Yasushi Ishihama
Sep 1, 2005; 4:1265-1272
Research

M el-Saadani
Apr 1, 1989; 30:627-630
Articles

Otto Overkamp
Trans. Amer. Math. Soc. 377 (), 5863-5903.
Abstract, references and article information

Lasse L. Wolf and Hong-Wei Zhang
Proc. Amer. Math. Soc. 152 (), 5445-5453.
Abstract, references and article information

Giovanni Catino and Alberto Roncoroni
Proc. Amer. Math. Soc. 152 (), 5339-5354.
Abstract, references and article information

Xiaoshang Jin
Proc. Amer. Math. Soc. 152 (), 5327-5337.
Abstract, references and article information

A father who pleaded guilty to sexually molesting his 13-year-old daughter was sentenced to several years of imprisonment in the St Catherine Circuit Court on Tuesday.

Heme oxygenase-2 (HO2) and -1 (HO1) catalyze heme degradation to biliverdin, CO, and iron, forming an essential link in the heme metabolism network. Tight regulation of the cellular levels and catalytic activities of HO1 and HO2 is important for maintaining heme homeostasis. HO1 expression is transcriptionally regulated; however, HO2 expression is constitutive. How the cellular levels and activity of HO2 are regulated remains unclear. Here, we elucidate the mechanism of post-translational regulation of cellular HO2 levels by heme. We find that, under heme-deficient conditions, HO2 is destabilized and targeted for degradation, suggesting that heme plays a direct role in HO2 regulation. HO2 has three heme binding sites: one at its catalytic site and the others at its two heme regulatory motifs (HRMs). We report that, in contrast to other HRM-containing proteins, the cellular protein level and degradation rate of HO2 are independent of heme binding to the HRMs. Rather, under heme deficiency, loss of heme binding to the catalytic site destabilizes HO2. Consistently, an HO2 catalytic site variant that is unable to bind heme exhibits a constant low protein level and an enhanced protein degradation rate compared with the WT HO2. Finally, HO2 is degraded by the lysosome through chaperone-mediated autophagy, distinct from other HRM-containing proteins and HO1, which are degraded by the proteasome. These results reveal a novel aspect of HO2 regulation and deepen our understanding of HO2's role in maintaining heme homeostasis, paving the way for future investigation into HO2's pathophysiological role in heme deficiency response.

Intrinsically disordered protein domains often have multiple binding partners. It is plausible that the strength of pairing with specific partners evolves from an initial low affinity to a higher affinity. However, little is known about the molecular changes in the binding mechanism that would facilitate such a transition. We previously showed that the interaction between two intrinsically disordered domains, NCBD and CID, likely emerged in an ancestral deuterostome organism as a low-affinity interaction that subsequently evolved into a higher-affinity interaction before the radiation of modern vertebrate groups. Here we map native contacts in the transition states of the low-affinity ancestral and high-affinity human NCBD/CID interactions. We show that the coupled binding and folding mechanism is overall similar but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex and more heterogeneous transient interactions, including electrostatic pairings, and an increased disorder for the human complex. Adaptation to new binding partners may be facilitated by this ability to exploit multiple alternative transient interactions while retaining the overall binding and folding pathway.

Chorismate mutase (CM), an essential enzyme at the branch-point of the shikimate pathway, is required for the biosynthesis of phenylalanine and tyrosine in bacteria, archaea, plants, and fungi. MtCM, the CM from Mycobacterium tuberculosis, has less than 1% of the catalytic efficiency of a typical natural CM and requires complex formation with 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase for high activity. To explore the full potential of MtCM for catalyzing its native reaction, we applied diverse iterative cycles of mutagenesis and selection, thereby raising kcat/Km 270-fold to 5 × 105 m−1s−1, which is even higher than for the complex. Moreover, the evolutionarily optimized autonomous MtCM, which had 11 of its 90 amino acids exchanged, was stabilized compared with its progenitor, as indicated by a 9 °C increase in melting temperature. The 1.5 Å crystal structure of the top-evolved MtCM variant reveals the molecular underpinnings of this activity boost. Some acquired residues (e.g. Pro52 and Asp55) are conserved in naturally efficient CMs, but most of them lie beyond the active site. Our evolutionary trajectories reached a plateau at the level of the best natural enzymes, suggesting that we have exhausted the potential of MtCM. Taken together, these findings show that the scaffold of MtCM, which naturally evolved for mediocrity to enable inter-enzyme allosteric regulation of the shikimate pathway, is inherently capable of high activity.

