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COVID-19 has had unprecedented impacts on urban life on a global scale, representing the worst pandemic in living memory. In this introduction to the first of two parts of a Special Issue on urban public health emergencies, we suggest that the COVID-19 outbreak, and associated attempts to manage the pandemic, reproduced and ultimately exacerbated the social and spatial divides that striate the contemporary city. Here, we draw on evidence from the papers in Part 1 of the Special Issue to summarise the uneven urban geographies of COVID-19 evident at the inter- and intra-urban level, emphasising the particular vulnerabilities and risks borne by racialised workers who found it difficult to practise social distancing in either their home or working life. Considering the interplay of environmental, social and biological factors that conspired to create hotspots of COVID-19 infection, and the way these are connected to the racialised capitalism that underpins contemporary urban development, this introduction suggests that reflection on public health emergencies in the city is not just essential from a policy perspective but helps enrich theoretical debates on the nature of contemporary urbanisation in its ‘planetary’ guise.

ImportanceDysregulated metabolism is a hallmark of renal cell carcinoma (RCC). Glutaminase is a key enzyme that fuels tumor growth by converting glutamine to glutamate. Telaglenastat is an investigational, first-in-class, selective, oral glutaminase inhibitor that blocks glutamine utilization and downstream pathways. Preclinically, telaglenastat synergized with cabozantinib, a VEGFR2/MET/AXL inhibitor, in RCC models.ObjectiveTo compare the efficacy and safety of telaglenastat plus cabozantinib (Tela + Cabo) vs placebo plus cabozantinib (Pbo + Cabo).Design, Setting, and ParticipantsCANTATA was a randomized, placebo-controlled, double-blind, pivotal trial conducted at sites in the US, Europe, Australia, and New Zealand. Eligible patients had metastatic clear-cell RCC following progression on 1 to 2 prior lines of therapy, including 1 or more antiangiogenic therapies or nivolumab plus ipilimumab. The data cutoff date was August 31, 2020. Data analysis was performed from December 2020 to February 2021.InterventionsPatients were randomized 1:1 to receive oral cabozantinib (60 mg daily) with either telaglenastat (800 mg twice daily) or placebo until disease progression or unacceptable toxicity.Main Outcomes and MeasuresThe primary end point was progression-free survival (Response Evaluation Criteria in Solid Tumors version 1.1) assessed by blinded independent radiology review.ResultsA total of 444 patients were randomized: 221 to Tela + Cabo (median [range] age, 61 [21-81] years; 47 [21%] women and 174 [79%] men) and 223 to Pbo + Cabo (median [range] age, 62 [29-83] years; 68 [30%] women and 155 [70%] men). A total of 276 (62%) patients had received prior immune checkpoint inhibitors, including 128 with prior nivolumab plus ipilimumab, 93 of whom had not received prior antiangiogenic therapy. Median progression-free survival was 9.2 months for Tela + Cabo vs 9.3 months for Pbo + Cabo (HR, 0.94; 95% CI, 0.74-1.21; P = .65). Overall response rates were 31% (69 of 221) with Tela + Cabo vs 28% (62 of 223) with Pbo + Cabo. Treatment-emergent adverse event (TEAE) rates were similar between arms. Grade 3 to 4 TEAEs occurred in 160 patients (71%) with Tela + Cabo and 172 patients (79%) with Pbo + Cabo and included hypertension (38 patients [17%] vs 40 patients [18%]) and diarrhea (34 patients [15%] vs 29 patients [13%]). Cabozantinib was discontinued due to AEs in 23 patients (10%) receiving Tela + Cabo and 33 patients (15%) receiving Pbo + Cabo.Conclusions and RelevanceIn this randomized clinical trial, telaglenastat did not improve the efficacy of cabozantinib in metastatic RCC. Tela + Cabo was well tolerated with AEs consistent with the known risks of both agents.Trial RegistrationClinicalTrials.gov Identifier: NCT03428217

International trade law has long been the site of a battle over who or what the state can represent. Today, that battle is taking a new form. While for decades the WTO was considered a centerpiece of the international economic order, the policy landscape is now awash with claims that the US should abandon WTO disciplines, critiques of the WTO as the vehicle for a coherent neoliberalism, and concerns about the implications of trade law for domestic industry, democratic participation, climate action, and national security. While I am a long-standing critic of trade law’s excesses, I don’t see that sudden shift as a cause for celebration. In order to understand why, I argue that it is necessary to pay careful attention to the different forms the battle for the state at the WTO has taken. This article explores the conditions and stakes of three key moments in that battle – the negotiation of the GATT and the era of decolonization, the end of the Cold War and the creation of the WTO, and the recent transformations caused by the decline of US power, the rise of China, and the systemic shock of climate change. I conclude that we cannot automatically apply critiques developed in earlier eras to the current situation.

