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This article presents an overview and continuation of a study investigating how artist awareness and critical response might provide a better understanding of mindfulness and its practice within art education. While there are distinct advantages to mindfulness practices in education, these practices might also have problematic aspects, such as helping people conform to oppressive structures in education rather than questioning them. The pandemic of 2020–2021 accentuated student concerns with social, emotional, and mental health and illuminated possible benefits of mindfulness practice. Results show that preservice art education students used mindfulness and data visualization to connect art and self-inquiry. Important findings included the positive impact mindfulness practices had on students’ social–emotional learning and a refined distinction between mindfulness as a therapeutic educational intervention versus mindfulness an art educational experience.

Consider $n$ nodes communicating over an unreliable broadcast channel. Each node has a single packet that needs to be communicated to all other nodes. Time is slotted, and a time slot is long enough for each node to broadcast one packet. Each broadcast reaches a random subset of nodes. The objective is to minimise the time until all nodes have received all packets. We study two schemes, (i) random relaying, and (ii) random linear network coding, and analyse their performance in an asymptotic regime in which $n$ tends to infinity. Simulation results for a wide range of $n$ are also presented.

Sustainability disclosures are frequently included within integrated reports, in order to provide disclosures relating to the capitals identified in the International Framework (the Framework). South Africa has been at the forefront of integrated reporting, following the guidance of King III and subsequently the Framework. This study draws on data previously presented by the authors, and identifies the relationships and correlation between the application of principles from the Framework, such as materiality and conciseness, as well as the total number of sustainability disclosures and the industry classification, age and size of the companies, through the lens of legitimacy theory. The study uses data collected through interpretive content analysis of the integrated reports of South African companies in 2011 and 2015, as well as company metrics, which are analysed using Spearman’s rank correlation and a k-means cluster analysis. The results reveal that companies tend to consistently apply the principles from the Framework, and the size of the company was not consistently correlated. However, the age of the company was correlated to the materiality of disclosures provided. The findings are consistent with legitimacy theory and add to the legitimacy theory literature by identifying the sustainability reporting behaviour displayed by companies of various sizes, ages and industry classifications.

Defining the molecular networks orchestrating human brain formation is crucial for understanding neurodevelopment and neurological disorders. Challenges in acquiring early brain tissue have incentivized the use of three-dimensional human pluripotent stem cell (hPSC)-derived neural organoids to recapitulate neurodevelopment. To elucidate the molecular programs that drive this highly dynamic process, here, we generate a comprehensive trans-omic map of the phosphoproteome, proteome, and transcriptome of the exit of pluripotency and neural differentiation toward human cerebral organoids (hCOs). These data reveal key phospho-signaling events and their convergence on transcriptional factors to regulate hCO formation. Comparative analysis with developing human and mouse embryos demonstrates the fidelity of our hCOs in modeling embryonic brain development. Finally, we demonstrate that biochemical modulation of AKT signaling can control hCO differentiation. Together, our data provide a comprehensive resource to study molecular controls in human embryonic brain development and provide a guide for the future development of hCO differentiation protocols.

Self-reported symptoms during the COVID-19 pandemic have been used to train artificial intelligence models to identify possible infection foci. To date, these models have only considered the culmination or peak of symptoms, which is not suitable for the early detection of infection. We aimed to estimate the probability of an individual being infected with SARS-CoV-2 on the basis of early self-reported symptoms to enable timely self-isolation and urgent testing.

