Explore the vast range of titles available.

This is an eclectic and colourful celebration of the history of Edinburgh through the eyes of those who witnessed it. Not simply a book about the great and good, the famous and infamous; there is testimony from ordinary folk who may not have made their mark on history but who have contributed to Edinburgh's ever-expanding tapestry.

Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients. We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0–1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants. Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3–28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8–89·3) of 22 treatment-naive patients, seven (41·2%, 18·4–67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7–65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia). Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. Eisai and Merck Sharp & Dohme.

During the Early Bronze Age, populations of the western Eurasian steppe expanded across an immense area of northern Eurasia. Combined archaeological and genetic evidence supports widespread Early Bronze Age population movements out of the Pontic–Caspian steppe that resulted in gene flow across vast distances, linking populations of Yamnaya pastoralists in Scandinavia with pastoral populations (known as the Afanasievo) far to the east in the Altai Mountains 1 , 2 and Mongolia 3 . Although some models hold that this expansion was the outcome of a newly mobile pastoral economy characterized by horse traction, bulk wagon transport 4 – 6 and regular dietary dependence on meat and milk 5 , hard evidence for these economic features has not been found. Here we draw on proteomic analysis of dental calculus from individuals from the western Eurasian steppe to demonstrate a major transition in dairying at the start of the Bronze Age. The rapid onset of ubiquitous dairying at a point in time when steppe populations are known to have begun dispersing offers critical insight into a key catalyst of steppe mobility. The identification of horse milk proteins also indicates horse domestication by the Early Bronze Age, which provides support for its role in steppe dispersals. Our results point to a potential epicentre for horse domestication in the Pontic–Caspian steppe by the third millennium bc , and offer strong support for the notion that the novel exploitation of secondary animal products was a key driver of the expansions of Eurasian steppe pastoralists by the Early Bronze Age. Analysis of ancient proteins suggests that Early Bronze Age dairying and horse domestication catalysed eastern Yamnaya migrations.

Plasmon-coupled circular dichroism has emerged as a promising approach for ultrasensitive detection of biomolecular conformations through coupling between molecular chirality and surface plasmons. Chiral nanoparticle assemblies without chiral molecules present also have large optical activities. We apply single-particle circular differential scattering spectroscopy coupled with electron imaging and simulations to identify both structural chirality of plasmonic aggregates and plasmon-coupled circular dichroism induced by chiral proteins. We establish that both chiral aggregates and just a few proteins in interparticle gaps of achiral assemblies are responsible for the ensemble signal, but single nanoparticles do not contribute. We furthermore find that the protein plays two roles: It transfers chirality to both chiral and achiral plasmonic substrates, and it is also responsible for the chiral three-dimensional assembly of nanorods. Understanding these underlying factors paves the way toward sensing the chirality of single biomolecules.

We analyze the trading of corporate insiders at leading financial institutions during the 2007 to 2009 financial crisis. We find strong evidence of a relation between political connections and informed trading during the period in which Troubled Asset Relief Program (TARP) funds were disbursed, and that the relation is most pronounced among corporate insiders with recent direct connections. Notably, we find evidence of abnormal trading by politically connected insiders 30 days in advance of TARP infusions, and that these trades anticipate the market reaction to the infusion. Our results suggest that political connections can facilitate opportunistic behavior by corporate insiders.

Naturally, he did not consult his protg, nor she did she seem to mind, though they were not at that point romantically associated. He kitted her out in stage clothes, gave her jewellery, and a padded bra. Riding around in Ike's pink Cadillac, she felt rich and \"felt good\". They had a record, 'A Fool in Love', in the charts and their relationship metamorphosed from platonic to passionate. [Tina Turner] fell pregnant and Ike, ever the gentleman, did the right thing and proposed, though he already had a common law wife and a couple of kids. They were married in 1962 but even before the knot was tied Tina was beginning to wonder what she'd got herself into. When she hinted that she might want out, Ike beat her up. He was not that much of a gentleman. From the start, when Ike Turner spotted her in a St Louis night club, she looked the part of a rock moll. Her dresses were short, tight and minimalist. Ike, a gifted pianist and guitarist whose career was in limbo, recognised Tina had a voice so big it could drown out a bingo caller. Then, she was called Annie Mae Bullock, from Nutbush, Tennessee, where she was born in 1938. When Ike met her she was 16 and singing duets with her sister. Tina approached him at a gig and asked to sing. When she did he could scarcely believe his ears. If he closed his eyes, she sounded like James Brown. Ike, who had always wanted to work with a woman, signed her on the spot. The first thing he did was change her name. He called her Tina after a jungle queen in a long-forgotten television serial and Turner because Turner and Bullock sounded like a firm of plumbers. Anyhow Ike and Tina Turner tripped nicely off the tongue.

Dementia with Lewy bodies and Parkinson's disease dementia, jointly known as Lewy body dementia, are common neurodegenerative conditions. Patients with Lewy body dementia present with a wide range of cognitive, neuropsychiatric, sleep, motor, and autonomic symptoms. Presentation varies between patients and can vary over time within an individual. Treatments can address one symptom but worsen another, which makes disease management difficult. Symptoms are often managed in isolation and by different specialists, which makes high-quality care difficult to accomplish. Clinical trials and meta-analyses now provide an evidence base for the treatment of cognitive, neuropsychiatric, and motor symptoms in patients with Lewy body dementia. Furthermore, consensus opinion from experts supports the application of treatments for related conditions, such as Parkinson's disease, for the management of common symptoms (eg, autonomic dysfunction) in patients with Lewy body dementia. However, evidence gaps remain and future clinical trials need to focus on the treatment of symptoms specific to patients with Lewy body dementia.

Potassium ion (K + ) plays a critical role as an essential electrolyte in all biological systems. Genetically-encoded fluorescent K + biosensors are promising tools to further improve our understanding of K + -dependent processes under normal and pathological conditions. Here, we report the crystal structure of a previously reported genetically-encoded fluorescent K + biosensor, GINKO1, in the K + -bound state. Using structure-guided optimization and directed evolution, we have engineered an improved K + biosensor, designated GINKO2, with higher sensitivity and specificity. We have demonstrated the utility of GINKO2 for in vivo detection and imaging of K + dynamics in multiple model organisms, including bacteria, plants, and mice.