ObjectivesTo define the host mechanisms contributing to the pathological interferon (IFN) type 1 signature in Juvenile dermatomyositis (JDM).MethodsRNA-sequencing was performed on CD4+, CD8+, CD14+and CD19+cells sorted from pretreatment and on-treatment JDM (pretreatment n=10, on-treatment n=11) and age/sex-matched child healthy-control (CHC n=4) peripheral blood mononuclear cell (PBMC). Mitochondrial morphology and superoxide were assessed by fluorescence microscopy, cellular metabolism by13C glucose uptake assays, and oxidised mitochondrial DNA (oxmtDNA) content by dot-blot. Healthy-control PBMC and JDM pretreatment PBMC were cultured with IFN-α, oxmtDNA, cGAS-inhibitor, TLR-9 antagonist and/orn-acetyl cysteine (NAC). IFN-stimulated gene (ISGs) expression was measured by qPCR. Total numbers of patient and controls for functional experiments, JDM n=82, total CHC n=35.ResultsDysregulated mitochondrial-associated gene expression correlated with increased ISG expression in JDM CD14+ monocytes. Altered mitochondrial-associated gene expression was paralleled by altered mitochondrial biology, including ‘megamitochondria’, cellular metabolism and a decrease in gene expression of superoxide dismutase (SOD)1. This was associated with enhanced production of oxidised mitochondrial (oxmt)DNA. OxmtDNA induced ISG expression in healthy PBMC, which was blocked by targeting oxidative stress and intracellular nucleic acid sensing pathways. Complementary experiments showed that, under in vitro experimental conditions, targeting these pathways via the antioxidant drug NAC, TLR9 antagonist and to a lesser extent cGAS-inhibitor, suppressed ISG expression in pretreatment JDM PBMC.ConclusionsThese results describe a novel pathway where altered mitochondrial biology in JDM CD14+ monocytes lead to oxmtDNA production and stimulates ISG expression. Targeting this pathway has therapeutical potential in JDM and other IFN type 1-driven autoimmune diseases.

25.08.2022 відбулася робота Біологічної секції щорічної Міжнародної Гамовської конференції у режимі он-лайн на платформі Zoom. Традиційно Біологічна секція проходить під назвою “The Importance of G. Gamow's Ideas for Biology of the 21st Century”. У роботі секції брали участь відомі науковці, що ведуть дослідження в області молекулярної біології та генетики з провідних наукових установ України, Канади, США, Великої Британії і Німеччини, також брали участь аспіранти та студенти (загалом 52 учасника). Було представлено 13 усних доповідей, серед них доповіді – «Генетичні ресурси рослин для підвищення стресостійкості – на прикладі зернових культур» - проф., д.б.н. Бьорнер А. (Інститут генетики рослин і досліджень сільськогосподарських рослин імені Лейбніца, Гатерслебен, Німеччина); «Дослідження загальногеномних асоціації для виявлення локусів та генів-кандидатів, що впливають на вміст білка в зерні пшениці м’якої» – проф., д.б.н. Мішева С. (Інститут фізіології рослин і генетики Болгарської академії наук, Софія, Болгарія); «Дослідження молекулярної еволюції та таксономічне застосування 5S рДНК при аналізі роду Aconitum» – проф., д.б.н. Волков Р.А. (Чернівецький національний університет імені Юрія Федьковича, Чернівці, Україна); «Подолання селекційних бар'єрів для пшениці» - проф. Гріффітс С. і доктор Вінген Л.У. (Центр Джона Іннеса, Норвіч, Велика Британія); «Оцінка сучасного стану популяцій Gentiana lutea L. Українських Карпат: Еколого-генетичні підходи» – доц., к.б.н. Прокоп'як М.З. (Тернопільський національний педагогічний університет імені Володимира Гнатюка, Тернопіль, Україна); «Часова динаміка спектрів фонового світіння Photobacterium phosphoreum» – проф., д.б.н. Мартинюк В.С. (Київський національний університет імені Тараса Шевченка, Київ, Україна.); «Нові мутації STARD8 і STARD9 виявлені в 46 гонадах XY пацієнтів з дисгенезією, що підтримують ці гени як кандидатів на DSD» – Сіроха Д. і проф., д.б.н. Лівшиц Л.А. (Інститут молекулярної біології і генетики НАН України, Київ, Україна); «MYD88 і CXCR4, два гени, які відіграють вирішальну роль у макроглобулінемії Вальденстрема» – д.б.н. Мончак Ю. (Завідувач відділу молекулярної генетики, Центр охорони здоров'я університету Макгілла, Університет Макгілла та Монреальський університет, Канада); «Джордж Гамов і генетичний код ДНК» – проф., д.ф.н. Сегре Г. (Університет Пенсільванії, США). Серед підготовлених доповідей вважаємо необхідним відмітити високу якість та актуальність виконаних на сучасному рівні досліджень молодих та починаючих науковців: «Біоінформаційний аналіз нуклеотидних послідовностей локусів Gli-1 Triticum aestivum L.» – аспірант Попович Ю.А., проф., д.б.н. Чеботар С.В. (ОНУ імені І.І. Мечникова, Одеса, Україна); «Скринінг продуцентів тіопептидних антибіотиків за допомогою репортерної системи на основі промотору гена tipA» – аспірант Тістечок С.І. (Львівський національний університет імені Івана Франка, Україна); «Довгі та короткі варіанти 5S рДНК у геномах видів Apis» – аспірант Рошка Н.М. (Чернівецький національний університет імені Юрія Федьковича, Чернівці, Україна). Як позитивну рису роботи біологічної секції було відмічено багатоплановість охопленої тематики, що має генетичне підґрунтя, та перспективність досліджень, що виконуються на стику наук. Учасники Біологічної секції звернули увагу, що Г.А. Гамов зробив внесок у розвиток саме молекулярної біології, поставивши питання про розшифрування генетичного коду, тому необхідно у назву конференції додати – «molecular biology», щоб назва конференції виглядала наступним чином: «Аstronomy and Beyond: Astrophysics, Cosmology and Gravitation, Astroparticle physics, Rradioastronomy, Astrobiology and Molecular biology».

Objective The objective of this study was to describe the documented neurological assessment and investigations for neuroprognostication in patients after cardiac arrest. Design, setting, and participants This was a retrospective cohort study of adult patients after cardiac arrest, admitted to a tertiary intensive care unit (ICU), between January 2009 and December 2018. Main outcome measures The main outcome measures were the proportion of patients with a documented Glasgow Coma Scale (GCS) score and investigations for neuroprognostication. Results Four hundred twenty-seven patients formed the study cohort. The GCS score was documented for 267 (63%) patients at some time during their ICU stay. The proportion of patients with the GCS score documented decreased each day of ICU stay (59% at day 1, 20% at day 5). Pupil reflex to light was recorded in 352 (82%), corneal reflex in 155 (36%), and limb reflexes in 216 (51%) patients. Twenty-eight (6.6%) patients underwent brain magnetic resonance imaging, 10 (2.3%) an electroencephalogram, and two somatosensory evoked potentials. Withdrawal of life-sustaining treatments occurred in 166 (39%) patients, and 221 (52%) patients died in hospital. Conclusions In this single-centre study of patients admitted to the ICU after cardiac arrest, the GCS score was inconsistently documented, and investigations for neuroprognostication were infrequent.

