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Histidine and tyrosine residues are targets for SIRT6 ADP-ribosylation activity
Get PDFSIRT6, a highly conserved member of the sirtuin family, plays a critical role in diverse cellular processes, including gene regulation, DNA damage response and maintaining nuclear lamina integrity. These functions are essential in contexts such as differentiation, metabolic regulation, cancer development and ageing. Given the multifaceted influence of SIRT6 on cellular activities, there is an increasing interest in elucidating the regulatory mechanisms governing its enzymatic functions. SIRT6 exhibits two NAD+-dependent activities: deacetylation and ADP-ribosylation, with current research predominantly focusing on the former. However, the latter—its (ADP-ribosyl)transferase activity—remains underexplored, particularly concerning the specific amino acid targets it modifies and the (ADP-ribosyl)hydrolases that can reverse these modifications. In this study, we have utilized biochemical assays and proteomic techniques to investigate these aspects, revealing that SIRT6 transfers ADP-ribosyl moieties onto histidine and tyrosine residues. In addition, we reveal that the (ADP-ribosyl)hydrolase ARH3 has significant activity in erasing SIRT6-derived ADP-ribosylation in cells
Student protests against Israeli action in Gaza: a cross-European analysis of newspaper representations
No full textResearch into student political activity across Europe has shown how the media can play a key role in shaping how such activity is framed. For example, newspapers have often focused on the violent nature of student protest, which has had the effect of diverting attention away from the specific concerns of students, and presenting students, rather than the issues that they were protesting about, as a threat to society. This article develops this analysis – of the role of newspapers in mediating student protests – by focussing on coverage of protests against Israeli action in Gaza, which took place in many European countries in the spring and summer of 2024, inspired by similar action on US campuses. It draws on articles from four European countries (France, Ireland, Spain and the UK) to argue, first, that there is considerable cross-national variation in constructions of protesting students, raising questions about the sometimes-assumed homogenisation of European higher education; and, second, that it is erroneous to assume that the media always serves to delegitmise student protest – noting the celebratory discourses evident in both Ireland and Spain
EHRC guidance on single-sex spaces is lawful-R (Good Law Project) v Equality and Human Rights Commission
Get PDFPublic Law analysis: The Administrative Court has dismissed a judicial review brought by the Good Law Project and three individuals challenging the interim update issued by the Equality and Human Rights Commission in the aftermath of the Supreme Court decision in For Women Scotland Ltd v Scottish Ministers. The interim update warned that the provision of multi-user single-sex facilities and services on anything other than a biological sex basis could amount to direct and indirect discrimination and was likely unlawful. The update also warned that failure to provide suitable alternative accommodation for transgender people could amount to unlawful discrimination and encouraged service providers and employers to, where possible, provide an alternative mixed-sex option. The Good Law Project challenged this guidance on the grounds that it misstated the law and would give rise to breaches of the Article 8 rights of transgender people. Mr Justice Swift dismissed the challenge, upholding the interim update in its entirety
Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for Myotonic Dystrophy type 1
Get PDFMyotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by CTG repeat expansions in DM1 protein kinase DMPK. Mutant transcripts containing expanded CUG repeats form ribonuclear foci that sequester muscleblind-like (MBNL) splicing regulator proteins, key regulators of RNA splicing and metabolism. This functional depletion leads to widespread mis-splicing and persistence of fetal transcript profiles, which underlie muscle weakness, myotonia, and muscle atrophy. In addition, miR-23b is upregulated in DM1 muscle and further represses MBNL1 translation, amplifying molecular defects. We developed chemically optimized microRNA (miRNA)-targeting antisense oligonucleotides (antimiRs) to inhibit miR-23b and restore functional MBNL1 levels. Using a multistep screening process, we evaluated antimiRs with varying sequences, lengths, chemical modifications, and lipid conjugations. A key optimization was a 3′ -oleic acid conjugation combined with specific chemical modifications, which enhanced muscle uptake and efficacy. Lead candidates showed strong activity in preclinical models (human skeletal actin [HSA]LR and DMSXL mice and human myoblasts), increasing MBNL1 levels, correcting mis-splicing, improving muscle strength, and reducing myotonia. They also exhibited efficient biodistribution to skeletal muscle, a critical DM1-affected tissue. In vitro toxicology indicated a favorable safety profile with minimal immune or renal toxicity. The antimiR mechanism was conserved in rat and pig fibroblasts. Overall, two lead antimiRs emerged as promising therapeutic candidates for DM1, with improved pharmacokinetics, tissue targeting, and safety, supporting the potential of microRNA-based approaches to correct key molecular defects in this disorder
Refractory hypocalcemia from combined autosomal dominant hypocalcemia type 2 and postsurgical hypoparathyroidism
Get PDFA 49-yr-old female with a history of chronic hypocalcemia, diagnosed twenty years earlier, had serum calcium concentrations that ranged between 6.4 and 8.5 mg/dL (nl, 8.6-10.3 mg/dL) with inappropriately low to low-normal parathyroid hormone (PTH) concentrations. She did not report symptoms of hypocalcemia such as paresthesias, muscle cramping, or tetany. More recently, a thyroid nodule was discovered, and the patient subsequently underwent total thyroidectomy for papillary thyroid cancer. Parathyroid autotransplantation was not performed since parathyroid glands were not identified during the surgery. After total thyroidectomy, the patient developed a more severe symptomatic, refractory hypocalcemia with undetectable PTH concentrations. Postoperative pathologic examination identified a single hypercellular parathyroid gland. Despite medical treatment, including frequent and regular calcium gluconate infusions, serum calcium concentrations remained persistently low. A genetic evaluation identified a pathogenic GNA11 variant (c.178C > T, p.Arg60Cys), consistent with autosomal dominant hypocalcemia type 2 (ADH2). This case expands the understanding of ADH2 and raises important questions about optimal treatment strategies in patients with coexisting genetic and postsurgical hypoparathyroidism
ADP-Ribosylation of Cytidine: A Novel Nucleic Acid Modification Reversed by NADAR Hydrolases
Get PDFADP-ribosylation of nucleic acids is a modification found in both eukaryotes and bacteria, where it contributes to genome maintenance but can also serve as a toxic mechanism used by bacterial toxins to disrupt essential cellular processes. This modification is catalysed by ADP-ribosyltransferases and can be reversed by antagonistic ADP-ribosylgylcohydrolase enzymes. To date, ADP-ribosylation of nucleic acid bases has been described only for adenosine, guanosine, and thymidine. Here we report the ADP-ribosylation of cytidine, catalysed by members of the pierisin family of bacterial toxins-ScARP (SCO5461) and Scabin. We also show that ADP-ribosylation of cytidine is reversible through removal by certain NADAR family proteins, including NADAR proteins from the bacterium Streptomyces coelicolor (SCO5665) and the sponge Amphimedon queenslandica, as well as YbiA-type NADAR proteins. The conservation of cytidine de-ADP-ribosylating activity of NADAR proteins across phylogenetically distant species suggests that this modification may have important physiological significance
Genomic epidemiology of a 2023-2024 Oropouche virus disease outbreak in Iquitos, Peru: descriptive analysis of a case control study for acute febrile illness
Get PDFBackgroundOropouche virus (OROV) is an emerging vector-borne pathogen endemic to the Americas, which causes acute febrile illness (AFI) in humans. Starting in late 2023, surges in OROV infections were reported across Latin America, including an outbreak in Iquitos, a city in the Eastern Peruvian Amazon, where RIVERA, an ongoing AFI surveillance program detected and characterized incident OROV cases.MethodsAFI cases presenting to health facilities were screened for OROV using PCR. OROV-positive subjects were compared to AFI OROV negative cases to describe the principal features of clinical disease. Genomes from OROV strains were sequenced and compared using phylogenetic analysis with those from extant samples isolated from other locations in the Americas.FindingsIn early 2024, an 8.6% OROV-positivity rate (29 detections in 339 samples) in RIVERA subjects was recorded, a more than 20-fold increase compared with pre-outbreak levels. Illness was characterized by fever, arthralgia, myalgia and dysuria. Genome sequences from strains in this outbreak were phylogenetically distinct from those from a concurrent one in Brazil, but resembled strains from Colombia and Ecuador. The last common ancestor of outbreak strains from Peru and Brazil was 226 years prior to sampling, and that of Peru and Ecuador and Colombia approximately 10 and 8 years prior to sampling, respectively.InterpretationGenomic analysis suggests that the current outbreak in South America is multifocal in origin and not the result of geographic spread from Brazil. An existing AFI surveillance program successfully documented the emergence and characterized the symptom profile of this emerging arboviral disease.FundingCDC/HHS U01GH002270; NIH D43TW010913, K43TW012298, K01AI168493, 5T32AI007046-48
