Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure

Coastal Subsistence, Maritime Trade, and the Colonization of Small Offshore Islands in Eastern African Prehistory

Recent archaeological research has firmly established eastern Africa's offshore islands as important localities for understanding the region's pre-Swahili maritime adaptations and early Indian Ocean trade connections. While the importance of the sea and small offshore islands to the development of urbanized and mercantile Swahili societies has long been recognized, the formative stages of island colonization—and in particular the processes by which migrating Iron Age groups essentially became “maritime”—are still relatively poorly understood. Here we present the results of recent archaeological fieldwork in the Mafia Archipelago, which aims to understand these early adaptations and situate them within a longer-term trajectory of island settlement and pre-Swahili cultural developments. We focus on the results of zooarchaeological, archaeobotanical, and material culture studies relating to early subsistence and trade on this island to explore the changing significance of marine resources to the local economy. We also discuss the implications of these maritime adaptations for the development of local and long-distance Indian Ocean trade networks

Trajectory of vitamin D status during pregnancy in relation to neonatal birth size and fetal survival: a prospective cohort study

Background: We investigated the associations between vitamin D status in early and late pregnancy with neonatal small for gestational age (SGA), low birth weight (LBW) and preterm delivery. Furthermore, associations between vitamin D status and pregnancy loss were studied. Methods: Serum 25-hydroxyvitamin D (25OHD) was sampled in gestational week ≤ 16 (trimester 1 (T1), N = 2046) and > 31 (trimester 3 (T3), N = 1816) and analysed using liquid chromatography tandem mass spectrometry. Pregnant women were recruited at antenatal clinics in south-west Sweden at latitude 57–58°N. Gestational and neonatal data were retrieved from medical records. Multiple gestations and terminated pregnancies were excluded from the analyses. SGA was defined as weight and/or length at birth < 2 SD of the population mean and LBW as < 2500 g. Preterm delivery was defined as delivery < 37 + 0 gestational weeks and pregnancy loss as spontaneous abortion or intrauterine fetal death. Associations between neonatal outcomes and 25OHD at T1, T3 and change in 25OHD (T3-T1) were studied using logistic regression. Results: T1 25OHD was negatively associated with pregnancy loss and 1 nmol/L increase in 25OHD was associated with 1% lower odds of pregnancy loss (OR 0.99, p = 0.046). T3 25OHD ≥ 100 nmol/L (equal to 40 ng/ml) was associated with lower odds of SGA (OR 0.3, p = 0.031) and LBW (OR 0.2, p = 0.046), compared to vitamin D deficiency (25OHD < 30 nmol/L, or 12 ng/ml). Women with a ≥ 30 nmol/L increment in 25OHD from T1 to T3 had the lowest odds of SGA, LBW and preterm delivery. Conclusions: Vitamin D deficiency in late pregnancy was associated with higher odds of SGA and LBW. Lower 25OHD in early pregnancy was only associated with pregnancy loss. Vitamin D status trajectory from early to late pregnancy was inversely associated with SGA, LBW and preterm delivery with the lowest odds among women with the highest increment in 25OHD. Thus, both higher vitamin D status in late pregnancy and gestational vitamin D status trajectory can be suspected to play a role in healthy pregnancy

Metal organic frameworks : from anticancer multifunctional drug delivery systems to novel vaccine adjuvants