Background Frailty is independently associated with morbidity and mortality in critically ill patients. However, the association between preadmission frailty and the degree of treatment received in the intensive care unit (ICU) remains unclear. Objective To describe patient length of stay in an ICU and the treatments provided according to the extent of patient frailty. Methods Single-centre retrospective cohort study of adult patients admitted to a tertiary ICU between January 2018 and December 2019. Frailty was assessed using the Clinical Frailty Scale (CFS). The primary outcome was ICU length of stay stratified by CFS score (1–8). Secondary outcomes were the proportion of patients with each CFS score treated with vasoactive agents, invasive ventilation, noninvasive ventilation, renal replacement therapy, and tracheostomy. Poisson regression and competing risks regression was used to analyse associations between ICU length of stay and potential confounders. Results The study cohort comprised 2743 patients, with CFS scores known for 2272 (83%). Length of stay in the ICU increased with each increment in the CFS up to a score of 5, beyond which it decreased with higher frailty scores. After adjusting for age, illness severity, admission type, and treatment limitation, CFS scores were not independently associated with length of stay in the ICU (P = 0.31). The proportion of patients receiving specific ICU treatments peaked at different CFS scores, being highest for vasoactive agents at CFS 5 (47%), invasive ventilation CFS 3 (51%), noninvasive ventilation CFS 6 (11%), renal replacement therapy CFS 6 (8.2%), and tracheostomy CFS 5 (2.2%). Increasing frailty was associated with increased mortality and discharge to a destination other than home. Conclusions The extent of frailty is not independently associated with length of stay in the ICU. The proportion of patients receiving specific ICU treatments peaked at different CFS scores.

To estimate the prevalence of family members affected by addictive disorders (FMA) with regard to various types of addictive disorders, and self-rated health and depression in the general population.Cross-sectional general population survey.The German Health Update study (GEDA) 2014/2015, a nationally representative panel of German residents aged 15 years or older.A total of 24 824 residents aged 15 years or older.Participants were asked if they had a family member with current or past addictive disorder, the type of addiction and the relationship status. In addition, self-rated health and depression were assessed using standardized questionnaires.Of the respondents, 9.5% [95% confidence interval (CI) = 9.0-10.0] reported being affected by a current addictive disorder of a relative (cFMA), with a further 4.5% (95% CI = 4.2-4.9) reported having been affected by the addictive disorders of a relative in the past but not within the last 12 months (pFMA). Most FMAs reported having been affected by disorders due to alcohol, followed by cannabis and other drugs. Compared with life-time non-FMAs, FMAs reported significantly (P 0.001) higher odds ratios for depression (cFM = 2.437; 95% CI = 2.082-2.853; pFMA = 1.850; 95% CI = 1.519-2.253) and ill-health (cFMA = 1.574; 95% CI = 1.374-1.805; pFMA = 1.297; 95% CI = 1.082-1.555).In Germany, family members affected by addictive disorder are a substantial group within the general population. This group is characterized by ill-health and has not yet been adequately addressed by the addiction treatment system.

Alva Myrdal was a feminist public intellectual, social policy researcher, ambassador, socialist internationalist, and eventual Nobel Peace Prize Laureate. She is remembered both as one of the major architects of the Swedish welfare state and as a significant figure in international disarmament. For much of her life she was engaged in debates about social policy, initially within Sweden and then on the international stage, first as principal director at the UN Department of Social Affairs in New York from 1949, then director of the Department of Social Sciences at UNESCO from 1951, and finally as Swedish Ambassador to India from 1955 to 1961, before becoming the head of Sweden’s delegation to the UN Committee on Disarmament from 1962 to 1973. Alva Myrdal’s life and work offers a window into social democratic internationalism at the period when it was at its most idealistic and influential. As this chapter shows, the struggle over how to interpret her legacy is closely tied up with the rise and fall of social democratic internationalism in Sweden and beyond.

Background In wheat, nitrogen (N) remobilization from vegetative tissues to developing grains largely depends on genetic and environmental factors. The evaluation of genetic potential of crops under limited resource inputs such as limited N supply would provide an opportunity to identify N-efficient lines with improved N utilisation efficiency and yield potential. We assessed the genetic variation in wheat recombinant inbred lines (RILs) for uptake, partitioning, and remobilization of N towards grain, its association with grain protein concentration (GPC) and grain yield. Methods We used the nested association mapping (NAM) population (195 lines) derived by crossing Paragon (P) with CIMMYT core germplasm (P × Cim), Baj (P × Baj), Watkins (P × Wat), and Wyalkatchem (P × Wya). These lines were evaluated in the field for two seasons under limited N supply. The plant sampling was done at anthesis and physiological maturity stages. Various physiological traits were recorded and total N uptake and other N related indices were calculated. The grain protein deviation (GPD) was calculated from the regression of grain yield on GPC. These lines were grouped into different clusters by hierarchical cluster analysis based on grain yield and N-remobilization efficiency (NRE). Results The genetic variation in accumulation of biomass at both pre- and post-anthesis stages were correlated with grain-yield. The NRE significantly correlated with aboveground N uptake at anthesis (AGNa) and grain yield but negatively associated with AGN at post-anthesis (AGNpa) suggesting higher N uptake till anthesis favours high N remobilization during grain filling. Hierarchical cluster analysis of these RILs based on NRE and yield resulted in four clusters, efficient (31), moderately efficient (59), moderately inefficient (58), and inefficient (47). In the N-efficient lines, AGNa contributed to 77% of total N accumulated in grains, while it was 63% in N-inefficient lines. Several N-efficient lines also exhibited positive grain protein deviation (GPD), combining high grain yield and GPC. Among crosses, the P × Cim were superior and N-efficient, while P × Wya responded poorly to low N input. Conclusions We propose that traits favouring pre- or post-anthesis biomass accumulation and pre-anthesis N uptake may be targeted for breeding to improve grain-yield under limited N. The lines with positive GPD, a first report of genotype-dependent GPD associated with both AGNpa and AGNa in wheat, may be used as varieties or genetic resources to improve grain yield with high GPC for sustainable development under limited N conditions.