Sampling, Mobility, and Anchoring in Small‐Body Sampling Robots: A Comprehensive Review
Get PDFSmall‐body sampling robots are crucial for asteroid and comet exploration as well as in situ resource utilization, yet they face unique challenges of microgravity, irregular terrain, and uncertain surface properties. Although existing studies have advanced sampling, mobility, and anchoring technologies, current reviews often treat these technologies in isolation, failing to reveal their intrinsic coupling relationships and hinder holistic research and development. To address this gap, this review provides a unified review of small‐body sampling robots, focusing on the mechanical aspects of the three core functional modules: sampling, mobility, and anchoring. It surveys state‐of‐the‐art techniques demonstrated in missions, highlights emerging approaches and compares performance trade‐offs in efficiency, adaptability, and technology readiness. The review further highlights critical challenges, including the coupling effects among the three functional modules as well as additional challenges arising from other factors. Finally, this review outlines the prospective development trends of small‐body sampling robots. By consolidating lessons from past missions and emerging innovations, this work aims to serve as both a reference for ongoing research and a road map for the design of next‐generation autonomous sampling robots
Decolonising geography education: spaces, processes, politics and people
No full textIn this chapter, we reflect on the ‘decolonial turn’ in geography education. Through critical engagement with literature and debate about the nature of geography education across phases and spaces, we consider how, why and to whom this turn is significant. Following this, we use a content analysis of the Journal of Geography in Higher Education (JGHE) to examine how the discourses associated with decol* and postcol* have been mobilised in scholarship. We consider how these discourses have been used in the framing, context and signposting of papers; in discussions about knowledge production and publications, and in reflections on pedagogy. We conclude by reflecting on the often deeply place-based discourses of postcolonialism and decolonisation in geography education, as scholars grapple not only with the complexities of educating students in their classrooms and lecture theatres but also with the geographies and histories of the places that they teach in and about
Archaeobotanical evidence reveals the nature of cereal agriculture at eighth- and ninth-century A.D. Sedgeford, East Anglia, U.K
No full textSedgeford’s multi-feature malting complex, dated to the eighth- to ninth-centuries A.D., is the earliest known of the early medieval era in England (the approximately contemporaneous, sizeable malting kiln at Higham Ferrers not being part of a larger complex). Three complementary approaches are here used to reveal cultivation practices for cereal grains (predominantly rye and free-threshing wheat) malted at Sedgeford. Specifically, these are used to determine evidence for the three elements of the medieval ‘mouldboard plough package’: namely, ‘extensive’ cultivation, the use of a mouldboard plough and crop rotation. In terms of cultivation intensity, functional weed ecology (FWE) reveals an extensive crop husbandry regime (i.e. maintaining low levels of fertility), whilst stable nitrogen isotope analyses indicate low levels of manuring. FWE also reveals high levels of disturbance, consistent with mouldboard plough use. Finally, all three approaches are used to assess evidence for crop rotation. First, correspondence analyses of the assemblage are used to explore seasonality in crop cultivation. Results of correspondence analyses, together with those from FWE and carbon and nitrogen stable isotope analyses all provide evidence for early crop rotation in fields supplying the malting complex. In sum, evidence suggests that all three elements of the medieval ‘mouldboard plough package’ were present at eighth- and ninth-century A.D. Sedgeford