15 July 2020

21 August 2020

Viral infection is one environmental factor that may contribute to the initiation of pancreatic β-cell destruction during the development of autoimmune diabetes. Picornaviruses, such as encephalomyocarditis virus (EMCV), induce a pro-inflammatory response in islets leading to local production of cytokines, such as IL-1, by resident islet leukocytes. Furthermore, IL-1 is known to stimulate β-cell expression of iNOS and production of the free radical nitric oxide. The purpose of this study was to determine whether nitric oxide contributes to the β-cell response to viral infection. We show that nitric oxide protects β-cells against virally mediated lysis by limiting EMCV replication. This protection requires low micromolar, or iNOS-derived, levels of nitric oxide. At these concentrations nitric oxide inhibits the Krebs enzyme aconitase and complex IV of the electron transport chain. Like nitric oxide, pharmacological inhibition of mitochondrial oxidative metabolism attenuates EMCV-mediated β-cell lysis by inhibiting viral replication. These findings provide novel evidence that cytokine signaling in β-cells functions to limit viral replication and subsequent β-cell lysis by attenuating mitochondrial oxidative metabolism in a nitric oxide–dependent manner.

Juntuo Zhou
Nov 30, 2020; 0:RA120.002384v1-mcp.RA120.002384
Research

Matthias Schittmayer
Dec 1, 2020; 19:2104-2114
Research

Philipp Emanuel Geyer
Dec 17, 2020; 0:RA120.002359v1-mcp.RA120.002359
Research

Protein quality control is maintained by a number of integrated cellular pathways that monitor the folding and functionality of the cellular proteome. Defects in these pathways lead to the accumulation of misfolded or faulty proteins that may become insoluble and aggregate over time. Protein aggregates significantly contribute to the development of a number of human diseases such as amyotrophic lateral sclerosis, Huntington's disease, and Alzheimer's disease. In vitro, imaging-based, cellular studies have defined key biomolecular components that recognize and clear aggregates; however, no unifying method is available to quantify cellular aggregates, limiting our ability to reproducibly and accurately quantify these structures. Here we describe an ImageJ macro called AggreCount to identify and measure protein aggregates in cells. AggreCount is designed to be intuitive, easy to use, and customizable for different types of aggregates observed in cells. Minimal experience in coding is required to utilize the script. Based on a user-defined image, AggreCount will report a number of metrics: (i) total number of cellular aggregates, (ii) percentage of cells with aggregates, (iii) aggregates per cell, (iv) area of aggregates, and (v) localization of aggregates (cytosol, perinuclear, or nuclear). A data table of aggregate information on a per cell basis, as well as a summary table, is provided for further data analysis. We demonstrate the versatility of AggreCount by analyzing a number of different cellular aggregates including aggresomes, stress granules, and inclusion bodies caused by huntingtin polyglutamine expansion.

AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism that phosphorylates a wide range of proteins to maintain cellular homeostasis. AMPK consists of three subunits: α, β, and γ. AMPKα and β are encoded by two genes, the γ subunit by three genes, all of which are expressed in a tissue-specific manner. It is not fully understood, whether individual isoforms have different functions. Using RNA-Seq technology, we provide evidence that the loss of AMPKβ1 and AMPKβ2 lead to different gene expression profiles in human induced pluripotent stem cells (hiPSCs), indicating isoform-specific function. The knockout of AMPKβ2 was associated with a higher number of differentially regulated genes than the deletion of AMPKβ1, suggesting that AMPKβ2 has a more comprehensive impact on the transcriptome. Bioinformatics analysis identified cell differentiation as one biological function being specifically associated with AMPKβ2. Correspondingly, the two isoforms differentially affected lineage decision toward a cardiac cell fate. Although the lack of PRKAB1 impacted differentiation into cardiomyocytes only at late stages of cardiac maturation, the availability of PRKAB2 was indispensable for mesoderm specification as shown by gene expression analysis and histochemical staining for cardiac lineage markers such as cTnT, GATA4, and NKX2.5. Ultimately, the lack of AMPKβ1 impairs, whereas deficiency of AMPKβ2 abrogates differentiation into cardiomyocytes. Finally, we demonstrate that AMPK affects cellular physiology by engaging in the regulation of hiPSC transcription in an isoform-specific manner, providing the basis for further investigations elucidating the role of dedicated AMPK subunits in the modulation of gene expression.