This paper provides new insight into the evolution of geographical information science and systems (GIS) research via a computational analysis (in R) of 120,000 bibliographic records (from 1970 to 2022) downloaded from Scopus. We conduct an exploratory analysis of the data, then attempt to discover the thematic/topical structure of the GIS literature using the Structural Topic Model (STM) framework. We show how topics in GIS have evolved and discuss how our findings contribute to the understanding of the evolution and trajectory of GIS research. We conclude by highlighting the limitations of the approach and explaining our future research plans.

Purpose:Dual inhibition of glucose and glutamine metabolism results in synergistic anticancer effects in solid tumor models. Telaglenastat, an investigational, small-molecule, glutaminase inhibitor, exhibits modest single-agent activity in renal cell carcinoma (RCC) patients. This phase Ib trial evaluated telaglenastat plus cabozantinib or everolimus, agents known to impair glucose metabolism in patients with metastatic RCC (mRCC).Patients and Methods:mRCC patients received escalating doses of telaglenastat [400–800 mg per os (p.o.) twice daily] in a 3 + 3 design, plus either everolimus (10 mg daily p.o.; TelaE) or cabozantinib (60 mg daily p.o.; TelaC). Tumor response (RECISTv1.1) was assessed every 8 weeks. Endpoints included safety (primary) and antitumor activity.Results:Twenty-seven patients received TelaE, 13 received TelaC, with median 2 and 3 prior therapies, respectively. Treatment-related adverse events were mostly grades 1 to 2, most common including decreased appetite, anemia, elevated transaminases, and diarrhea with TelaE, and diarrhea, decreased appetite, elevated transaminases, and fatigue with TelaC. One dose-limiting toxicity occurred per cohort: grade 3 pruritic rash with TelaE and thrombocytopenia with TelaC. No maximum tolerated dose (MTD) was reached for either combination, leading to a recommended phase II dose of 800-mg telaglenastat twice daily with standard doses of E or C. TelaE disease control rate (DCR; response rate + stable disease) was 95.2% [20/21, including 1 partial response (PR)] among 21 patients with clear cell histology and 66.7% (2/3) for papillary. TelaC DCR was 100% (12/12) for both histologies [5/10 PRs as best response (3 confirmed) in clear cell].Conclusions:TelaE and TelaC showed encouraging clinical activity and tolerability in heavily pretreated mRCC patients.

Purpose:Glutaminase is a key enzyme, which supports elevated dependency of tumors on glutamine-dependent biosynthesis of metabolic intermediates. Dual targeting of glucose and glutamine metabolism by the mTOR inhibitor everolimus plus the oral glutaminase inhibitor telaglenastat showed preclinical synergistic anticancer effects, which translated to encouraging safety and efficacy findings in a phase I trial of 2L+ renal cell carcinoma (RCC). This study evaluated telaglenastat plus everolimus (TelaE) versus placebo plus everolimus (PboE) in patients with advanced/metastatic RCC (mRCC) in the 3L+ setting (NCT03163667).Patients and Methods:Eligible patients with mRCC, previously treated with at least two prior lines of therapy [including ≥1 VEGFR-targeted tyrosine kinase inhibitor (TKI)] were randomized 2:1 to receive E, plus Tela or Pbo, until disease progression or unacceptable toxicity. Primary endpoint was investigator-assessed progression-free survival (PFS; one-sided α Results:Sixty-nine patients were randomized (46 TelaE, 23 PboE). Patients had a median three prior lines of therapy, including TKIs (100%) and checkpoint inhibitors (88%). At median follow-up of 7.5 months, median PFS was 3.8 months for TelaE versus 1.9 months for PboE [HR, 0.64; 95% confidence interval (CI), 0.34–1.20; one-sided P = 0.079]. One TelaE patient had a partial response and 26 had stable disease (SD). Eleven patients on PboE had SD. Treatment-emergent adverse events included fatigue, anemia, cough, dyspnea, elevated serum creatinine, and diarrhea; grade 3 to 4 events occurred in 74% TelaE patients versus 61% PboE.Conclusions:TelaE was well tolerated and improved PFS versus PboE in patients with mRCC previously treated with TKIs and checkpoint inhibitors.

Supplementary Figure from Telaglenastat plus Everolimus in Advanced Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled, Phase II ENTRATA Trial

Supplementary Table from Telaglenastat plus Everolimus in Advanced Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled, Phase II ENTRATA Trial

Supplementary Data from Telaglenastat Plus Cabozantinib or Everolimus for Advanced or Metastatic Renal Cell Carcinoma: An Open-Label Phase I Trial

Supplementary Figure from Telaglenastat Plus Cabozantinib or Everolimus for Advanced or Metastatic Renal Cell Carcinoma: An Open-Label Phase I Trial

Sleep is rarely considered in drug development studies. Pre-existing sleep problems or changes in sleep parameters in response to therapeutics have the potential to diminish the true utility of the agent under development. Sleep is integral to human health and affects virtually every disease. We present evidence that indicates how sleep quality and quantity can be predictive of disease risk, progression, remission, and recurrence. Supporting the premise that we should conceptualize sleep as a 'vital sign' and measure sleep as an integral component in drug development. We highlight the emergence of digital health technologies that have enabled the capture of this 'vital sign' and ask the question: why is sleep still largely ignored in drug development studies?