The etiology of diabetic nephropathy in type 2 diabetes is multifactorial. Sustained hyperglycemia is a major contributor, but additional contributions come from the hypertension, obesity, and hyperlipidemia that are also commonly present in patients with type 2 diabetes and nephropathy. The leptin deficient BTBR ob/obmouse is a model of type 2 diabetic nephropathy in which hyperglycemia, obesity, and hyperlipidemia, but not hypertension, are present. We have shown that reversal of the constellation of these metabolic abnormalities with leptin replacement can reverse the morphologic and functional manifestations of diabetic nephropathy. Here we tested the hypothesis that reversal specifically of the hypertriglyceridemia, using an antisense oligonucleotide directed against ApoC-III, an apolipoprotein that regulates the interactions of VLDL (very low density lipoproteins) with the LDL receptor, is sufficient to ameliorate the nephropathy of Type 2 diabetes. Antisense treatment resulted in reduction of circulating ApoC-III protein levels and resulted in substantial lowering of triglycerides to near-normal levels in diabetic mice versus controls. Antisense treatment did not ameliorate proteinuria or pathologic manifestations of diabetic nephropathy, including podocyte loss. These studies indicate that pathologic manifestations of diabetic nephropathy are unlikely to be reduced by lipid-lowering therapeutics alone, but does not preclude a role for such interventions to be used in conjunction with other therapeutics commonly employed in the treatment of diabetes and its complications.

The etiology of diabetic nephropathy in type 2 diabetes is multifactorial. Sustained hyperglycemia is a major contributor, but additional contributions come from the hypertension, obesity, and hyperlipidemia that are also commonly present in patients with type 2 diabetes and nephropathy. The leptin deficient BTBR ob/obmouse is a model of type 2 diabetic nephropathy in which hyperglycemia, obesity, and hyperlipidemia, but not hypertension, are present. We have shown that reversal of the constellation of these metabolic abnormalities with leptin replacement can reverse the morphologic and functional manifestations of diabetic nephropathy. Here we tested the hypothesis that reversal specifically of the hypertriglyceridemia, using an antisense oligonucleotide directed against ApoC-III, an apolipoprotein that regulates the interactions of VLDL (very low density lipoproteins) with the LDL receptor, is sufficient to ameliorate the nephropathy of Type 2 diabetes. Antisense treatment resulted in reduction of circulating ApoC-III protein levels and resulted in substantial lowering of triglycerides to near-normal levels in diabetic mice versus controls. Antisense treatment did not ameliorate proteinuria or pathologic manifestations of diabetic nephropathy, including podocyte loss. These studies indicate that pathologic manifestations of diabetic nephropathy are unlikely to be reduced by lipid-lowering therapeutics alone, but does not preclude a role for such interventions to be used in conjunction with other therapeutics commonly employed in the treatment of diabetes and its complications.

The Fairwork Project is an international action-research project that currently operates in over 20 countries. The project focuses on working conditions in the platform economy, in order to develop ‘fairness ratings’ for digital labour platforms. With respect to Germany, the project evaluated the working conditions offered by ten digital labour platforms, by scoring them against the Fairwork principles and producing a national league table. We found that even in a highly regulated labour market context like the German one, platform workers experience precarity and insecurity and have limited access to employment rights. A number of platform workers are classified as employees rather than self-employed, and this guarantees a number of employment rights, including entitlement to minimum wage, health and safety protection and social protection. However, the existence of an employment relationship does not necessarily ensure platform work to be fair as other factors, including the existence of complex networks of subcontracting, erode labour standards and deprive workers of basic employment rights.

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Reports of long-lasting coronavirus disease 2019 (COVID-19) symptoms, the so-called ‘long COVID’, are rising but little is known about prevalence, risk factors or whether it is possible to predict a protracted course early in the disease. We analyzed data from 4,182 incident cases of COVID-19 in which individuals self-reported their symptoms prospectively in the COVID Symptom Study app1. A total of 558 (13.3%) participants reported symptoms lasting ≥28 days, 189 (4.5%) for ≥8 weeks and 95 (2.3%) for ≥12 weeks. Long COVID was characterized by symptoms of fatigue, headache, dyspnea and anosmia and was more likely with increasing age and body mass index and female sex. Experiencing more than five symptoms during the first week of illness was associated with long COVID (odds ratio = 3.53 (2.76–4.50)). A simple model to distinguish between short COVID and long COVID at 7 days (total sample size, n= 2,149) showed an area under the curve of the receiver operating characteristic curve of 76%, with replication in an independent sample of 2,472 individuals who were positive for severe acute respiratory syndrome coronavirus 2. This model could be used to identify individuals at risk of long COVID for trials of prevention or treatment and to plan education and rehabilitation services.