Stephanie E. Hood
Dec 1, 2020; 61:1720-1732
Research Articles

Lipins are eukaryotic proteins with functions in lipid synthesis and the homeostatic control of energy balance. They execute these functions by acting as phosphatidate phosphatase enzymes in the cytoplasm and by changing gene expression after translocation into the cell nucleus, in particular under fasting conditions. Here, we asked whether nuclear translocation and the enzymatic activity of Drosophila Lipin serve essential functions and how gene expression changes, under both fed and fasting conditions, when nuclear translocation is impaired. To address these questions, we created a Lipin null mutant, a mutant expressing Lipin lacking a nuclear localization signal (Lipin^NLS), and a mutant expressing enzymatically dead Lipin. Our data support the conclusion that the enzymatic but not nuclear gene regulatory activity of Lipin is essential for survival. Notably, adult Lipin^NLS flies were not only viable but also exhibited improved life expectancy. In contrast, they were highly susceptible to starvation. Both the improved life expectancy in the fed state and the decreased survival in the fasting state correlated with changes in metabolic gene expression. Moreover, increased life expectancy of fed flies was associated with a decreased metabolic rate. Interestingly, in addition to metabolic genes, genes involved in feeding behavior and the immune response were misregulated in Lipin^NLS flies. Altogether, our data suggest that the nuclear activity of Lipin influences the genomic response to nutrient availability with effects on life expectancy and starvation resistance. Thus, nutritional or therapeutic approaches that aim at lowering nuclear translocation of lipins in humans may be worth exploring.

The assembly of the postsynaptic transmitter sensing machinery at inhibitory nerve cell synapses requires the intimate interplay between cell adhesion proteins, scaffold and adaptor proteins, and γ-aminobutyric acid (GABA) or glycine receptors. We developed an in vitro membrane system to reconstitute this process, to identify the essential protein components, and to define their mechanism of action, with a specific focus on the mechanism by which the cytosolic C terminus of the synaptic cell adhesion protein Neuroligin-2 alters the conformation of the adaptor protein Collybistin-2 and thereby controls Collybistin-2-interactions with phosphoinositides (PtdInsPs) in the plasma membrane. Supported hybrid membranes doped with different PtdInsPs and 1,2-dioleoyl-sn-glycero-3-{[N-(5-amino-1-carboxypentyl)iminodiacetic acid]succinyl} nickel salt (DGS-NTA(Ni)) to allow for the specific adsorption of the His6-tagged intracellular domain of Neuroligin-2 (His-cytNL2) were prepared on hydrophobically functionalized silicon dioxide substrates via vesicle spreading. Two different collybistin variants, the WT protein (CB2SH3) and a mutant that adopts an intrinsically 'open' and activated conformation (CB2SH3/W24A-E262A), were bound to supported membranes in the absence or presence of His-cytNL2. The corresponding binding data, obtained by reflectometric interference spectroscopy, show that the interaction of the C terminus of Neuroligin-2 with Collybistin-2 induces a conformational change in Collybistin-2 that promotes its interaction with distinct membrane PtdInsPs.

Tandem mass tag (TMT) is a multiplexing technology widely-used in proteomic research. It enables relative quantification of proteins from multiple biological samples in a single MS run with high efficiency and high throughput. However, experiments often require more biological replicates or conditions than can be accommodated by a single run, and involve multiple TMT mixtures and multiple runs. Such larger-scale experiments combine sources of biological and technical variation in patterns that are complex, unique to TMT-based workflows, and challenging for the downstream statistical analysis. These patterns cannot be adequately characterized by statistical methods designed for other technologies, such as label-free proteomics or transcriptomics. This manuscript proposes a general statistical approach for relative protein quantification in MS- based experiments with TMT labeling. It is applicable to experiments with multiple conditions, multiple biological replicate runs and multiple technical replicate runs, and unbalanced designs. It is based on a flexible family of linear mixed-effects models that handle complex patterns of technical artifacts and missing values. The approach is implemented in MSstatsTMT, a freely available open-source R/Bioconductor package compatible with data processing tools such as Proteome Discoverer, MaxQuant, OpenMS, and SpectroMine. Evaluation on a controlled mixture, simulated datasets, and three biological investigations with diverse designs demonstrated that MSstatsTMT balanced the sensitivity and the specificity of detecting differentially abundant proteins, in large-scale experiments with multiple biological mixtures.