Whole-body dual X-ray absorptiometry (DXA) accurately measures lean mass but is not routinely used in clinical practice. Hip and spine DXA are used in the diagnosis of osteoporosis, and with the common co-occurrence of sarcopenia with osteoporosis, regional DXA scans provide an opportunity for assessment of lean mass. The aim of this study is to develop predictive equations for the estimation of whole-body lean mass (WBLM), appendicular lean mass (ALM) and whole-body fat mass (WBFM) from regional DXA scans. A total of 2427 participants (ages 20–96 year; 57.7% men) from the Geelong Osteoporosis Study who underwent both regional and whole-body DXA were included in the analysis. Using forward stepwise multivariable linear regression, percentage fat (spine%fat, hip%fat) values from lumbar spine and femoral neck DXA were used in combination with clinical data to develop and validate equations for the estimation of WBLM, WBFM and ALM. Mean age was 53.5 year (± 19.2), weight 78.2 kg (± 15.4), height 169.6 cm (± 9.4), WBLM 50.4 kg (± 11.1), ALM 22.8 kg (± 5.4) and WBFM 24.3 kg (± 10.4). Spine%fat (r = 0.21) and hip%fat (r = − 0.34) were correlated with whole-body lean mass (p

This article argues that the old international law of empires, greater spaces, and regional orders did not disappear with the creation of the United Nations. While revisionist histories of international law have complicated the claim that a Westphalian order of independent states completely replaced a world of more varied political forms in the mid-seventeenth century, international lawyers nonetheless largely accept that such a transformation did take place at some point. The state is treated as the normative political subject of international law, and any move away from the geography of statehood as the foundation of the international legal system is seen as novel, exceptional, or illegal. The narrative that the state has become the primary political subject and spatial form of international law masks the persistence of regional orders as a core feature of the contemporary legal system. This article shows that international lawyers have been engaged in justifying, making sense of, narrating, and assembling regional orders for at least the past century. It explores the rival regionalisms promoted during the inter-war period, the struggles over regional orders during the early decades of decolonization, the expansive vision of regional orders consolidated in the early post-Cold War decades by the United States and its allies, and the regional ambitions of China in the twenty-first century. It analyses how regional orders are assembled and resisted through international law, what values are proclaimed to justify different forms of regional ordering, whose interests are represented, and the relation between grand narratives and technical transactions in that legal work. The article concludes that bringing the concept of regional orders to the foreground can open up a new and timely set of questions about politics, representation, and the future of international law.

Zymoseptoria triticiis the fungal pathogen responsible for Septoria tritici blotch on wheat. Disease outcome in this pathosystem is partly determined by isolate-specific resistance, where wheat resistance genes recognize specific fungal factors triggering an immune response. Despite the large number of known wheat resistance genes, fungal molecular determinants involved in such cultivar-specific resistance remain largely unknown. We identified the avirulence factorAvrStb9using association mapping and functional validation approaches. PathotypingAvrStb9transgenic strains onStb9cultivars, near isogenic lines and wheat mapping populations, showed thatAvrStb9interacts withStb9resistance gene, triggering an immune response.AvrStb9encodes an unusually large avirulence gene with a predicted secretion signal and a protease domain. It belongs to a S41 protease family conserved across different filamentous fungi in the Ascomycota class and may constitute a core effector.AvrStb9is also conserved among a globalZ. triticipopulation and carries multiple amino acid substitutions caused by strong positive diversifying selection. These results demonstrate the contribution of an ‘atypical’ conserved effector protein to fungal avirulence and the role of sequence diversification in the escape of host recognition, adding to our understanding of host-pathogen interactions and the evolutionary processes underlying pathogen adaptation.Author SummaryFungal avirulence (Avr) genes are involved in gene-for-gene relationships with host resistance genes.Avrgenes may at the same time target host defenses to allow infection and be recognized by a host resistance gene triggering a defense response. The fungusZymoseptoria triticicauses Septoria tritici blotch, a major disease of wheat worldwide.Z. triticipopulations rapidly adapt to selection pressures such as host resistance, leading to resistance breakdown. We report the identification of the avirulence geneAvrStb9based on genetic mapping, sequence polymorphisms and allele swapping.AvrStb9is involved in the interaction withStb9resistance gene following the gene-for-gene model, and its recognition hinders disease symptoms in hosts carrying the corresponding resistance gene. Unlike other knownZ. tritici Avreffectors,AvrStb9encodes for an unusually large Avr protein with a predicted protease S41 domain conserved among diverse ascomycete lineages. We also highlight several gene mutations likely involved in escapingStb9-mediated recognition.

