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Background: Across the life course, women and girls with learning disabilities and their carers report difficulties in accessing information and support with menstruation, yet their experiences are often overlooked in initiatives to improve menstrual health and wellbeing. Our aim was to collaborate with women with learning disabilities to co-produce future research priorities in a UK context. Methods: We undertook a two-part scoping exercise to explore what is known about this topic from a life course perspective, beginning pre-menarche and extending to post-menopause support. This combined a rapid scoping review of the literature since 1980 with a stakeholder consultation where people with learning disabilities, family carers, advocacy groups and staff working across education, health and social care were invited to share their experiences of menstruation support. Findings: UK and international literature provided insight across five narrative themes. Seventy stakeholders took part in our consultation, enabling the identification of five key themes. Findings across both highlight examples of supportive practice and valued resources alongside enduring health inequalities and barriers to menstruation support faced by women and girls with learning disabilities across the life course. Conclusion: Our scoping exercise identified multiple gaps in research and practice, ongoing reproductive health inequalities and a need for improved access to peer support, resources and training that take a life course approach. The scoping exercise indicates the need for further empirical research on menstruation and learning disability, with a particular focus on collating people's lived experiences.

Phosphorylation of myofilament proteins critically regulates beat-to-beat cardiac contraction and is typically altered in heart failure (HF). β-Adrenergic activation induces phosphorylation in numerous substrates at the myofilament. Nevertheless, how cardiac β-adrenoceptors (βARs) signal to the myofilament in healthy and diseased hearts remains poorly understood. The aim of this study was to uncover the spatiotemporal regulation of local βAR signaling at the myofilament and thus identify a potential therapeutic target for HF. Phosphoproteomic analysis of substrate phosphorylation induced by different βAR ligands in mouse hearts was performed. Genetically encoded biosensors were used to characterize cyclic adenosine and guanosine monophosphate signaling and the impacts on excitation-contraction coupling induced by β1AR ligands at both the cardiomyocyte and whole-heart levels. Myofilament signaling circuitry was identified, including protein kinase G1 (PKG1)-dependent phosphorylation of myosin light chain kinase, myosin phosphatase target subunit 1, and myosin light chain at the myofilaments. The increased phosphorylation of myosin light chain enhances cardiac contractility, with a minimal increase in calcium (Ca2+) cycling. This myofilament signaling paradigm is promoted by carvedilol-induced β1AR-nitric oxide synthetase 3 (NOS3)-dependent cyclic guanosine monophosphate signaling, drawing a parallel to the β1AR-cyclic adenosine monophosphate-protein kinase A pathway. In patients with HF and a mouse HF model of myocardial infarction, increasing expression and association of NOS3 with β1AR were observed. Stimulating β1AR-NOS3-PKG1 signaling increased cardiac contraction in the mouse HF model. This research has characterized myofilament β1AR-PKG1-dependent signaling circuitry to increase phosphorylation of myosin light chain and enhance cardiac contractility, with a minimal increase in Ca2+ cycling. The present findings raise the possibility of targeting this myofilament signaling circuitry for treatment of patients with HF.