The research presented in this thesis aims to assess the capacity of metal organic frameworks for potential applications as drug delivery systems and novel vaccine adjuvants. The opening chapter (Chapter 1) provides a reader with a background to the field, metal organic frameworks synthesis routes and their potential applications in medicine and insight into the basics of immunology and biological assays as well as the anti-cancer drugs mechanisms and how it can be used to target the tumour cells. Chapter 3 describes the experimental techniques used in this research combining biological with chemical testing. Investigation of Zr-MOFs (UiO66 and UiO66-NH₂) and CPO – 27 (CPO Mg and CPO Ni) for their potential application as drug delivery systems for cisplatin is presented and compared in Chapter 4, as well as two different drug incorporation techniques (conjugation and physical encapsulation) in the case of UiO66-NH₂. The route proved to be more efficient when compared with encapsulation for the same MOF, and overall the most promising candidate for a drug delivery system for cisplatin, due to its large pores, was UiO66. Chapter 5 focuses on the potential application of Zr-MOFs and CPO-27 (Mg and Ni) as a drug delivery system for 5-Fluorouracil, a drug which because of its sparse solubility in water is challenging when it comes to its administration in the human body. Chapter 7 investigates the possibility to design multiple drug delivery systems utilising MOFs that contain cisplatin and fluorouracil in their framework, loading them with nitric oxide to increase the anti-cancer action and also to prevent thrombosis that may pose a danger to patients who undergo anti-cancer therapies. Chapter 6 describes the new concept of investigating MOFs (Zr-MOFs and Al-MOFs) as potential candidates as vaccine adjuvants. The research concluded that the performance of Al-MOFs, was better when compared to commercially available adjuvants

The Port of Berenike Troglodytica on the Red Sea: A Landscape-Based Approach to the Study of its Harbour and its Role in Indo-Mediterranean Trade

The port site of Berenike Troglodytica - located on the Egyptian Red Sea coast - served the spice and incense routes that linked the Mediterranean World (specifically the Roman Empire) to India, Southern Arabia and East Africa. In the Greco-Roman period the site was at the cutting edge of what was then the embryonic global economy, ideally situated as a key node connecting Indian Ocean and Mediterranean trade for almost 800 years. It is now located in an arid, marginal, hostile environment but the situation must have been very different 2300 years ago, at the time of its founding. At the time of elephant-hunting trips during the Hellenistic period before the inception of its important role in the global markets of the day in the Roman period Berenike would have to have looked much different to what we can now imagine. What was it like then, when the first prospectors visited this location at the time of Ptolemy II? Why this particular place, and this particular landscape setting seemed such a propitious location for the siting of an important new harbour? Given the importance of the port over almost a millennium it is perhaps surprising that very little is known about the different factors impacting on the foundation, evolution, heyday and subsequent decline of the city; or the size, shape, and capacity of its harbour. The intention of this research is to address this shortfall in our knowledge, to examine the drivers behind the rise and fall of this port city, and to explore the extent to which the dynamics of the physical landscape were integral to this story. Using an innovative Earth Science approach, changes in the archaeological 'coastscape' have been reconstructed and correlated with periods of occupation and abandonment of the port, shedding light on the nature, degree and directionality of human-environment interactions at the site. This work has revealed profound changes in the configuration of the coastal landscape and environment (including the sea level) during the lifespan of Berenike, highlighting the ability of people to exploit changes in their immediate environment, and demonstrating that, ultimately, the decline of the port was partly due to these landscape dynamics. To further explore these themes the landscape reconstructions have been supplemented by semi-quantitative analyses of a suite of variables likely to influence the initial siting of new ports of trade. These have shown that although the site of Berenike was ideal in terms of its coastal landscape potential, possessing a natural sheltered bay and lagoon system, the choice of location was not solely influenced by its environmental conditions. Additionally, a detailed review of vessels that plied Red Sea and Indian Ocean routes is presented here in order to better understand the design and functioning of Berenikeâs harbour. This serves the purpose of identifying unifying features that provide more detail about the size and draught of vessels and the potential capacity of the harbour basin. By using this multi-scalar approach it has been possible to reconstruct the 'coastscape' of the site through the key periods of its occupancy and those phases immediately before and after its operation. This has wide-ranging implications for researchers studying ancient ports along this trade network as a larger database will tease out more details about how influential the landscape was in the initial siting of the port and its subsequent use and decline.</p

Non-Conjugated Small Molecule FRET for Differentiating Monomers from Higher Molecular Weight Amyloid Beta Species