Natural compounds that can stimulate salivary secretion are of interest in developing treatments for xerostomia, the perception of a dry mouth, that affects between 10 and 30% of the adult and elderly population. Chemesthetic transient receptor potential (TRP) channels are expressed in the surface of the oral mucosa. The TRPV1 agonists capsaicin and piperine have been shown to increase salivary flow when introduced into the oral cavity but the sialogogic properties of other TRP channel agonists have not been investigated. In this study we have determined the influence of different TRP channel agonists on the flow and protein composition of saliva. Mouth rinsing with the TRPV1 agonist nonivamide or menthol, a TRPM8 agonist, increased whole mouth saliva (WMS) flow and total protein secretion compared with unstimulated saliva, the vehicle control mouth rinse or cinnamaldehyde, a TRPA1 agonist. Nonivamide also increased the flow of labial minor gland saliva but parotid saliva flow rate was not increased. The influence of TRP channel agonists on the composition and function of the salivary proteome was investigated using a multi-batch quantitative MS method novel to salivary proteomics. Inter-personal and inter-mouth rinse variation was observed in the secreted proteomes and, using a novel bioinformatics method, inter-day variation was identified with some of the mouth rinses. Significant changes in specific salivary proteins were identified after all mouth rinses. In the case of nonivamide, these changes were attributed to functional shifts in the WMS secreted, primarily the over representation of salivary and nonsalivary cystatins which was confirmed by immunoassay. This study provides new evidence of the impact of TRP channel agonists on the salivary proteome and the stimulation of salivary secretion by a TRPM8 channel agonist, which suggests that TRP channel agonists are potential candidates for developing treatments for sufferers of xerostomia.

Renal Cell Carcinoma (RCC) is one of the most commonly diagnosed cancers worldwide with research efforts dramatically improving understanding of the biology of the disease. To investigate the role of the immune system in treatment-naïve clear cell Renal Cell Carcinoma (ccRCC), we interrogated the immune infiltrate in patient-matched ccRCC tumor samples, benign normal adjacent tissue (NAT) and peripheral blood mononuclear cells (PBMCs isolated from whole blood, focusing our attention on the myeloid cell infiltrate. Using flow cytometric, MS, and ExCYT analysis, we discovered unique myeloid populations in PBMCs across patient samples. Furthermore, normal adjacent tissues and ccRCC tissues contained numerous myeloid populations with a unique signature for both tissues. Enrichment of the immune cell (CD45⁺) fraction and subsequent gene expression analysis revealed a number of myeloid-related genes that were differentially expressed. These data provide evidence, for the first time, of an immunosuppressive and pro-tumorigenic role of myeloid cells in early, clinically localized ccRCC. The identification of a number of immune proteins for therapeutic targeting provides a rationale for investigation into the potential efficacy of earlier intervention with single-agent or combination immunotherapy for ccRCC.

Despite the crucial function of the small intestine in nutrient uptake our understanding of the molecular events underlying the digestive function is still rudimentary. Recent studies demonstrated that enterocytes do not direct the entire dietary triacylglycerol toward immediate chylomicron synthesis. Especially after high-fat challenges, parts of the resynthesized triacylglycerol are packaged into cytosolic lipid droplets for transient storage in the endothelial layer of the small intestine. The reason for this temporary storage of triacylglycerol is not completely understood. To utilize lipids from cytosolic lipid droplets for chylomicron synthesis in the endoplasmic reticulum, stored triacylglycerol has to be hydrolyzed either by cytosolic lipolysis or lipophagy. Interestingly, triacylglycerol storage and chylomicron secretion rates are unevenly distributed along the small intestine, with the proximal jejunum exhibiting the highest intermittent storage capacity. We hypothesize that correlating hydrolytic enzyme activities with the reported distribution of triacylglycerol storage and chylomicron secretion in different sections of the small intestine is a promising strategy to determine key enzymes in triacylglycerol remobilization. We employed a serine hydrolase specific activity-based labeling approach in combination with quantitative proteomics to identify and rank hydrolases based on their relative activity in 11 sections of the small intestine. Moreover, we identified several clusters of enzymes showing similar activity distribution along the small intestine. Merging our activity-based results with substrate specificity and subcellular localization known from previous studies, carboxylesterase 2e and arylacetamide deacetylase emerge as promising candidates for triacylglycerol mobilization from cytosolic lipid droplets in enterocytes.