Pendent metals bound to heterocubanes are components of well-known active sites in enzymes that mediate difficult chemical transformations. Investigations into the specific role of these metal ions, sometimes referred to as "danglers", have been hindered by a paucity of rational synthetic routes to appropriate model structures. To generate pendent metal ions bonded to an oxo cubane through a carboxylate bridge, the cubane Co4(μ3-O)4(OAc)4(t-Bupy)4 (OAc = acetate, t-Bupy = 4-tert-butylpyridine) was exposed to various metal acetate complexes. Reaction with Cu(OAc)2 gave the structurally characterized (by X-ray diffraction) dicopper dangler Cu2Co4(μ4-O)2(μ3-O)2(OAc)6(Cl)2(t-Bupy)4. In contrast, the analogous reaction with Mn(OAc)2 produced the MnIV-containing cubane cation [MnCo3(μ3-O)4(OAc)4(t-Bupy)4]+ by way of a metal-metal exchange that gives Co(OAc)2 and [CoIII(μ-OH)(OAc)]n oligomers as byproducts. Additionally, reaction of the formally CoIV cubane complex [Co4(μ3-O)4(OAc)4(t-Bupy)4][PF6] with Mn(OAc)2 gave the corresponding Mn-containing cubane in 80% yield. A mechanistic examination of the related metal-metal exchange reaction between Co4(μ3-O)4(OBz)4(py)4 (OBz = benzoate) and [Mn(acac)2(py)2][PF6] by ultraviolet-visible (UV-vis) spectroscopy provided support for a process involving rate-determining association of the reactants and electron transfer through a μ-oxo bridge in the adduct intermediate. The rates of exchange correlate with the donor strength of the cubane pyridine and benzoate ligand substituents; more electron-donating pyridine ligands accelerate metal-metal exchange, while both electron-donating and -withdrawing benzoate ligands can accelerate exchange. These experiments suggest that the basicity of the cubane oxo ligands promotes metal-metal exchange reactivity. The redox potentials of the Mn and cubane starting materials and isotopic labeling studies suggest an inner-sphere electron-transfer mechanism in a dangler intermediate.

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.

A dinucleating 1,8-naphthyridine ligand featuring fluorene-9,9-diyl-linked phosphino side arms (PNNPFlu) was synthesized and used to obtain the cationic dicopper complexes 2, [(PNNPFlu)Cu2(μ-Ph)][NTf2]; [NTf2] = bis(trifluoromethane)sulfonimide, 6, [(PNNPFlu)Cu2(μ-CCPh)][NTf2], and 3, [(PNNPFlu)Cu2(μ-OtBu)][NTf2]. Complex 3 reacted with diboranes to afford dicopper μ-boryl species (4, with μ-Bcat; cat = catecholate and 5, with μ-Bpin; pin = pinacolate) that are more reactive in C(sp)-H bond activations and toward activations of CO2 and CS2, compared to dicopper μ-boryl complexes supported by a 1,8-naphthyridine-based ligand with di(pyridyl) side arms. The solid-state structures and DFT analysis indicate that the higher reactivities of 4 and 5 relate to changes in the coordination sphere of copper, rather than to perturbations on the Cu-B bonding interactions. Addition of xylyl isocyanide (CNXyl) to 4 gave 7, [(PNNPFlu)Cu2(μ-Bcat)(CNXyl)][NTf2], demonstrating that the lower coordination number at copper is chemically significant. Reactions of 4 and 5 with CO2 yielded the corresponding dicopper borate complexes (8, [(PNNPFlu)Cu2(μ-OBcat)][NTf2]; 9, [(PNNPFlu)Cu2(μ-OBpin)][NTf2]), with 4 demonstrating catalytic reduction in the presence of excess diborane. Related reactions of 4 and 5 with CS2 provided insertion products 10, {[(PNNPFlu)Cu2]2[μ-S2C(Bcat)2]}[NTf2]2, and 11, [(PNNPFlu)Cu2(μ,κ2-S2CBpin)][NTf2], respectively. These products feature Cu-S-C-B linkages analogous to those of proposed CO2 insertion intermediate.

Reports on a panel discussion held at LILAC 2022 on student academic reading during the COVID-19 pandemic. Draws on data from two surveys, but also discusses the implications of this research for teachers and information literacy (IL) practitioners. In summary, students carried out almost all their academic reading in electronic format, due to the restrictions in place. However, in common with research conducted prior to the pandemic, their preferences for reading in print format remained. Students also report doing less of their assigned readings, feeling more tired as well as reporting other negative health benefits from excess use of screens and devices. The study has implications for librarians, learning developers and for academic staff assigning course readings to students. Ongoing research in this area is recommended.

