cancer detection and treatment options with minimal off-target effects. Further understanding of the tropism mechanisms and impact on host immunity and microbiome is required to progress to clinical translation

Plutonium(IV) Sorption during Ferrihydrite Nanoparticle Formation

Understanding interactions between iron (oxyhydr)oxide nanoparticles and plutonium is essential to underpin technology to treat radioactive effluents, in cleanup of land contaminated with radionuclides, and to ensure the safe disposal of radioactive wastes. These interactions include a range of adsorption, precipitation, and incorporation processes. Here, we explore the mechanisms of plutonium sequestration during ferrihydrite precipitation from an acidic solution. The initial 1 M HNO3 solution with Fe(III)((aq)) and Pu-242(IV)((aq)) underwent controlled hydrolysis via the addition of NaOH to pH 9. The majority of Fe(III)((aq)) and Pu(IV)((aq)) was removed from solution between pH 2 and 3 during ferrihydrite formation. Analysis of Pu-ferrihydrite by extended X-ray absorption fine structure (EXAFS) spectroscopy showed that Pu(IV) formed an inner-sphere tetradentate complex on the ferrihydrite surface, with minor amounts of PuO2 present. Best fits to the EXAFS data collected from Pu-ferrihydrite samples aged for 2 and 6 months showed no statistically significant change in the Pu(IV)-Fe oxyhydroxide surface complex despite the ferrihydrite undergoing extensive recrystallization to hematite. This suggests the Pu remains strongly sorbed to the iron (oxyhydr)oxide surface and could be retained over extended time periods.Peer reviewe