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No full textReverse evel: The House of Lords Reform Between Individual and Multi-Layered Subjecthood
No full textThe article examines the recent calls to reform of the House of Lords (hl) through two lenses: theoretical and prescriptive. Theoretically, it revisits the classics of constitutional theory to underscore the nexus between the function of a second chamber and the concept of ‘constitutional subjecthood’. This pertains to the criteria governing majority formation and representative voting. The article demonstrates a conceptual tension within the UK’s territorial constitution. Despite the multi-layered nature of the constitution, the House of Lords’ voting structure rejects multi-layered subjecthood in favour of a unitary conception. This inconsistency exacerbates territorial disparities and undermines the House of Lords’ function, weakening the role of devolved territories in ‘shared rule’. To address this conceptual tension, the prescriptive part of the article proposes a Standing Order for the hl analogous to the English Vote for English Laws (evel) framework, albeit with an inverse scope and fortified by a robust theoretical foundation. This proposal promises to harmonise the theoretical tension and provide political teeth to the Sewel Convention, while at the same time not being contingent on a full reconstruction of the hl’s function, nor composition
Oligomerisation and Stereoselective Polymerisation of Alkenes and Alkynes Using Pyridyl-based Al(III) Catalysts
No full textDealkylation of the dimers [R2Al(2-py')]2 (2-py’ = 6-substituted pyridyl, R = Me, iBu) with [Ph 3 /sub>C][B(C6 F 5 ) 4 ] gives the putativecations [RAl( 2 -py') 2 (μ-R)AlR] + which can polymerise a range of alkenes with a high degree...
Dealkylation of the dimers [R2Al(2-py')]2 (2-py’ = 6-substituted pyridyl, R = Me, iBu) with [Ph 3 /sub>C][B(C6 F 5 ) 4 ] gives the putativecations [RAl( 2 -py') 2 (μ-R)AlR] + which can polymerise a range of alkenes with a high degree of stereo-regularity (syndiotacticity in the case of polystyrene) and cylotrimerise terminal alkynes to tri-substituted benzenes and a fulvene. This is the first report of stereoselective Al(III) polymerisation and of the cyclotrimerisation of alkynes by static catalysis using a main group metal
Multinational assessment of absolute neutrophil counts and white blood cell counts among healthy Duffy-null adults.
No full textLaboratory reference intervals must reflect population diversity for accurate medical decisions. The Duffy-null variant lowers absolute neutrophil counts (ANC), but existing dedicated reference intervals are based on a single African American cohort. The impact across other ethnic groups and regions remains unclear, and no white blood cell count (WBC) intervals exist for Duffy-null individuals. This study aimed to establish and compare Duffy-null ANC and WBC reference intervals across 4 continents. A cross-sectional study was conducted assessing healthy Duffy-null individuals from dedicated cohorts (blood donors in Namibia, Saudi Arabia, and the United Kingdom; primary care patients in the United States) and biobanks (participants from the United Kingdom and the United States). Among 8018 participants (880 from dedicated cohorts and 7138 from biobanks), novel ANC and WBC reference intervals were established (Namibia [ANC, 820/μL to 6370/μL; WBC, 2.51 × 109/L to 9.85 × 109/L]; Saudi Arabia [ANC, 1140/μL to 5290/μL; WBC, 3.72 × 109/L to 10.71 × 109/L]; United Kingdom (ANC, 1185/μL to 5462/μL; WBC, 3.1 × 109/L to 8.8 × 109/L]; the United States [ANC, 1210/μL to 5390/μL; WBC, 3.00 × 109/L to 9.66 × 109/L]), with no significant differences between cohorts. Institutional reference intervals misclassified 27.9% (Namibia), 50.9% (Saudi Arabia), 26.0% (United Kingdom), and 21.7% (the United States) as neutropenic. Biobank analyses confirmed no significant difference in ANC between Black and non-Black Duffy-null participants. Duffy-null individuals consistently exhibit lower ANC and WBC across ethnic groups and regions. Current reference intervals overlook this variation, risking misdiagnosis and health inequities. Implementing Duffy-specific reference intervals is essential for equitable and accurate clinical decisions worldwide
CRISPR-Cas9-directed gene therapy for spinocerebellar ataxia type 1
No full textSpinocerebellar ataxia type 1 (SCA1) is a debilitating neurodegenerative disorder characterized by progressive motor dysfunction and cerebellar degeneration resulting from a CAG trinucleotide repeat expansion in the ATXN1 gene. Despite extensive research efforts, effective treatments remain elusive. Current interventions are limited to symptomatic management or transient knockdown of ATXN1 expression using antisense oligonucleotides and RNA interference, approaches that require repeated administration and rely on endogenous cellular mechanisms.1 The advent of CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats associated with CRISPR-associated protein 9) gene editing technology offers a transformative approach by enabling precise, long-lasting genomic modifications
The ethics of multi-cancer screening.