Reaction of the ruthenium carbene complex Cp*(IPr)RuCl (1) (IPr = 1,3-bis(Dipp)imidazol-2-ylidene; Dipp = 2,6-diisopropylphenyl) with sodium phosphaethynolate (NaOCP) led to intramolecular dearomatization of one of the Dipp substituents on the Ru-bound carbene to afford a Ru-bound phosphanorcaradiene, 2. Computations by DFT reveal a transition state characterized by a concerted process whereby CO migrates to the Ru center as the P atom adds to the π system of the aryl group. The phosphanorcaradiene possesses ambiphilic properties and reacts with both nucleophilic and electrophilic substrates, resulting in rearomatization of the ligand aryl group with net P atom transfer to give several unusual metal-bound, P-containing main-group moieties. These new complexes include a metallo-1-phospha-3-azaallene (Ru─P═C═NR), a metalloiminophosphanide (Ru─P═N─R), and a metallophosphaformazan (Ru─P(═N─N═CPh2)2). Reaction of 2 with the carbene 2,3,4,5-tetramethylimidazol-2-ylidene (IMe4) produced the corresponding phosphaalkene DippP═IMe4.

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.

Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly population. We performed genome-wide DNA methylation mapping of cerebellar tissue from pathologically confirmed DLB cases and controls to study the epigenetic profile of this understudied disease. After quality control filtering, 728,197 CpG-sites in 278 cases and 172 controls were available for the analysis. We undertook an epigenome-wide association study, which found a differential methylation signature in DLB cases. Our analysis identified seven differentially methylated probes and three regions associated with DLB. The most significant CpGs were located in ARSB (cg16086807), LINC00173 (cg18800161), and MGRN1 (cg16250093). Functional enrichment evaluations found widespread epigenetic dysregulation in genes associated with neuron-to-neuron synapse, postsynaptic specialization, postsynaptic density, and CTCF-mediated synaptic plasticity. In conclusion, our study highlights the potential importance of epigenetic alterations in the pathogenesis of DLB and provides insights into the modified genes, regions and pathways that may guide therapeutic developments.

Abstract The use of conductive and corrosion-resistant protective layers represents a key strategy for improving the durability of light absorber materials in photoelectrochemical water splitting. For high performance photoanodes such as Si, GaAs, and GaP, amorphous TiO2 protective overlayers, deposited by atomic layer deposition, are conductive for holes via a defect band in the TiO2. However, when coated on simply prepared, low-cost photoanodes such as metal oxides, no charge transfer is observed through amorphous TiO2. Here, we report a hybrid polyethyleneimine/TiO2 layer that facilitates hole transfer from model oxides BiVO4 and Fe2O3, enabling access to a broader scope of available materials for practical water oxidation. A thin polyethyleneimine layer between the light absorber and the hybrid polyethyleneimine/TiO2 acts as a hole-selective interface, improving the optoelectronic properties of the photoanode devices. These polyethyleneimine/TiO2 modified photoanodes exhibit high photostability for solar water oxidation over 400 h.

Abstract Background Parkinson’s disease is a progressive neurodegenerative disease characterized by clinical motor signs and non-motor symptoms that severely impact quality of life. There is an urgent need for therapies that might slow, halt or even reverse the progression of existing symptoms or delay the onset of new symptoms. Photobiomodulation is a therapy that has shown potential to alleviate some symptoms of Parkinson’s disease in animal studies and in small clinical trials. Objective To assess long-term effectiveness of photobiomodulation therapy in a cohort of Parkinson’s disease individuals after five years of continuing therapy. Methods Eight participants of the initial 12 in a previously published study agreed to be reassessed after five years. Seven of these participants had continued home-based, self-applied photobiomodulation therapy three times per week for five years. One participant had discontinued treatment after one year. Participants were assessed for a range of clinical motor signs, including MDS-UPDRS-III, measures of mobility and balance. Cognition was assessed objectively, and quality of life and sleep quality were assessed using self-reported questionnaires. A Wilcoxon Signed Ranks test was used to evaluate change in outcome measures between baseline (before treatment) and after five years, with the alpha value set to 0.05. Results Of the seven participants who had continued photobiomodulation therapy, one had a preliminary diagnosis of multisystem atrophy and was excluded from the group analysis. For the remaining six participants, there was a significant improvement in walk speed, stride length, timed up-and-go tests, tests of dynamic balance, and cognition compared to baseline and nonsignificant improvements in all other measures, apart from MDS-UPDRS-III, which was unchanged and one measure of static balance (single leg stance, standing on the unaffected leg with eyes open) which declined. Five of six participants either improved or showed no decline in MDS-UPDRS-III score and most participants showed improvement or no decline in all other outcome measures. No adverse effects of the photobiomodulation therapy were reported. Conclusions This study provides a signal that photobiomodulation therapy might safely reduce important clinical motor signs and non-motor symptoms in some Parkinson’s disease patients, with improvements maintained over several years. Home-based photobiomodulation therapy has the potential to complement standard therapies to manage symptoms and potentially delay Parkinson’s symptom progression. Trial registration Australian New Zealand Clinical Trials Registry, registration number ACTRN12618000038291p, registered on 12/01/2018.