Figure drawing is a rich and problematic context for exploring drawing conventions with many connections to contemporary art and visual culture. The human figure can inspire students to more fully develop their own artistic practice and to critically engage with contemporary art and visual culture. Representations of the human body in art and visual culture are also relevant to important issues in the lives of students. Figure drawing has a long history associated with technical skills, ideas about mastery and the artist’s training. Skill, knowledge and drawing techniques, when combined with critical conversations about representing the human body, provide rich topics for discussion and reflection. How the human form is dressed, undressed and depicted in art and popular visual culture reflects vital issues about gender, race, identity, beauty, compliance and agency. This paper describes a range of different methods to give the skills associated with drawing the human form context within contemporary issues and to disrupt conventional and uncritical approaches.

Ceralasertib is currently being evaluated in multiple phase I/II clinical trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with a chiral morpholine, a cyclopropyl sulfoximine and an azaindole, makes it a challenging molecule to synthesize on a large scale. Several features of the medicinal chemistry and early development route make it unsuitable for the long-term commercial manufacture of the active pharmaceutical ingredient. We describe the investigation and development of a new and improved route which introduces the cyclopropyl moiety in a novel process from methyl 2,4-dibromobutyrate. Following construction of the pyrimidine ring, large-scale chlorination with phosphoryl chloride was performed with a safe and robust work-up. An SNAr reaction required an innovative work-up to remove the unwanted regio-isomer, and then a Baeyer–Villiger monooxygenase enzyme was used to enable asymmetric sulfur oxidation to a sulfoxide. A safe and scalable metal-free sulfoximine formation was developed, and then optimization of a Suzuki reaction enabled the manufacture of high-quality ceralasertib with excellent control of impurities and an overall yield of 16%.

New route development activities toward ceralasertib (AZD6738) have resulted in the discovery of an efficient, acid additive-free, photoredox Minisci reaction. Mechanistic understanding resulting from LED-NMR reaction profiling, quantum yield measurements, and Stern–Volmer quenching studies have enabled optimization of the catalyst system, resulting in a significant enhancement in the rate of reaction. A large-scale continuous photoflow process has been developed, providing encouraging proof-of-concept data for the future application of this technology in the clinical manufacture of ceralasertib.

With the introduction of integrated reporting, organisations are now encouraged to integrate sustainability disclosures within their integrated reports, in addition to traditional sustainability reporting practices. The purpose of this study is to investigate whether the International < IR > Framework (the Framework) led to a change in how South African listed companies included sustainability disclosures in their integrated reports, looking specifically at the degree of integration of sustainability disclosures, the use of sustainability key performance indicators (KPIs), and the materiality and balance of sustainability disclosures included, which are all based on principles in the Framework. Interpretive content analysis is used to compare the integrated reports in 2011, when integrated reporting became mandatory in South Africa, and 2015, when the Framework was adopted. The results show that there was a significant change in the level of integration and materiality of sustainability disclosures, but there was no significant change in the use of KPIs and the balance of disclosures. This study does not seek to measure the quality of the sustainability disclosures included in the integrated reports beyond the level of the application of Framework principles. This study provides unique insight into how South African companies adapted their sustainability disclosures within their integrated reports in response to the Framework.

BackgroundMental health issues have been reported after SARS-CoV-2 infection. However, comparison to prevalence in uninfected individuals and contribution from common risk factors (eg, obesity and comorbidities) have not been examined. We identified how COVID-19 relates to mental health in the large community-based COVID Symptom Study.MethodsWe assessed anxiety and depression symptoms using two validated questionnaires in 413148 individuals between February and April 2021; 26998 had tested positive for SARS-CoV-2. We adjusted for physical and mental prepandemic comorbidities, body mass index (BMI), age and sex.FindingsOverall, 26.4% of participants met screening criteria for general anxiety and depression. Anxiety and depression were slightly more prevalent in previously SARS-CoV-2-positive (30.4%) vs SARS-CoV-2-negative (26.1%) individuals. This association was small compared with the effect of an unhealthy BMI and the presence of other comorbidities, and not evident in younger participants (≤40 years). Findings were robust to multiple sensitivity analyses. Association between SARS-CoV-2 infection and anxiety and depression was stronger in individuals with recent (<30 days) versus more distant (>120 days) infection, suggesting a short-term effect.InterpretationA small association was identified between SARS-CoV-2 infection and anxiety and depression symptoms. The proportion meeting criteria for self-reported anxiety and depression disorders is only slightly higher than prepandemic.

