Peripheral neuropathy: An important contributor to physical limitation and morbidity in stages 3 and 4 chronic kidney disease

Background: Impaired physical function drives adverse outcomes in chronic kidney disease (CKD). Peripheral neuropathy is highly prevalent in CKD, though its contribution to physical function in CKD patients is unknown. This study examined the relationships between peripheral neuropathy, walking speed and quality of life (QoL) in stages 3 and 4 CKD. Methods: This was a prospective observational study investigating neuropathy in CKD patients with an estimated glomerular filtration rate (eGFR) 15-60 mL/min/1.73 m2. A total of 109 patients were consecutively recruited. The presence and severity of peripheral neuropathy was determined using the total neuropathy score. Walking speed was assessed at both usual and maximal speed, and QoL was assessed using the Short- Form 36 (SF-36) questionnaire. Results: Peripheral neuropathy was highly prevalent: 40% demonstrated mild neuropathy and 37% had moderate-severe neuropathy. Increasing neuropathy severity was the primary predictor of reduced walking speed (R2 = -0.41, P < 0.001) and remained so after multivariable analysis adjustment for diabetes. This association was evident for both usual and maximal walking speeds. Neuropathy correlated significantly with low scores on multiple domains of SF-36 including physical function (r = -0.570, P < 0.001). Subanalysis according to diabetic status revealed a high prevalence of neuropathy both with and without diabetes; relationships to walking speed remained evident in subgroup analysis. However, those with diabetes demonstrated greater severity of neuropathy, slower walking speed and lower scores in QoL. Conclusions: Moderate to severe peripheral neuropathy was common in stages 3 and 4 CKD, associated with reduced walking speed independent of diabetes status and was correlated with patient-reported QoL. This suggests that neuropathy is an important contributor to declining physical function in CKD irrespective of diabetes status. Targeted diagnosis and management of peripheral neuropathy during CKD progression may improve functional outcomes and QoL

Blood-Based Transcriptomic Biomarkers Are Predictive of Neurodegeneration Rather Than Alzheimer\u27s Disease

Alzheimer\u27s disease (AD) is a growing global health crisis affecting millions and incurring substantial economic costs. However, clinical diagnosis remains challenging, with misdiagnoses and underdiagnoses being prevalent. There is an increased focus on putative, blood-based biomarkers that may be useful for the diagnosis as well as early detection of AD. In the present study, we used an unbiased combination of machine learning and functional network analyses to identify blood gene biomarker candidates in AD. Using supervised machine learning, we also determined whether these candidates were indeed unique to AD or whether they were indicative of other neurodegenerative diseases, such as Parkinson\u27s disease (PD) and amyotrophic lateral sclerosis (ALS). Our analyses showed that genes involved in spliceosome assembly, RNA binding, transcription, protein synthesis, mitoribosomes, and NADH dehydrogenase were the best-performing genes for identifying AD patients relative to cognitively healthy controls. This transcriptomic signature, however, was not unique to AD, and subsequent machine learning showed that this signature could also predict PD and ALS relative to controls without neurodegenerative disease. Combined, our results suggest that mRNA from whole blood can indeed be used to screen for patients with neurodegeneration but may be less effective in diagnosing the specific neurodegenerative disease

Global sustainable city-regions: Stockholm, Berlin, Kolkata, Abu Dhabi/Masdar, Bengaluru, Malawi, Belfast, Hong Kong, Seoul, Helsinki, & Scotland