Throughout history, Historically Black Colleges and Universities (HBCUs) have overcome countless challenges to achieve their goals of maintaining cultural traditions, providing key leadership and role models, assuring economic functions, addressing issues between minority and majority populations, and producing Black agents for research, institutional training, and information dissemination within the Black and other minority communities. Using a Scholarly Personal Narrative (SPN), this article focuses on the function, legacy, and relevance of current HBCUs. Using W. E. B. Du Bois's "double consciousness" as a theoretical framework, each of the 12 contributing scholars address these questions: How have you reconciled your individual strivings? Has the HBCU placed a role in your reconciliation process? What SPN is emblematic of your reconciliation process? These questions are addressed through vivid narrative accounts that speak to the critical constructs of belonging--Black identity; gifted education, selfhood, spirituality, and theoretical frameworks. Each of these constructs represents an identity vector that points inward to the core--the HBCU.

This article advances transdisciplinarity as a potentially useful applied theatre theory and method. It maps the ways transdisciplinary research principles informed and framed an applied theatre project and suggests that making applied theatre explicit rather than implicit as a transdisciplinary research process may help practitioners conceptualise and manage projects. In our case, it also increased our ability to contribute to second-order (systemic) change. I argue that applied theatre was always-already transdisciplinary research but articulating this alignment may be helpful to both practice and analysis. The project presented here implemented applied theatre in a university-community partnership addressing youth justice.

Reactions of a dicopper(I) tert-butoxide complex with alkynes possessing boryl or silyl capping groups resulted in formation of unprecedented tetracopper(I) μ-acetylide/diyne complexes that were characterized by NMR and UV/Vis spectroscopy, mass spectrometry and single-crystal X-ray diffraction. These compounds possess an unusual μ4 -η1 :η1 :η1 :η1 coordination mode for the bridging organic fragment, enforced by the rigid and dinucleating nature of the ligand utilized. Thus, the central π system remains unperturbed and accessible for subsequent reactivity and modification. This has been corroborated by addition of a fifth copper atom, giving rise to a pentacopper acetylide complex. This work may provide a new approach by which metal-metal cooperativity can be exploited in the transformation of acetylide and diyne groups to a variety of substrates, or as a starting point for the controlled synthesis of copper(I) alkyne-containing clusters.