CD4+ T cell responses are crucial for inducing and maintaining effective anti-cancer immunity, and the identification of human leukocyte antigen class II (HLA-II) cancer-specific epitopes is key to the development of potent cancer immunotherapies. In many tumor types, and especially in glioblastoma (GBM), HLA-II complexes are hardly ever naturally expressed. Hence, little is known about immunogenic HLA-II epitopes in GBM. With stable expression of the class II major histocompatibility complex transactivator (CIITA) coupled to a detailed and sensitive mass spectrometry based immunopeptidomics analysis, we here uncovered a remarkable breadth of the HLA-ligandome in HROG02, HROG17 and RA GBM cell lines. The effect of CIITA expression on the induction of the HLA-II presentation machinery was striking in each of the three cell lines, and it was significantly higher compared to interferon gamma (IFN) treatment. In total, we identified 16,123 unique HLA-I peptides and 32,690 unique HLA-II peptides. In order to genuinely define the identified peptides as true HLA ligands, we carefully characterized their association with the different HLA allotypes. In addition, we identified 138 and 279 HLA-I and HLA-II ligands, respectively, most of which are novel in GBM, derived from known GBM-associated tumor-antigens that have been used as source proteins for a variety of GBM vaccines. Our data further indicate that CIITA-expressing GBM cells acquired an antigen presenting cell-like phenotype as we found that they directly present external proteins as HLA-II ligands. Not only that CIITA-expressing GBM cells are attractive models for antigen discovery endeavors, but also such engineered cells have great therapeutic potential through massive presentation of a diverse antigenic repertoire.

The histopathological subtype of lung adenocarcinoma (LUAD) is closely associated with prognosis. Micropapillary or solid predominant LUAD tends to relapse after surgery at an early stage, whereas lepidic pattern shows a favorable outcome. However, the molecular mechanism underlying this phenomenon remains unknown. Here, we recruited 31 lepidic predominant LUADs (LR: low-risk subtype group) and 28 micropapillary or solid predominant LUADs (HR: high-risk subtype group). Tissues of these cases were obtained and label-free quantitative proteomic and bioinformatic analyses were performed. Additionally, prognostic impact of targeted proteins was validated using The Cancer Genome Atlas databases (n=492) and tissue microarrays composed of early-stage LUADs (n=228). A total of 192 differentially expressed proteins were identified between tumor tissues of LR and HR and three clusters were identified via hierarchical clustering excluding eight proteins. Cluster 1 (65 proteins) showed a sequential decrease in expression from normal tissues to tumor tissues of LR and then to HR and was predominantly enriched in pathways such as tyrosine metabolism and ECM-receptor interaction, and increased matched mRNA expression of 18 proteins from this cluster predicted favorable prognosis. Cluster 2 (70 proteins) demonstrated a sequential increase in expression from normal tissues to tumor tissues of LR and then to HR and was mainly enriched in pathways such as extracellular organization, DNA replication and cell cycle, and high matched mRNA expression of 25 proteins indicated poor prognosis. Cluster 3 (49 proteins) showed high expression only in LR, with high matched mRNA expression of 20 proteins in this cluster indicating favorable prognosis. Furthermore, high expression of ERO1A and FEN1 at protein level predicted poor prognosis in early-stage LUAD, supporting the mRNA results. In conclusion, we discovered key differentially expressed proteins and pathways between low-risk and high-risk subtypes of early-stage LUAD. Some of these proteins could serve as potential biomarkers in prognostic evaluation.

The goal of clinical proteomics is to identify, quantify, and characterize proteins in body fluids or tissue to assist diagnosis, prognosis, and treatment of patients. In this way, it is similar to more mature omics technologies, such as genomics, that are increasingly applied in biomedicine. We argue that, similar to those fields, proteomics also faces ethical issues related to the kinds of information that is inherently obtained through sample measurement, although their acquisition was not the primary purpose. Specifically, we demonstrate the potential to identify individuals both by their characteristic, individual-specific protein levels and by variant peptides reporting on coding single nucleotide polymorphisms. Furthermore, it is in the nature of blood plasma proteomics profiling that it broadly reports on the health status of an individual – beyond the disease under investigation. Finally, we show that private and potentially sensitive information, such as ethnicity and pregnancy status, can increasingly be derived from proteomics data. Although this is potentially valuable not only to the individual, but also for biomedical research, it raises ethical questions similar to the incidental findings obtained through other omics technologies. We here introduce the necessity of - and argue for the desirability for - ethical and human rights-related issues to be discussed within the proteomics community. Those thoughts are more fully developed in our accompanying manuscript. Appreciation and discussion of ethical aspects of proteomic research will allow for deeper, better-informed, more diverse, and, most importantly, wiser guidelines for clinical proteomics.