Myo-inositol (MI) is incorporated into numerous biomolecules, including phosphoinositides and inositol phosphates. Disturbance of inositol availability or metabolism is associated with various disorders, including neurological conditions and cancers, while supplemental MI has therapeutic potential in conditions such as depression, polycystic ovary syndrome and congenital anomalies. Inositol status may be influenced by diet, synthesis, transport, utilisation and catabolism.We aimed to investigate potential genetic regulation of circulating MI status and to evaluate correlation of MI concentration with other metabolites.Gas chromatography mass spectrometry was used to determine plasma MI concentration of more than 2,000 healthy, young adults (aged 18-28 years) from the Trinity Student Study. Genotyping data was used to test association of plasma MI with SNPs in candidate genes, encoding inositol transporters and synthesising enzymes, and test for genome-wide association. We evaluated potential correlation of plasma MI with D-chiro inositol, glucose and other metabolites by Spearman's rank correlation.Mean plasma MI showed a small but significant difference between males and females (28.5 and 26.9 µM, respectively). Candidate gene analysis revealed several nominally significant associations with plasma MI, most notably for SLC5A11, encoding a sodium-coupled inositol transporter, also known as SMIT2 (sodium-dependent myo-inositol transporter 2). However, these did not survive correction for multiple testing. Subsequent testing for genome-wide association with plasma MI did not identify associations of genome-wide significance (p 5 × 10-8). However, 8 SNPs exceeded the threshold for suggestive significant association with plasma MI concentration (p 1 × 10-5), 3 of which were located within or close to genes: MTDH, LAPTM4B and ZP2. We found significant positive correlation of plasma MI concentration with concentration of D-chiro-inositol and several other biochemicals including glucose, methionine, betaine, sarcosine and tryptophan.Our findings suggest potential for modulation of plasma MI in young adults by variation in SLC5A11 which is worthy of further investigation.

Senescence is a complex trait under genetic and environmental control, in which resources are remobilized from vegetative tissue into grain. Delayed senescence, or ‘staygreen’ traits, can confer stress tolerance, with extended photosynthetic activity hypothetically sustaining grain filling. The genetics of senescence regulation are largely unknown, with senescence variation often correlated with phenological traits. Here, we confirm staygreen phenotypes of two Triticum aestivum cv. Paragon ethyl methane sulfonate mutants previously identified during a forward genetic screen and selected for their agronomic performance, similar phenology, and differential senescence phenotypes. Grain filling experiments confirmed a positive relationship between onset of senescence and grain fill duration, reporting an associated ~14% increase in final dry grain weight for one mutant (P, Two staygreen mutants were identified for which grain fill duration and grain weight were enhanced. Independent amino acid substitutions within NAC subdomain IV of NAM-1 homoeologues are proposed as causative.

Background: Globally, there is growing concern regarding the impact of pharmaceutical pollution on aquatic wildlife. In recent years, a primary research focus has been if, and how, exposure to pharmaceuticals alters animal behaviour—a key determinant of animal reproduction and survival. Scientists, environmental managers, and policy-makers alike, are increasingly interested in using behavioural endpoints in chemical regulation. With pharmaceutical pollution recognized as an emerging environmental concern, and an international spotlight placed on their management, synthesizing the data currently available is an incredibly timely and necessary step. Objectives: The objective of this systematic map is to identify, catalogue, and synthesize all studies on the effects of human and veterinary pharmaceuticals on aquatic wildlife behaviour, with a particular focus on pharmaceuticals that are psychoactive, psychiatric or behaviour-modifying. Search and criteria: The literature search will be conducted using electronic databases (e.g., Web of Science, Scopus). The search string has been developed using a “PECO” framework, to capture eligible studies that used an aquatic organism (P, population), to test the impacts of a pharmaceutical (E, exposure) on behaviour (O, outcome). Eligible studies must also have a control group (C, comparison). Studies will be screened in two stages, title and abstract screening, followed by full-text screening and data extraction. Decision trees have been designed a priori to appraise studies for inclusion at both stages of screening. Both stages will be completed by two independent reviewers. A minimum of one reviewer inclusion is needed for title-abstract screening, and two reviewers must agree on the inclusion/exclusion criteria for full-texting screening. Synthesis: The information extracted from the included studies, as well as their bibliometric data, will be mapped, synthesized, and analysed. The results will be published open-access, and all data associated with the study will be publicly available through an open online database.

Neuroendocrine liver metastases (LM-NEN) develop in a considerable proportion of patients with gastroenteropancreatic neuroendocrine neoplasms. There is a paucity of experimental models that accurately recapitulate this complex metastatic human liver microenvironment precluding scientific and clinical advancements. Here, we describe the development of a novel personalised immunocompetent precision cut tumour slice (PCTS) model for LM-NEN using resected human liver tissue. The histological assessment throughout the culture demonstrated that slices maintain viability for at least 7 days and retain the cellular heterogeneity of the original tumour. Essential clinical features, such as patient-specific histoarchitecture, tumour grade, neuroendocrine differentiation and metabolic capacity, are preserved in the slices. The PCTS also replicate the tumor-specific immunological profile as shown by the innate and adaptive immunity markers analysis. Furthermore, the study of soluble immune checkpoint receptors in the culture supernatants proves that these immunomodulators are actively produced by LM-NEN and suggests that this process is epithelium-dependent. This model can be employed to investigate these pathways and provides a powerful platform for mechanistic, immunological and pre-clinical studies.

Background The molecular drivers of early sporadic Parkinson’s disease (PD) remain unclear, and the presence of widespread end stage pathology in late disease masks the distinction between primary or causal disease-specific events and late secondary consequences in stressed or dying cells. However, early and mid-stage Parkinson’s brains (Braak stages 3 and 4) exhibit alpha-synuclein inclusions and neuronal loss along a regional gradient of severity, from unaffected-mild-moderate-severe. Here, we exploited this spatial pathological gradient to investigate the molecular drivers of sporadic PD. Methods We combined high precision tissue sampling with unbiased large-scale profiling of protein expression across 9 brain regions in Braak stage 3 and 4 PD brains, and controls, and verified these results using targeted proteomic and functional analyses. Results We demonstrate that the spatio-temporal pathology gradient in early-mid PD brains is mirrored by a biochemical gradient of a changing proteome. Importantly, we identify two key events that occur early in the disease, prior to the occurrence of alpha-synuclein inclusions and neuronal loss: (i) a metabolic switch in the utilisation of energy substrates and energy production in the brain, and (ii) perturbation of the mitochondrial redox state. These changes may contribute to the regional vulnerability of developing alpha-synuclein pathology. Later in the disease, mitochondrial function is affected more severely, whilst mitochondrial metabolism, fatty acid oxidation, and mitochondrial respiration are affected across all brain regions. Conclusions Our study provides an in-depth regional profile of the proteome at different stages of PD, and highlights that mitochondrial dysfunction is detectable prior to neuronal loss, and alpha-synuclein fibril deposition, suggesting that mitochondrial dysfunction is one of the key drivers of early disease.