Base-stabilized [BP3iPr](H)2CoSiH2(DMAP) (1, [BP3iPr] = PhB(CH2PiPr2)3-; DMAP = 4-dimethylaminopyridine) is a rare instance of a synthon for the simplest parent silylene complex (LM═SiH2). Complex 1 was accessed in high yields via double Si-H bond activation in SiH4 by [BP3iPr]Co(DMAP), and in solution, it undergoes rapid exchange between bound and free DMAP by an associative mechanism (as determined by variable-temperature 1H NMR dynamic studies). The DMAP ligand of 1 is readily displaced by metal-based fragments that bind silicon and cleave the Si-H bonds of the SiH2 moiety to produce bimetallic [Co═Si═M] (M = Co, Fe) molecular silicides. Thus, treatment of 1 with 0.5 equiv of (LCoI)2(μ-N2) (L = a tripodal ligand) resulted in the spontaneous formation of [BP3iPr](H)2Co═Si═Co(H)2L (L = [BP2tBuPz], PhB(CH2PtBu2)2(pyrazolyl)- (3); Tp″, HB(3,5-diisopropylpyrazolyl)3- (4)) with the concomitant release of DMAP. The symmetrical silicide [BP3iPr](H)2Co═Si═Co(H)2[BP3iPr] (5) was prepared by treatment of a mixture of 1 and [BP3iPr]Co(DMAP) with 2 equiv of Ph3B, which in this case is required to sequester DMAP as the elimination product Ph3B-DMAP. A heterobimetallic silicide, [BP3iPr](H)2Co═Si═Fe(H)2[SiP3iPr] (7; [SiP3iPr] = PhSi(CH2PiPr2)3), was obtained via in situ KC8 reduction of [SiP3iPr]FeCl and subsequent addition of 1 and Ph3B. These transformations involving a metal-SiH2 derivative demonstrate a fundamentally new type of reactivity for silylene complexes and provide a unique synthetic method for construction of molecular silicide complexes.

Understanding population connectivity is paramount for effective conservation. While genetic tools have elucidated sea turtle migration patterns, notable data gaps limit our understanding of ocean-wide connectivity, especially regarding east Atlantic green turtles. We characterized the genetic composition of a globally important green turtle foraging aggregation at the Banc d’Arguin, Mauritania, incorporating data from 323 individuals captured between 2018 and 2021. Using extended mitochondrial DNA D-loop (738 base pairs [bp]) and mitochondrial short tandem repeat (mtSTR; ~200 bp) markers, we assessed the genetic structure of Atlantic green turtle foraging aggregations and estimated the most likely origin of immature green turtles from the Banc d’Arguin using mixed stock analyses (MSAs). We identified 6 D-loop haplotypes, with a clear dominance of CM-A8.1 (91.8%) followed by CM-A5.1 (6.3%) and 4 rare haplotypes: CM-A1.4, CMA6.1, CM24.1 and CM36.1. We found 13 mtSTR haplotypes, with ‘7-12-4-4’ being dominant (89.0%). The genetic composition at the Banc d’Arguin differed significantly from the only foraging aggregation studied in West Africa to date—in the archipelago of Cabo Verde (located ca. 750 km from the Banc d’Arguin)—dominated by haplotype CM-A5. The MSA combining both genetic markers indicated that 87.6% of immature green turtles at the Banc d’Arguin originate from the major East Atlantic rookery at Poilão (Guinea-Bissau), but 11.6% come from more distant rookeries in South America (8.1%) and potentially Ascension Island (3.4%). We suggest that green turtle transatlantic movements may be more common than previously thought and highlight the importance of the Banc d’Arguin as a regional foraging hub for this species.

Abstract Plasmodium falciparum is the causative agent of malaria and remains a pathogen of global importance. Asexual blood stage replication, via a process called schizogony, is an important target for the development of new antimalarials. Here we use ultrastructure-expansion microscopy to probe the organisation of the chromosome-capturing kinetochores in relation to the mitotic spindle, the centriolar plaque, the centromeres and the apical organelles during schizont development. Conditional disruption of the kinetochore components, PfNDC80 and PfNuf2, is associated with aberrant mitotic spindle organisation, disruption of the centromere marker, CENH3 and impaired karyokinesis. Surprisingly, kinetochore disruption also leads to disengagement of the centrosome equivalent from the nuclear envelope. Severing the connection between the nucleus and the apical complex leads to the formation of merozoites lacking nuclei. Here, we show that correct assembly of the kinetochore/spindle complex plays a previously unrecognised role in positioning the nascent apical complex in developing P. falciparum merozoites.