The origin recognition complex (ORC), composed of six subunits, ORC1–6, binds to origins of replication as a ring-shaped heterohexameric ATPase that is believed to be essential to recruit and load MCM2–7, the minichromosome maintenance protein complex, around DNA and initiate DNA replication. We previously reported the creation of viable cancer cell lines that lacked detectable ORC1 or ORC2 protein without a reduction in the number of origins firing. Here, using CRISPR-Cas9–mediated mutations, we report that human HCT116 colon cancer cells also survive when ORC5 protein expression is abolished via a mutation in the initiator ATG of the ORC5 gene. Even if an internal methionine is used to produce an undetectable, N terminally deleted ORC5, the protein would lack 80% of the AAA+ ATPase domain, including the Walker A motif. The ORC5-depleted cells show normal chromatin binding of MCM2–7 and initiate replication from a similar number of origins as WT cells. In addition, we introduced a second mutation in ORC2 in the ORC5 mutant cells, rendering both ORC5 and ORC2 proteins undetectable in the same cells and destabilizing the ORC1, ORC3, and ORC4 proteins. Yet the double mutant cells grow, recruit MCM2–7 normally to chromatin, and initiate DNA replication with normal number of origins. Thus, in these selected cancer cells, either a crippled ORC lacking ORC2 and ORC5 and present at minimal levels on the chromatin can recruit and load enough MCM2–7 to initiate DNA replication, or human cell lines can sometimes recruit MCM2–7 to origins independent of ORC.

Can Liberation Movements Really Rid Southern Africa of Corruption? Expert comment sysadmin 16 December 2019

Southern Africa’s national liberation movements have survived ‘end of decade’ elections across the region. Combating corruption has been at the heart of many of the campaigns, but the question is can they succeed?

Swapo’s victory in Namibia two weeks ago was the last in a series of recent ‘end of decade’ elections that have returned dominant parties to power across Southern Africa. However, the “enduring appeal of liberation” is wearing thin.

Experiences across the region show that if governments are to deliver on their electoral promises, they must empower institutions, actively promote a culture of accountability and transparency within their party ranks and pursue economic reforms that untangle the web of party-state-business alliances. Such actions are critical for the survival of national liberation movements as the dominant force in the politics of Southern Africa – but will be difficult to implement.

Avoid political factionalism

South Africa, Botswana, Angola and Zimbabwe all saw new presidents take over just before elections. All used the rhetoric of anti-corruption to distance themselves from the tainted image of their predecessors. But acting on this requires a shift in mind-set in parties that have always preferred to deal with their problems behind closed doors. High profile adversaries from past regimes make tempting targets but could also drive party divisions.

In Angola, the transition of power was safeguarded by an agreement that former president José Eduardo dos Santos would be immune from prosecution. But this week his son faced corruption charges before the country’s supreme court, a high-profile example of a wave of anti-corruption cases across Southern Africa, driven by dominant parties wary of their future.

The allegations against José Filemino De Sousa Dos Santos, nickname ‘Zenu’, include a $500-million fraud involving the country’s central bank. Pressure is also mounting on Zenu’s sister Isabel — once prominent in Angola, she is now absent from public life.

Other leaders have had to tread more carefully. Immunity was a luxury Cyril Ramaphosa was neither willing nor politically able to grant Jacob Zuma in South Africa. Reliant on a few close allies at the top of the party, Ramaphosa lacks foot soldiers at the grassroots level, and his campaign against corruption within the ANC has faced persistent opposition.

Rebuilding institutions and empowering authorities takes time, and with few high-profile cases to point to, people are getting restless. This is also the case in Zimbabwe, where a worsening economic situation has left policy reformers politically isolated.

Party, state, and business

Long term incumbency has blurred the distinction between the party and the state. Liberation movements have created vast party-linked business empires. Political allegiance grants access to economic resources through appointments to lucrative positions in state-owned enterprises, preferential bids for tenders and licenses, and direct access to decision makers.

In Angola, this was fuelled by oil revenues. In South Africa, state capture flourished in an environment where the ANC and its constituent elements had significant power on the panels that chose leaders for state-owned enterprises (SOEs). In Namibia, an Icelandic fishing company paid backhanders to officials for fishing rights in what has become known as the ‘Fishrot’ scandal. Zanu-PF officials’ access to preferential foreign exchange rates present them with lucrative opportunities in Zimbabwe.

Ending this bureaucratic rent seeking goes beyond appointing ‘clean’ officials, which has been central to the anti-corruption campaigns in Angola and South Africa. Governments must also allow scrutiny of the state and empower those institutions designed for that role, such as the National Prosecuting Authority and the Public Protector in South Africa. Zimbabwe’s auditor general has published an in-depth report of the state of corruption in the country’s SOEs.