No full textMulti-cancer detection tests offer a new paradigm in cancer screening — the use of a single test to simultaneously screen for many cancers — but they raise important ethical questions for their development, evaluation and possible implementation
Hunter-gatherer sea voyages extended to remotest Mediterranean islands
No full textThe Maltese archipelago is a small island chain that is among the most remote in the Mediterranean. Humans were not thought to have reached and inhabited such small and isolated islands until the regional shift to Neolithic lifeways, around 7.5 thousand years ago (ka)1. In the standard view, the limited resources and ecological vulnerabilities of small islands, coupled with the technological challenges of long-distance seafaring, meant that hunter-gatherers were either unable or unwilling to make these journeys2, 3–4. Here we describe chronological, archaeological, faunal and botanical data that support the presence of Holocene hunter-gatherers on the Maltese islands. At this time, Malta’s geographical configuration and sea levels approximated those of the present day, necessitating seafaring distances of around 100 km from Sicily, the closest landmass. Occupations began at around 8.5 ka and are likely to have lasted until around 7.5 ka. These hunter-gatherers exploited land animals, but were also able to take advantage of marine resources and avifauna, helping to sustain these groups on a small island. Our discoveries document the longest yet-known hunter-gatherer sea crossings in the Mediterranean, raising the possibility of unknown, precocious connections across the wider region
Hypoxia-inducible factor signaling regulates embryonic interneuron development, GRIN2B expression and adult cortical function.
No full textAlthough hypoxia-inducible factors (HIFs) are central regulators of cellular adaptation to oxygen and metabolic fluctuations in the mammalian brain, potential roles for HIF regulation during inhibitory neuron development are poorly understood. Here, we report that Nkx2.1-cre-driven conditional deletion of Hif1/2a in the medial ganglionic eminence (MGE) leads to reduced proliferation of Lhx6-positive interneuron precursors, whereas loss of von Hippel-Lindau (vHL), required for HIF degradation, drives increased precursor proliferation. Integrating single-cell transcriptomics, we identified HIF targets regulating proliferation and synaptogenesis. We also show that HIF1A directly activates glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B), encoding glutamate ionotropic receptor N-methyl-D-aspartate (NMDA) subunit 2B. In the adult HIF1 conditional knockout (cKO) cortex, we observed decreased numbers of parvalbumin (PV) interneurons and fewer GABAergic synapses and GRIN2B/Bassoon puncta on layer 2/3 excitatory neurons, resulting in attenuated long-term potentiation. These findings identify non-canonical roles for HIF signaling that are essential for PV interneuron production, GRIN2B expression, and cortical circuit maturation and function
Spatial distribution of isoprenoid enzymes and MpABCG1 transporter influences sesquiterpene accumulation in Marchantia polymorpha oil bodies.
No full textMarchantia polymorpha oil bodies (OBs) are specialized cell structures housing a diverse array of C15-terpenes, called sesquiterpenes. These compounds act as herbivore repellents, yet the enzymes responsible for the biosynthesis of their precursors remain poorly characterized. We investigated the localization of isoprenoid biosynthetic enzymes using translational and transcriptional reporters, coupled with confocal microscopy. Most enzymes localized as predicted (e.g., cytosol, plastid and the endoplasmic reticulum), and OB cells were identified as the primary sites of sesquiterpene biosynthesis. To explore OBs as potential storage sites for terpenes, we attempted to produce exogenous but easily identifiable compounds in Marchantia, such as the diterpene taxadiene and the triterpene β-amyrin. Targeting to OB cells resulted in measurable amounts of these compounds, but their yields remained unaffected by the overexpression of key precursor genes, underscoring challenges in redirecting metabolic flux. To further investigate terpene accumulation in OBs, we focused on MpABCG1, an ABC transporter previously reported to localize at the OB membrane. While MpABCG1 overexpression mildly increased endogenous sesquiterpene levels, its disruption via CRISPR dramatically reduced sesquiterpene accumulation. These findings establish that MpABCG1 is necessary for sesquiterpene accumulation in OBs and add to current knowledge of terpene synthesis compartmentalisation in Marchantia polymorpha
Lead exposure and antisocial behavior: A systematic review of human and animal evidence.
No full textBACKGROUND: Despite decades of research and interventions, lead (Pb) exposure remains a global public health concern. In addition to well-documented impacts on cognition, there is growing evidence of Pb's impacts on antisocial behaviors, including aggression, conduct or antisocial disorders, and violation of social norms. We conduct a systematic review on the association between Pb and antisocial behavior from human and animal data. METHODS: We followed our protocol with selected modifications for practicality. Peer-reviewed epidemiology and toxicology literature from PubMed, BIOSIS, and Web of Science were searched through June 2024 and screened for relevance, leveraging machine-learning. Details for each Population, Exposure, Comparator, Outcome (PECO)-relevant study were summarized. Studies were evaluated for potential bias and sensitivity according to predefined metrics through the Health Assessment Workspace Collaborative (HAWC) system. Evidence was synthesized by sub-outcome (human: aggression; antisocial diagnoses or domains; violation of social norms; animal: aggression; social behavior) and then integrated across evidence streams, based on approaches adapted from the U.S. EPA. RESULTS: More than 15,000 studies were identified. After screening and scoping refinements, 43 epidemiological and 37 animal studies were included for narrative review. In the epidemiological database, there was lack of comparability in outcome assessment methods, precluding quantitative meta-analysis. Human and animal evidence for impacts on aggression was slight. Human and animal evidence for impacts on antisocial-related disorders or domains and social behavior, respectively, was moderate. Human evidence for impacts on violation of social norms was moderate. CONCLUSIONS: From our updated review of epidemiological and toxicological data, we find that evidence indicates a likely causal association between Pb and antisocial behavior