Nation’s Businesswas a monthly business magazine published by the U.S. Chamber of Commerce, with a subscription list larger thanBusiness Week,Forbes, orFortune. This study explores how the magazine responded and adapted to the rise of environmentalism, and environmental regulation of business, by exploring its treatment of four topics: DDT, environmentalists, government regulation, and renewable energy. It is built on a full-text review of all issues ofNation’s Businesspublished between 1945 and 1981. It reveals the development of a variety of anti-environmental logics and discourses, including the delegitimization of environmentalism as emotional and irrational, the undermining of scientific conclusions as uncertain, the monetization of decision-making using cost-benefit analysis, and the problematization of government overregulation. The study thus traces the origins of the anti-environmental policies of the Reagan Administration to the business community of the preceding decade.

BACKGROUND Palliative care and advance care planning are important components of diabetes and other chronic disease management plans. Most people with diabetes do not have conversations about palliative/end of life (EOL) care or advance care directives; often because diabetes clinicians are reluctant to discuss these issues. Guidelines for conversations and decision aids can assist shared decision-making for both clinicians and patients. The aim was to co-design information with older people with diabetes, families and clinicians to facilitate conversations about palliative and EOL care and to identify the language (words) people with diabetes, families and diabetes clinicians use to discuss death and dying. METHODS We co-designed and tailored the information with advisory groups: (I) older people with diabetes/families, (II) interdisciplinary expert clinicians and undertook a scoping literature review to identify relevant content. The penultimate versions were independently evaluated in focus groups and via written feedback from representative stakeholder clinicians, people with diabetes and international experts in communication, palliative care and diabetes. RESULTS The information met design and language criteria: 62 people participated in focus groups (48 clinicians, 14 older people with diabetes and 4 family members). There were important differences between people with diabetes and diabetes clinicians concerning the words used to refer to death: 'the language of death'. Diabetes clinicians choose soft words/euphemisms such as 'passed away' and 'gone' and indicated they mirrored patient language. People with diabetes preferred clear language and indicated euphemisms were confusing and misleading. Diabetes clinicians, rarely encountered death in their practice and indicated they lacked education about how to discuss diabetes EOL care. CONCLUSIONS Co-design with key end-users improved relevance to these groups. Diabetes clinicians prefer to use euphemisms for death and would benefit from education and strategies to help them initiate conversations about EOL diabetes care.

Objective: Examine values, preferences and goals elicited by doctors following goals-of-care (GOC) discussions with critically ill patients who had life-limiting illnesses. Design: Descriptive qualitative study using four-stage latent content analysis. Setting: Tertiary intensive care unit (ICU) in South Western Victoria. Participants: Adults who had life-limiting illnesses and were admitted to the ICU with documented GOC, between October 2016 and July 2018. Intervention: The iValidate program, a shared decision-making clinical communication education and clinical support program, for all ICU registrars in August 2015. Main outcome measures: Matrix of themes and subthemes categorised into values, preferences and goals. Results: A total of 354 GOC forms were analysed from 218 patients who had life-limiting illnesses and were admitted to the ICU. In the categories of values, preferences and goals, four themes were identified: connectedness and relational autonomy, autonomy of decision maker, balancing quality and quantity of life, and physical comfort. The subthemes — relationships, sense of place, enjoyment of activities, independence, dignity, cognitive function, quality of life, longevity and physical comfort — provided a matrix of issues identified as important to patients. Relationship, place, independence and physical comfort statements were most frequently identified; longevity was least frequently identified. Conclusion: Our analysis of GOC discussions between medical staff and patients who had life-limiting illnesses and were admitted to the ICU, using a shared decision-making training and support program, revealed a framework of values, preferences and goals that could provide a structure to assist clinicians to engage in shared decision making.

Zymoseptoria tritici is the fungal pathogen responsible for Septoria tritici blotch on wheat. Disease outcome in this pathosystem is partly determined by isolate-specific resistance, where wheat resistance genes recognize specific fungal factors triggering an immune response. Despite the large number of known wheat resistance genes, fungal molecular determinants involved in such cultivar-specific resistance remain largely unknown. We identified the avirulence factor AvrStb9 using association mapping and functional validation approaches. Pathotyping AvrStb9 transgenic strains on Stb9 cultivars, near isogenic lines and wheat mapping populations, showed that AvrStb9 interacts with Stb9 resistance gene, triggering an immune response. AvrStb9 encodes an unusually large avirulence gene with a predicted secretion signal and a protease domain. It belongs to a S41 protease family conserved across different filamentous fungi in the Ascomycota class and may constitute a core effector. AvrStb9 is also conserved among a global Z. tritici population and carries multiple amino acid substitutions caused by strong positive diversifying selection. These results demonstrate the contribution of an ‘atypical’ conserved effector protein to fungal avirulence and the role of sequence diversification in the escape of host recognition, adding to our understanding of host-pathogen interactions and the evolutionary processes underlying pathogen adaptation.