Companies must also be held to account for their role in aiding, and at worst directly benefitting, from state graft. International businesses have actively sought to benefit from corruption. They are now starting to face the consequences. A former Credit Suisse banker has pleaded guilty in the US over handling alleged kickbacks in Mozambique’s $2-billion “tuna bond” scandal. Global banks and consultancies continue to feel the squeeze for their complicity in state capture in South Africa.

Competition and pluralism

National liberation movements may only have a limited window within which to act. Across the region civil society campaigns and investigative journalists have shed light on some of the worst abuses of power. Anti-corruption campaigns are starting to bite. The state will continue to play a central role in Southern African economies, an important arbiter of economic transformation able to balance the region’s highly unequal and resource-dependent economies.

But opposition, civil society and the media are also critical for the progression towards democratic competition and pluralism in Southern Africa. Parliaments remain vital for holding rulers to account. Long used to unchallenged dominance, liberation movements have significant adjustments to make to rise to the challenge of a new era.

This article was originally published in the Mail and Guardian.

Ukraine crisis could trigger cascading risks globally Expert comment NCapeling 16 March 2022

The effects on the wider world from the Ukraine invasion go far beyond the waves of shock and horror being felt from this escalating conflict.

Russia and Ukraine rank 11th and 55th respectively in terms of their national economies but, for the global supply of critical resources such as energy, food, and minerals, these two countries together are far bigger hitters – and both the threat and reality of resource flows from them being reduced have already driven up global prices.

The world is already facing a cost-of-living squeeze coming out of the COVID-19 pandemic, so further price spikes or supply constraints have the potential to seriously undermine food and energy security, equitable access to basic goods and services, and social stability around the world – which can then potentially create systemic risks for economies and societies.

The global implications of the Ukraine conflict are only just beginning to be explored fully but the immediate impacts of the crisis on global markets are already well-documented. In the first few days after Russia’s invasion, energy prices spiked, triggering further fertilizer price rises – as fertilizer production is highly energy intensive – which in turn is contributing to food price rises because fertilizer costs are an important factor in food production.

Interruptions to shipping in the region around Ukraine – as well as globally – have impeded the flow of goods which pushed prices up even further, while economic sanctions on cross-border flows of goods and finance are further adding to market pressures. But this is just the start – these impacts will bring ripple effects which propagate far beyond their point of origin, known as ‘cascading risks’.

Risk is a combination of hazard, exposure, and vulnerability – in terms of the Ukraine invasion, the hazard is the conflict and its immediate impacts on the societies and economies of Ukraine and Russia, while exposure relates to the degree to which other countries are likely to be affected depending on how much they are integrated into the global economy or the ‘just in time’ nature of their supply chains.

Vulnerability relates to a society’s capacity to mitigate the harmful impacts of the conflict, such as controlling borders, sourcing alternative goods from suppliers, or protecting against price or supply shocks.

Risk cascades – the second- and third-order impacts of the original hazard and of responses to that hazard – can interact across sectoral boundaries – as with energy and food, for example – and their compound effect can lead to overall systemic risks for society.

Anticipating this potential is essential to understanding the nature and scale of the global ramifications being felt from the Ukraine conflict. Recent work in the UK to assess levels of cascading risks resulting from a changing climate – the UK Climate Change Risk Assessment – provides a valuable framework for thinking about this area.

It examines key pathways for risk to cascade through global systems – when applied to the situation in Ukraine, these pathways and their interactions offer an indication of the scale of crisis that citizens face far beyond Ukraine’s and Russia’s borders.

Interruptions to the flows of goods and energy

In globalized trade networks, localized disruption to supply chains rapidly yields widespread international impacts – of particular concern is the immediate supply of food because most countries rely on lean supply chains and some may only have a few days food within their own borders.

Experience from previous food price crises indicate even small interruptions to trade can result in runs on the market and rapid price inflation. In the case of this conflict, the trade interruption will be far from small because, between them, Russia and Ukraine export around one-quarter of all traded wheat, more than three-quarters of traded sunflower oil, and one-sixth of traded maize.

Energy markets are also a concern because many countries use more energy than they produce and therefore rely on imports of energy or fuel for domestic use. Russia produces around ten per cent of the world’s commercial energy with a concentration of sales in major regions such as the European Union (EU) and China.

As with food, a shortfall in energy provision leads to market runs and rapid inflation as actors compete in a tightening space, while poorly designed policy interventions by nations trying to ensure their own security add further pressure to global supply and worsen price rises. In addition, the closely interconnected nature of energy markets means disruption to one fuel – such as gas in this case – affects global prices for other forms of energy.