This policy report, entitled ‘Global Sustainable City-Regions,’ covers the work developed by the lecturer, Dr Igor Calzada, MBA, FeRSA, as the editor of the publica- tion and students of the second edition of the Master course MSc in Leadership for Global Sustainable Cities from September to December 2016. Specifically, this policy report follows a two-sequential-module structure: • The first module, entitled ‘Global Cities: Sustainability and Society,’ consists of six methodological units. • Thereafter, the second module, entitled ‘Public Policy, Governance and Strategic Change in Cities,’ consists of five methodological units. The policy report focuses on three urban global issues in a comparative basis. The MSc was developed in a team-based dynamic by applying qualitative action research methodologies to understand and interpret each case and to benchmark and contrast with other cases that addressed the same global urban issue. The cases were selected jointly by the lecturer and the students in a dynamic process in order to achieve a suitable selection of cases that would allow them to: • arrange groups around one specific global urban issue, • compare cases around the same specific urban issue, and • produce a full case study by applying the two-sequential-module methodology. • Transformative Smart Cities: In recent years, the smart city paradigm has gained traction in urban policy and governance. Underlying the smart city discourse is the techno-utopian belief that the use of information and communication technologies (ICTs) is imperative to confront the challenges of urbanization and sustainable development. Although, little has been researched about the differences between this paradigm and its consequences in the Global South and in the Global North. In addition to this, since the smart city as a buzzword has conquered policy agendas worldwide, a transformational push is occurring in some innovative cities and regions worldwide. This urban issue called ‘Transformative Smart Cities’ is explained comparatively through five cases as follows: Stockholm, Kolkata, Masdar, Bengaluru, and Seoul. • Changing Social Innovation: Urban issues are usually complex and interconnected phenomena. Poverty, political conflicts, environmental awareness, mobility and transport mechanisms, geopolitical path-dependence, ethno-political unrest, digital connectivity and self-determination could be researched from the social innovation changing perspective. The capacity to think across and between as well as within the thematic factors is crucial. Likewise, a clear understanding of the way in which different disciplines can contribute to a step change in delivery against these changing challenges is therefore required. Ultimately, an awareness of the underlying factors and contexts (including social, political, economic, cultural, technological and historial), interdependencies, synergies, tensions and trade-offs that promote, obstruct or even reverse delivery against social innovation, both individually and collectively are key to understand changing dynamics in city-regions. This urban issue called ‘Changing Social Innovation’ is explained comparatively through six cases as follows: Berlin, Belfast, Malawi, Hong Kong, Helsinki, and Glasgow

Global sustainable city-regions: Stockholm, Berlin, Kolkata, Abu Dhabi/Masdar, Bengaluru, Malawi, Belfast, Hong Kong, Seoul, Helsinki, & Scotland

This policy report, entitled ‘Global Sustainable City-Regions,’ covers the work developed by the lecturer, Dr Igor Calzada, MBA, FeRSA, as the editor of the publica- tion and students of the second edition of the Master course MSc in Leadership for Global Sustainable Cities from September to December 2016. Specifically, this policy report follows a two-sequential-module structure: • The first module, entitled ‘Global Cities: Sustainability and Society,’ consists of six methodological units. • Thereafter, the second module, entitled ‘Public Policy, Governance and Strategic Change in Cities,’ consists of five methodological units. The policy report focuses on three urban global issues in a comparative basis. The MSc was developed in a team-based dynamic by applying qualitative action research methodologies to understand and interpret each case and to benchmark and contrast with other cases that addressed the same global urban issue. The cases were selected jointly by the lecturer and the students in a dynamic process in order to achieve a suitable selection of cases that would allow them to: • arrange groups around one specific global urban issue, • compare cases around the same specific urban issue, and • produce a full case study by applying the two-sequential-module methodology. • Transformative Smart Cities: In recent years, the smart city paradigm has gained traction in urban policy and governance. Underlying the smart city discourse is the techno-utopian belief that the use of information and communication technologies (ICTs) is imperative to confront the challenges of urbanization and sustainable development. Although, little has been researched about the differences between this paradigm and its consequences in the Global South and in the Global North. In addition to this, since the smart city as a buzzword has conquered policy agendas worldwide, a transformational push is occurring in some innovative cities and regions worldwide. This urban issue called ‘Transformative Smart Cities’ is explained comparatively through five cases as follows: Stockholm, Kolkata, Masdar, Bengaluru, and Seoul. • Changing Social Innovation: Urban issues are usually complex and interconnected phenomena. Poverty, political conflicts, environmental awareness, mobility and transport mechanisms, geopolitical path-dependence, ethno-political unrest, digital connectivity and self-determination could be researched from the social innovation changing perspective. The capacity to think across and between as well as within the thematic factors is crucial. Likewise, a clear understanding of the way in which different disciplines can contribute to a step change in delivery against these changing challenges is therefore required. Ultimately, an awareness of the underlying factors and contexts (including social, political, economic, cultural, technological and historial), interdependencies, synergies, tensions and trade-offs that promote, obstruct or even reverse delivery against social innovation, both individually and collectively are key to understand changing dynamics in city-regions. This urban issue called ‘Changing Social Innovation’ is explained comparatively through six cases as follows: Berlin, Belfast, Malawi, Hong Kong, Helsinki, and Glasgow

Plasmodium falciparum heterochromatin protein 1 binds to tri-methylated histone 3 lysine 9 and is linked to mutually exclusive expression of var genes