Background: Home-based cancer care offers new ways of delivering supportive therapies, including post-chemotherapy hydration, traditionally delivered in hospital settings. Understanding how programs are developed and how parents perceive managing care at home offers opportunities to improve services and experiences. Aim: To describe the implementation process and evaluation of a home intravenous hydration program for children with cancer and thus to provide practical information for future initiatives. Methods: Data were prospectively collected on clinical impact, safety indicators, and estimated costs; these were tabulated and analysed. Semi-structured interviews were undertaken with a subset of parents regarding their experience and analysed using content analysis. Results: Over 34 months, 21 children were eligible, and 16 parents were educated and assessed competent with providing home care. All 16 children received home hydration with a median of 5.5 days per child (IQR 6.65 days). This avoided 116 hospital bed-days and associated costs, at an estimated total value of USD $ 105,521, on average saving USD $ 910 per day and USD $ 6,596 per child. There were no adverse events reported, and no child required re-admission to hospital while receiving home hydration. Parents were overwhelmingly positive in their feedback about the program. Verbatim quotes were synthesized under one overarching theme—supporting normality promotes recovery. Conclusion: When adequately trained and well supported, parents highly value providing home-based care to their children. This offers opportunities to improve experiences and outcomes for children and families as well as reduce costs to health services, achieving clinical impact without reducing safety.

Wnt signaling pathway mutations leading to constitutive activation of the driver oncogene β-catenin occur in at least 20% of all human cancers, but β-catenin itself has remained undruggable by traditional modalities. In order to inhibit the activity of β-catenin, we have developed conformationally hyperstabilized α-helical peptides (Helicons) that are cellularly permeable and bind directly to β-catenin in order to block its interaction with TCF family of transcription factors. Starting with a helical peptide derived from phage display, a combination of structural biology insights and medicinal chemistry optimization improved β-catenin binding of lead peptides to picomolar affinity. Cellular permeability was achieved by modification of physical properties as well as cyclization strategies to enforce helicity and manage backbone amide bonds. Helicons show excellent pharmacokinetic profiles suitable for intermittent dosing. β-catenin targeting helicons demonstrate on-target activity and potent inhibition of Wnt-driven tumor growth in vivo. Citation Format: Brian H. White, Yaguang Si, Sarah Cappucci, Zhi Li, Jessica D. Ramirez, Charles M. Ponthier, Erica Visness, Peicheng Du, Minjung Choi, Pieter C. Beerepoot, Paula C. Ortet, Ivan T. Jewett, Josue Alfaro-Lopez, Sorabh Agarwal, Daniel La, Aaron Fulgham, John H. McGee, Keith Orford, Jonathan B. Hurov, Martin R. Tremblay, Gregory L. Verdine. Discovery of a HeliconTM peptide inhibitor of the beta-catenin-TCF interaction with in vivo activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3094.

Genetic and epigenetic alterations in the Wnt signaling pathway leading to constitutive activation of the driver oncogene Β-catenin occur in at least 20% of all human cancers. We have developed conformationally hyperstabilized α-helical peptides (Helicons) that bind directly to Β-catenin with picomolar affinity and block its interaction with TCF transcription factors. We describe here the characterization of anti-tumor efficacy, pharmacodynamic biomarkers and mechanism of action using multiple in vivo patient-derived xenograft (PDX) models treated with Helicons. Helicon treatment leads to dose-dependent anti-tumor effects and durable regressions in PDX models from multiple indications with Wnt pathway activating mutations. Anti-tumor responses are seen in the presence of additional driver mutations, including KRAS and PIK3CA. RNA-sequencing and Gene Set Enrichment Analysis confirm Helicon treatment inhibits both Wnt/Β-catenin and MYC-regulated gene sets. Inhibiting Β-catenin-TCF interaction with Helicons represents a first-in-class therapeutic approach for the treatment of cancers resulting from aberrant transcriptional signaling via Β-catenin. Citation Format: YaGuang Si, Minjung Choi, Xinwei Han, Brian White, Ziyang Wu, Erica Visness, Pieter Beerepoot, Elizabeth Jaensch, Jessica Ramirez, Charles Ponthier, Xiaogang Han, Paula Ortet, Peicheng Du, Sorabh Agarwal, Mirek Lech, Aaron Fulgham, Sarah Cappucci, Zhi Li, John McGee, Lihua Yu, Martin Tremblay, Keith Orford, Gregory Verdine, Jonathan Hurov. Anti-tumor activity of Helicon inhibitors of Β-catenin-TCF interaction in patient-derived xenograft models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4972.

Remote ischaemic conditioning (RIC) has been shown to reduce ischaemia-reperfusion injury(IRI) in multiple organ systems. IRI is seen in multiple bowel pathologies in the newborn, including NEC. We investigated the potential of RIC as a novel therapy for various intestinal pathologies in the newborn.We used an established intestinal IRI model in rat pups which results in similar intestinal injury to necrotising enterocolitis (NEC). Animals were randomly allocated to IRI only(n = 14), IRI + RIC(n = 13) or sham laparotomy(n = 10). The macroscopic extent of intestinal injury is reported as a percentage of total small bowel. Injury severity was measured using Chiu-Park scoring. Neutrophil infiltration/activation was assayed by myeloperoxidase activity. Immunohistochemistry was used to assess the expression of hypoxia-inducible factor alpha (HIF-1α). Data are median (interquartile range).Animals that underwent RIC showed a decreased extent of macroscopic injury from 100%(85-100%) in the IRI only group to 58%(15-84%, p = 0.003) in the IRI + RIC group. Microscopic injury score was significantly lower in animals that underwent RIC compared to IRI alone (3.5[1.25-5] vs 5.5[4-6], p = 0.014). Intestinal myeloperoxidase activity in animals exposed to IRI was 3.4 mU/mg of tissue (2.5-3.7) and 2.1 mU/mg(1.5-2.8) in the IRI + RIC group(p = 0.047). HIF-1α expression showed a non-significant trend towards reduced expression in the IRI + RIC group.RIC reduces the extent and severity of bowel injury in this animal model, supporting the hypothesis that RIC has therapeutic potential for intestinal diseases in the newborn.