Background: Systematic differentiation of amyloid (Aβ) species could be important for diagnosis of Alzheimer's disease (AD). In spite of significant progress, controversies remain regarding which species are the primary contributors to the AD pathology, and which species could be used as the best biomarkers for its diagnosis. These controversies are partially caused by the lack of reliable methods to differentiate the complicated subtypes of Aβ species. Particularly, differentiation of Aβ monomers from toxic higher molecular weight species (HrMW) would be beneficial for drug screening, diagnosis, and molecular mechanism studies. However, fast and cheap methods for these specific aims are still lacking. Principal Findings: We demonstrated the feasibility of a non-conjugated FRET (Förster resonance energy transfer) technique that utilized amyloid beta (Aβ) species as intrinsic platforms for the FRET pair assembly. Mixing two structurally similar curcumin derivatives that served as the small molecule FRET pair with Aβ40 aggregates resulted in a FRET signal, while no signal was detected when using Aβ40 monomer solution. Lastly, this FRET technique enabled us to quantify the concentrations of Aβ monomers and high molecular weight species in solution. Significance: We believe that this FRET technique could potentially be used as a tool for screening for inhibitors of Aβ aggregation. We also suggest that this concept could be generalized to other misfolded proteins/peptides implicated in various pathologies including amyloid in diabetes, prion in bovine spongiform encephalopathy, tau protein in AD, and α-synuclein in Parkinson disease.National Institute on Aging (K25AG036760

The Profumo affair in popular culture: The Keeler Affair (1963) and ‘the commercial exploitation of a public scandal’

This article demonstrates that the Profumo affair, which obsessed Britain for large parts of 1963, was not simply a political scandal, but was also an important cultural event. Focussing on the production of The Keeler Affair, a feature film that figured prominently in contemporary coverage of the scandal but which has been largely overlooked since, the article shows that this film emerged from a situation in which cultural entrepreneurs, many of them associated with the satire boom, sought to exploit the scandal for financial gain. Many Profumo-related cultural products found an audience, and thus formed an integral part of, and helped to shape public attitudes towards, the Profumo affair. However, these products did not go uncontested, and resistance to them, and especially to the idea that Keeler might benefit materially from her role in the scandal, speak to concerns about cultural mediations of sex, politics and humour in early-1960s Britain

Predicting survival in malignant pleural effusion: development and validation of the LENT prognostic score

BACKGROUND: Malignant pleural effusion (MPE) causes debilitating breathlessness and predicting survival is challenging. This study aimed to obtain contemporary data on survival by underlying tumour type in patients with MPE, identify prognostic indicators of overall survival and develop and validate a prognostic scoring system. METHODS: Three large international cohorts of patients with MPE were used to calculate survival by cell type (univariable Cox model). The prognostic value of 14 predefined variables was evaluated in the most complete data set (multivariable Cox model). A clinical prognostic scoring system was then developed and validated. RESULTS: Based on the results of the international data and the multivariable survival analysis, the LENT prognostic score (pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group (ECOG) performance score (PS), neutrophil-to-lymphocyte ratio and tumour type) was developed and subsequently validated using an independent data set. Risk stratifying patients into low-risk, moderate-risk and high-risk groups gave median (IQR) survivals of 319 days (228–549; n=43), 130 days (47–467; n=129) and 44 days (22–77; n=31), respectively. Only 65% (20/31) of patients with a high-risk LENT score survived 1 month from diagnosis and just 3% (1/31) survived 6 months. Analysis of the area under the receiver operating curve revealed the LENT score to be superior at predicting survival compared with ECOG PS at 1 month (0.77 vs 0.66, p<0.01), 3 months (0.84 vs 0.75, p<0.01) and 6 months (0.85 vs 0.76, p<0.01). CONCLUSIONS: The LENT scoring system is the first validated prognostic score in MPE, which predicts survival with significantly better accuracy than ECOG PS alone. This may aid clinical decision making in this diverse patient population