The impact of moving people and money

As the last decade richly illustrates, the cross-border flows of people impact those societies absorbing them – for example, contributing to a rise in nationalism – as well as increase the costs of supplying essential resources. Given many people are understandably fleeing this conflict, other countries may struggle to cope as the cost-of-living crisis and urgent efforts to bolster national security infrastructure may squeeze available public funds.

Financial flows are crucial to the functioning of global economies, whether for inward investment or insurance and – as Russian citizens may be about to discover – restricting the global flow of money has a serious impact on households. Beyond Russia, the outflow of money from major financial centres such as London to meet insurance claims or to enable infrastructure reinvestment post-conflict may also have severe knock-on economic impacts.

The impact on governance and health

The global spikes in energy and food prices resulting from these supply chain disruptions will see many countries struggle with rising food and energy insecurity as well as increased inequality. Taken together these conditions create many issues beyond immigration pressures and the associated politics, including increased inequality and civil unrest.

This potentially destabilizes governments which has consequences for the stability of an entire region such as interrupted supply chains, the need to deploy peacekeeping forces, or significant flows of aid – all with global consequences far beyond the countries in question.

Populations may suffer mental health impacts arising from the Ukraine invasion, whether from the trauma of being forced to leave home to escape conflict, anxiety for the wellbeing and safety of families and friends caught up in it, or a more general anxiety arising from the perception of living in an unstable world.

Neoadjuvant therapy in patients with locally advanced rectal cancer (LARC) has achieved good pathologic complete response (pCR) rates, potentially eliminating the need for surgical intervention. This study investigated preoperative methods for predicting pCR after neoadjuvant short-course radiotherapy (SCRT) combined with immunochemotherapy. Methods: Treatment-naïve patients with histologically confirmed LARC were enrolled from February 2023 to July 2023. Before surgery, the patients received neoadjuvant SCRT followed by 2 cycles of capecitabine and oxaliplatin plus camrelizumab. ⁶⁸Ga-labeled fibroblast activation protein inhibitor ([⁶⁸Ga]Ga-FAPI-04) PET/MRI, [¹⁸F]FDG PET/CT, and contrast-enhanced MRI were performed before treatment initiation and before surgery in each patient. PET and MRI features and the size and number of lesions were also collected from each scan. Each parameter’s sensitivity, specificity, and diagnostic cutoff were derived via receiver-operating-characteristic curve analysis. Results: Twenty eligible patients (13 men, 7 women; mean age, 60.2 y) were enrolled and completed the entire trial, and all patients had proficient mismatch repair or microsatellite-stable LARC. A postoperative pCR was achieved in 9 patients (45.0%). In the visual evaluation, both [⁶⁸Ga]Ga-FAPI-04 PET/MRI and [¹⁸F]FDG PET/CT were limited to forecasting pCR. Contrast-enhanced MRI had a low sensitivity of 55.56% to predict pCR. In the quantitative evaluation, [⁶⁸Ga]Ga-FAPI-04 change in SUL_peak percentage, where SUL_peak is SUV_peak standardized by lean body mass, had the largest area under the curve (0.929) with high specificity (sensitivity, 77.78%; specificity, 100.0%; cutoff, 63.92%). Conclusion: [⁶⁸Ga]Ga-FAPI-04 PET/MRI is a promising imaging modality for predicting pCR after SCRT combined with immunochemotherapy. The SUL_peak decrease exceeding 63.92% may provide valuable guidance in selecting patients who can forgo surgery after neoadjuvant therapy.

Billy Napier will remain in place as head football coach at Florida, despite the Gators producing another lackluster campaign during his third season, athletic director Scott Stricklin announced Thursday.

Mysterious black balls that washed up on Sydney, Australia, beaches were initially suspected to be tar balls but turned out to be miniature "fatbergs" containing human feces.

The Pentagon on Monday ordered all Department of Defense civilian employees to be fully vaccinated against COVID-19 by no later than Nov. 22.

The epidemic of sexually transmitted infections (STIs) in the United States appears to be cooling off after more than two decades, a new Centers for Disease Control and Prevention (CDC) study says.

There’s a myth that it takes 21 days to form a habit. Experts explain why it might take some people longer—or shorter

Amid a mounting mental health crisis among farmers, experts are working to make help more accessible

Actress Megan Fox and musician Machine Gun Kelly are expecting a child together.

The four-member SpaceX Crew-8 aboard Crew Dragon Endeavour returned to Earth early Friday, completing their nearly eight-month mission in space.

Struggling to be kind to yourself? Learn how to direct compassion inwards with these simple techniques.