ObjectivePoor metabolic health and unhealthy lifestyle factors have been associated with risk and severity of COVID-19, but data for diet are lacking. We aimed to investigate the association of diet quality with risk and severity of COVID-19 and its interaction with socioeconomic deprivation.DesignWe used data from 592 571 participants of the smartphone-based COVID-19 Symptom Study. Diet information was collected for the prepandemic period using a short food frequency questionnaire, and diet quality was assessed using a healthful Plant-Based Diet Score, which emphasises healthy plant foods such as fruits or vegetables. Multivariable Cox models were fitted to calculate HRs and 95% CIs for COVID-19 risk and severity defined using a validated symptom-based algorithm or hospitalisation with oxygen support, respectively.ResultsOver 3 886 274 person-months of follow-up, 31 815 COVID-19 cases were documented. Compared with individuals in the lowest quartile of the diet score, high diet quality was associated with lower risk of COVID-19 (HR 0.91; 95% CI 0.88 to 0.94) and severe COVID-19 (HR 0.59; 95% CI 0.47 to 0.74). The joint association of low diet quality and increased deprivation on COVID-19 risk was higher than the sum of the risk associated with each factor alone (Pinteraction=0.005). The corresponding absolute excess rate per 10 000 person/months for lowest vs highest quartile of diet score was 22.5 (95% CI 18.8 to 26.3) among persons living in areas with low deprivation and 40.8 (95% CI 31.7 to 49.8) among persons living in areas with high deprivation.ConclusionsA diet characterised by healthy plant-based foods was associated with lower risk and severity of COVID-19. This association may be particularly evident among individuals living in areas with higher socioeconomic deprivation.

The ride-hailing giant Uber has long circumvented labour regulations and commodified its drivers’ labour by existing at the conjuncture of multiple geographies – being simultaneously embedded and disembedded from the places where it operates. In this commentary, we argue that the COVID-19 pandemic has destabilised Uber’s ‘conjunctural’ existence and forced the company to become more embedded in the locations where it operates, bringing about a – perhaps temporary – turn towards the decommodification of its drivers’ labour.

ABSTRACTPlatforms in the urban environment are fundamentally unaccountable. They present themselves as too big to control, too new to regulate, and too innovative to stifle, and remain un-democratic, and usually distant, organizations with no interest in promoting local voices or investing in local priorities. This paper argues that platforms control urban interactions whilst remaining unaccountable through a strategic deployment of ‘conjunctural geographies’ – a way of being simultaneously embedded and disembedded from the space-times they mediate. These conjunctural geographies, however, render platforms vulnerable. The ephemeral nature of platforms means we can avoid them, circumvent them and replicate them; their material nature suggests points of regulation and resistance. The paper closes by pointing to three broad strategies —regulate, replicate, and resist - which can be deployed to build alternate platform futures. Each of which is built on understanding the simultaneously embedded and disembedded ways in which platforms occupy their conjunctural geographies.

The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC50= 6 nM) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.

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ABSTRACTBusiness process outsourcing (BPO) is seen by the South African government as key to employment generation. BPO operations are reasonably footloose and the industry’s immense focus on workplace control and high levels of attrition means that the development potential of the BPO industry on workers in South Africa is a matter of critical concern. This article uses the global production network (GPN) framework to understand the developmental potentials of contact center jobs for workers in South Africa. The key argument is that economic upgrading among contact center firms can lead to both social upgrading and downgrading among workers.

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During prolonged fasting, the liver plays a central role in maintaining systemic energy homeostasis by producing glucose and ketones in processes fueled by oxidation of fatty acids liberated from adipose tissue. In mice, this is accompanied by transient hepatic accumulation of glycerolipids. We found that the hepatic expression of monoacylglycerol acyltransferase 1 (Mogat1), an enzyme with monoacylglycerol acyltransferase (MGAT) activity that produces diacyl­glycerol from monoacylglycerol, was significantly increased in the liver of fasted mice compared with mice given ad libitum access to food. Basal and fasting-induced expression of Mogat1was markedly diminished in the liver of mice lacking the transcription factor PPARα. Suppressing Mogat1expression in liver and adipose tissue with antisense oligonucleotides (ASOs) reduced hepatic MGAT activity and triglyceride content compared with fasted controls. Surprisingly, the expression of many other PPARα target genes and PPARα activity was also decreased in mice given Mogat1ASOs. When mice treated with control or Mogat1ASOs were gavaged with the PPARα ligand, WY-14643, and then fasted for 18 h, WY-14643 administration reversed the effects of Mogat1ASOs on PPARα target gene expression and liver triglyceride content. In conclusion, Mogat1is a fasting-induced PPARα target gene that may feed forward to regulate liver PPARα activity during food deprivation.

Student teaching is one of the most important and demanding parts of teacher preparation. Student teachers balance many concerns, including classroom management, apathetic students, the demands and expectations of a full-time teacher, how to dress, how to get along with their mentor teacher, and how to meet the expectations of the licensure process that typically includes complex assessments of their teaching practices. These case studies illustrate how student teachers may also need to navigate philosophical differences with their mentoring teacher about art, education and classroom management. These differences also create distinct portraits of conflicts in art education between emerging and traditional pedagogical practices. Creating a productive collaboration between university and school and between the student teachers and their mentors is a challenge that requires careful attention to the existing culture and teaching practices of the mentoring teacher and the emerging methods of the student teacher.

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Diffusion metrics from three models correlated with isocitrate dehydrogenase genotype in grade II and III gliomas. Advanced diffusion models did not add significant diagnostic accuracy. Diffusion-tensor imaging plays a role in the identification of patients who may benefit from more aggressive treatments despite lacking high-grade features at neuropathologic examination.

ABSTRACTThe macroautophagy/autophagy-inducing disaccharide, trehalose, has been proposed to be a promising therapeutic agent against neurodegenerative and cardiometabolic diseases. We recently showed that trehalose attenuates hepatic steatosis in part by blocking hepatocyte glucose transport to induce hepatocyte autophagic flux. However, although every major demonstration of trehalose action invokes activating autophagic flux as its primary function, the mechanism of action of trehalose in whole-body energy metabolism remains poorly defined. Here, we demonstrate that trehalose induces hepatocyte TFEB (transcription factor EB)-dependent thermogenesis in vivo, concomitant with upregulation of hepatic and white adipose expression of UCP1 (uncoupling protein 1 [mitochondrial, protein carrier]). Mechanistically, we provide evidence that hepatocyte fasting transcriptional and metabolic responses depend upon PPARGC1A (peroxisome proliferative activated receptor, gamma, coactivator 1 alpha), TFEB, and FGF21 (fibroblast growth factor 21) signaling. Strikingly, hepatocyte-selective TFEB knockdown abrogated trehalose induction of thermogenesis and white adipose tissue UCP1 upregulation in vivo. In contrast, we found that trehalose action on thermogenesis was independent of LEP (leptin) and the autophagy pathway, as there was robust thermogenic induction in trehalose-treated ob/ob, Becn1, Atg16l1, and Epg5mutant mice. We conclude that trehalose induces metabolically favorable effects on whole-body thermogenesis in part via hepatocyte-centered fasting-like mechanisms that appear to be independent of autophagic flux. Our findings elucidate a novel mechanism by which trehalose acts as a metabolic therapeutic agent by activating hepatic fasting responses. More broadly, the hepatic glucose fasting response may be of clinical utility against overnutrition-driven disease, such as obesity and type 2 diabetes mellitus.