Increasing experimental evidence shows a prominent role of histone modifications in the coordinated control of gene expression in the human malaria parasite Plasmodium falciparum. The search for the histone-mark-reading machinery that translates histone modifications into biological processes, such as formation of heterochromatin and antigenic variation is of foremost importance. In this work, we identified the first member of a histone modification specific recognition protein, an orthologue of heterochromatin protein 1 (PfHP1). Analysis of the PfHP1 amino-acid sequence revealed the presence of the two characteristic HP1 domains: a chromodomain (CD) and a chromo shadow domain (CSD). Recombinant CD binds to di- and tri-methylated lysine 9 from histone H3, but not to unmodified or methylated histone H3 in lysine 4. PfHP1 is able to interact with itself to form dimers, underlying its potential role in aggregating nucleosomes to form heterochromatin. Antibodies raised against PfHP1 detect this molecule in foci at the perinuclear region. ChIP analysis using anti-PfHP1 shows that this protein is linked to heterochromatin of subtelomeric non-coding repeat regions and monoallelic expression of the major virulence var gene family. This is the first report implicating an HP1 protein in the control of antigenic variation of a protozoan parasite

Mitochondrial Associated Ubiquitin Fold Modifier-1 Mediated Protein Conjugation in Leishmania donovani

In this report, we demonstrate the existence of the ubiquitin fold modifier-1 (Ufm1) and its conjugation pathway in trypanosomatid parasite Leishmania donovani. LdUfm1 is activated by E1-like enzyme LdUba5. LdUfc1 (E2) specifically interacted with LdUfm1 and LdUba5 to conjugate LdUfm1 to proteinaceous targets. Mass spectrometry analysis revealed that LdUfm1 is conjugated to Leishmania protein targets that are associated with mitochondria. Immunofluorescence experiments showed that Leishmania Ufm1, Uba5 and Ufc1 are associated with the mitochondria. The demonstration that all the components of this system as well as the substrates are associated with mitochondrion suggests it may have physiological roles not yet described in any other organism. Overexpression of a non-conjugatable form of LdUfm1 and an active site mutant of LdUba5 resulted in reduced survival of Leishmania in the macrophage. Since mitochondrial activities are developmentally regulated in the life cycle of trypanosomatids, Ufm1 mediated modifications of mitochondrial proteins may be important in such regulation. Thus, Ufm1 conjugation pathway in Leishmania could be explored as a potential drug target in the control of Leishmaniasis

Expression of P. falciparum var Genes Involves Exchange of the Histone Variant H2A.Z at the Promoter

Plasmodium falciparum employs antigenic variation to evade the human immune response by switching the expression of different variant surface antigens encoded by the var gene family. Epigenetic mechanisms including histone modifications and sub-nuclear compartmentalization contribute to transcriptional regulation in the malaria parasite, in particular to control antigenic variation. Another mechanism of epigenetic control is the exchange of canonical histones with alternative variants to generate functionally specialized chromatin domains. Here we demonstrate that the alternative histone PfH2A.Z is associated with the epigenetic regulation of var genes. In many eukaryotic organisms the histone variant H2A.Z mediates an open chromatin structure at promoters and facilitates diverse levels of regulation, including transcriptional activation. Throughout the asexual, intraerythrocytic lifecycle of P. falciparum we found that the P. falciparum ortholog of H2A.Z (PfH2A.Z) colocalizes with histone modifications that are characteristic of transcriptionally-permissive euchromatin, but not with markers of heterochromatin. Consistent with this finding, antibodies to PfH2A.Z co-precipitate the permissive modification H3K4me3. By chromatin-immunoprecipitation we show that PfH2A.Z is enriched in nucleosomes around the transcription start site (TSS) in both transcriptionally active and silent stage-specific genes. In var genes, however, PfH2A.Z is enriched at the TSS only during active transcription in ring stage parasites. Thus, in contrast to other genes, temporal var gene regulation involves histone variant exchange at promoter nucleosomes. Sir2 histone deacetylases are important for var gene silencing and their yeast ortholog antagonises H2A.Z function in subtelomeric yeast genes. In immature P. falciparum parasites lacking Sir2A or Sir2B high var transcription levels correlate with enrichment of PfH2A.Z at the TSS. As Sir2A knock out parasites mature the var genes are silenced, but PfH2A.Z remains enriched at the TSS of var genes; in contrast, PfH2A.Z is lost from the TSS of de-repressed var genes in mature Sir2B knock out parasites. This result indicates that PfH2A.Z occupancy at the active var promoter is antagonized by PfSir2A during the intraerythrocytic life cycle. We conclude that PfH2A.Z contributes to the nucleosome architecture at promoters and is regulated dynamically in active var genes