Interaction of Pyrrolobenzodiazepine (PBD) Ligands with Parallel Intermolecular G-Quadruplex Complex Using Spectroscopy and ESI-MS

Studies on ligand interaction with quadruplex DNA, and their role in stabilizing the complex at concentration prevailing under physiological condition, has attained high interest. Electrospray ionization mass spectrometry (ESI-MS) and spectroscopic studies in solution were used to evaluate the interaction of PBD and TMPyP4 ligands, stoichiometry and selectivity to G-quadruplex DNA. Two synthetic ligands from PBD family, namely pyrene-linked pyrrolo[2,1-c][1,4]benzodiazepine hybrid (PBD1), mixed imine-amide pyrrolobenzodiazepine dimer (PBD2) and 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP4) were studied. G-rich single-stranded oligonucleotide d(5′GGGGTTGGGG3′) designated as d(T2G8), from the telomeric region of Tetrahymena Glaucoma, was considered for the interaction with ligands. ESI-MS and spectroscopic methods viz., circular dichroism (CD), UV-Visible, and fluorescence were employed to investigate the G-quadruplex structures formed by d(T2G8) sequence and its interaction with PBD and TMPyP4 ligands. From ESI-MS spectra, it is evident that the majority of quadruplexes exist as d(T2G8)2 and d(T2G8)4 forms possessing two to ten cations in the centre, thereby stabilizing the complex. CD band of PBD1 and PBD2 showed hypo and hyperchromicity, on interaction with quadruplex DNA, indicating unfolding and stabilization of quadruplex DNA complex, respectively. UV-Visible and fluorescence experiments suggest that PBD1 bind externally where as PBD2 intercalate moderately and bind externally to G-quadruplex DNA. Further, melting experiments using SYBR Green indicate that PBD1 unfolds and PBD2 stabilizes the G-quadruplex complex. ITC experiments using d(T2G8) quadruplex with PBD ligands reveal that PBD1 and PBD2 prefer external/loop binding and external/intercalative binding to quadruplex DNA, respectively. From experimental results it is clear that the interaction of PBD2 and TMPyP4 impart higher stability to the quadruplex complex

Summer warming explains widespread but not uniform greening in the Arctic tundra biome

Arctic warming can influence tundra ecosystem function with consequences for climate feedbacks, wildlife and human communities. Yet ecological change across the Arctic tundra biome remains poorly quantified due to field measurement limitations and reliance on coarse-resolution satellite data. Here, we assess decadal changes in Arctic tundra greenness using time series from the 30 m resolution Landsat satellites. From 1985 to 2016 tundra greenness increased (greening) at ~37.3% of sampling sites and decreased (browning) at ~4.7% of sampling sites. Greening occurred most often at warm sampling sites with increased summer air temperature, soil temperature, and soil moisture, while browning occurred most often at cold sampling sites that cooled and dried. Tundra greenness was positively correlated with graminoid, shrub, and ecosystem productivity measured at field sites. Our results support the hypothesis that summer warming stimulated plant productivity across much, but not all, of the Arctic tundra biome during recent decades

The horror of orthodoxy: Christina Mirabilis, thirteenth-century ‘zombie’ saint

In 1232, Thomas of Cantimpré wrote his Life of Christina Mirabilis (c. 1150–1224), an account of the miraculous life and three deaths of an unenclosed holy woman from the Low Countries. The text opens with an explicit vindication of Christina’s return(s) as divinely mandated. Yet, the narrative shows that her community struggles to deal with the revenant in their midst. Through her example, they must confront the terrifying mechanics of purgatory, resurrection, and the co-incidence of body and soul. A similar unease is found in modern scholarship, in which Christina is typically referred to dismissively in terms more commonly applied to cinematic monsters. I work with such dismissive language – specifically the term ‘zombie’ – to move beyond this heuristic roadblock. The terms of filmic zombie-ism provide new insight into the merging of orthodoxy and terror in Christina’s vita

Amplification of wildfire area burnt by hydrological drought in the humid tropics

Borneo’s diverse ecosystems, which are typical humid tropical conditions, are deteriorating rapidly, as the area is experiencing recurrent large-scale wildfires, affecting atmospheric composition1, 2, 3, 4 and influencing regional climate processes5, 6. Studies suggest that climate-driven drought regulates wildfires2, 7, 8, 9, but these overlook subsurface processes leading to hydrological drought, an important driver. Here, we show that models which include hydrological processes better predict area burnt than those solely based on climate data. We report that the Borneo landscape10 has experienced a substantial hydrological drying trend since the early twentieth century, leading to progressive tree mortality, more severe than in other tropical regions11. This has caused massive wildfires in lowland Borneo during the past two decades, which we show are clustered in years with large areas of hydrological drought coinciding with strong El Niño events. Statistical modelling evidence shows amplifying wildfires and greater area burnt in response to El Niño/Southern Oscillation (ENSO) strength, when hydrology is considered. These results highlight the importance of considering hydrological drought for wildfire prediction, and we recommend that hydrology should be considered in future studies of the impact of projected ENSO strength, including effects on tropical ecosystems, and biodiversity conservation

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone