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Abstract The NEMO-3 results for the double- $$\beta $$ β decay of $$^{150}$$ 150 Nd to the 0 $$^+_1$$ 1 + and 2 $$^+_1$$ 1 + excited states of $$^{150}$$ 150 Sm are reported. The data recorded during 5.25 year with 36.6 g of the isotope $$^{150}$$ 150 Nd are used in the analysis. The signal of the $$2\nu \beta \beta $$ 2 ν β β transition to the 0 $$^+_1$$ 1 + excited state is detected with a statistical significance exceeding 5 $$\sigma $$ σ . The half-life is measured to be $$T_{1/2}^{2\nu \beta \beta }(0^+_1) = \left[ 1.11 ^{+0.19}_{-0.14} \,\left( \hbox {stat}\right) ^{+0.17}_{-0.15}\,\left( \hbox {syst}\right) \right] \times 10^{20}$$ T 1 / 2 2 ν β β ( 0 1 + ) = 1 . 11 - 0.14 + 0.19 stat - 0.15 + 0.17 syst × 10 20 year, which is the most precise value that has been measured to date. 90% confidence-level limits are set for the other decay modes. For the $$2\nu \beta \beta $$ 2 ν β β decay to the 2 $$^+_1$$ 1 + level the limit is $$T^{2\nu \beta \beta }_{1/2}(2^+_1) > 2.42 \times 10^{20}~\hbox {year}$$ T 1 / 2 2 ν β β ( 2 1 + ) > 2.42 × 10 20 year . The limits on the $$0\nu \beta \beta $$ 0 ν β β decay to the 0 $$^+_1$$ 1 + and 2 $$^+_1$$ 1 + levels of $$^{150}$$ 150 Sm are significantly improved to $$T_{1/2}^{0\nu \beta \beta }(0^+_1) > 1.36 \times 10^{22}~\hbox {year}$$ T 1 / 2 0 ν β β ( 0 1 + ) > 1.36 × 10 22 year and $$T_{1/2}^{0\nu \beta \beta }(2^+_1) > 1.26 \times 10^{22}~\hbox {year}$$ T 1 / 2 0 ν β β ( 2 1 + ) > 1.26 × 10 22 year .

Abstract The full data set of the NEMO-3 experiment has been used to measure the half-life of the two-neutrino double beta decay of $$^{100}$$ 100 Mo to the ground state of $$^{100}$$ 100 Ru, $$T_{1/2} = \left[ 6.81 \pm 0.01\,\left( \text{ stat }\right) ^{+0.38}_{-0.40}\,\left( \text{ syst }\right) \right] \times 10^{18}$$ T1/2=6.81±0.01stat-0.40+0.38syst×1018 year. The two-electron energy sum, single electron energy spectra and distribution of the angle between the electrons are presented with an unprecedented statistics of $$5\times 10^5$$ 5×105 events and a signal-to-background ratio of $$\sim $$ ∼ 80. Clear evidence for the Single State Dominance model is found for this nuclear transition. Limits on Majoron emitting neutrinoless double beta decay modes with spectral indices of $$\mathrm{n}=2,3,7$$ n=2,3,7 , as well as constraints on Lorentz invariance violation and on the bosonic neutrino contribution to the two-neutrino double beta decay mode are obtained.

Abstract Using data from the NEMO-3 experiment, we have measured the two-neutrino double beta decay ($$2\nu \beta \beta $$ 2νββ ) half-life of $$^{82}$$ 82 Se as $$T_{\smash {1/2}}^{2\nu } \!=\! \left[ 9.39 \pm 0.17\left( \text{ stat }\right) \pm 0.58\left( \text{ syst }\right) \right] \times 10^{19}$$ T1/22ν=9.39±0.17stat±0.58syst×1019 y under the single-state dominance hypothesis for this nuclear transition. The corresponding nuclear matrix element is $$\left| M^{2\nu }\right| = 0.0498 \pm 0.0016$$ M2ν=0.0498±0.0016 . In addition, a search for neutrinoless double beta decay ($$0\nu \beta \beta $$ 0νββ ) using 0.93 kg of $$^{82}$$ 82 Se observed for a total of 5.25 y has been conducted and no evidence for a signal has been found. The resulting half-life limit of $$T_{1/2}^{0\nu } > 2.5 \times 10^{23} \,\text{ y } \,(90\%\,\text{ C.L. })$$ T1/20ν>2.5×1023y(90%C.L.) for the light neutrino exchange mechanism leads to a constraint on the effective Majorana neutrino mass of $$\langle m_{\nu } \rangle < \left( 1.2{-}3.0\right) \,\text{ eV }$$ ⟨mν⟩

Abstract Background Multiple sclerosis (MS) is a chronic condition of the central nervous system, affecting around 1 in every 600 people in the UK, with 130 new diagnoses every week. Cognitive difficulties are common amongst people with MS, with up to 70% experiencing deficits in higher-level brain functions—such as planning and problem-solving, attention, and memory. Cognitive deficits make it difficult for people with MS to complete everyday tasks and limit their abilities to work, socialise, and live independently. There is a clear need—and recognised research priority—for treatments that can improve cognitive functioning in people with MS. The absence of effective cognitive interventions exacerbates burdens on the services accessed by people with MS—requiring these services to manage sequelae of untreated cognitive deficits, including reduced quality of life, greater disability and dependence, and poorer adherence to disease-modifying treatments. Our planned research will fill the evidence gap through developing—and examining the feasibility of trialling—a novel online cognitive rehabilitation programme for people with MS (SMART). The SMART programme directly trains relational skills (the ability to flexibly relate concepts to one another) based on theory that these skills are critical to broader cognitive functioning. Methods The primary objective of this study aims to conduct a feasibility study to inform the development of a definitive trial of SMART for improving cognitive functioning in people with MS. The secondary objective is to develop the framework for a cost-effectiveness analysis alongside a definitive trial, and the exploratory objective is to assess the signal of efficacy. Discussion As a feasibility trial, outcomes are unlikely to immediately effect changes to NHS practice. However, this is a necessary step towards developing a definitive trial—and will give us a signal of efficacy, a prerequisite for progression to a definitive trial. If found to be clinically and cost-effective, the latter trial could create a step-change in MS cognitive rehabilitation—improving service delivery and optimising support with limited additional resources. Trial registration Registration ID: ClnicalTrials.gov: NCT04975685—registered on July 23rd, 2021. Protocol version: 2.0, 25 November 2021

This article provides a comparative analysis of Jihadist foreign fighters who traveled from Australia and Canada to engage in the conflict in Syria and Iraq. Data are provided on the demographics of those who traveled, group affiliations, when and how they traveled, and their social connections. Despite the strong similarities between these societies, significant differences are detected across levels of educational attainment, immediate familial status, and the degree of connection to existing Jihadist networks. The Australian and Canadian foreign fighters also differ, in key respects, from their European counterparts, and even those from the United States. Consideration is given to the possible significance of these differences, as well as the possible return of those currently detained in the region. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP) and associated inherited retinal diseases (IRDs) are caused by rod photoreceptor degeneration, necessitating therapeutics promoting rod photoreceptor survival. To address this, we tested compounds for neuroprotective effects in multiple zebrafish and mouse RP models, reasoning drugs effective across species and/or independent of disease mutation may translate better clinically. We first performed a large-scale phenotypic drug screen for compounds promoting rod cell survival in a larval zebrafish model of inducible RP. We tested 2934 compounds, mostly human-approved drugs, across six concentrations, resulting in 113 compounds being identified as hits. Secondary tests of 42 high-priority hits confirmed eleven lead candidates. Leads were then evaluated in a series of mouse RP models in an effort to identify compounds effective across species and RP models, that is, potential pan-disease therapeutics. Nine of 11 leads exhibited neuroprotective effects in mouse primary photoreceptor cultures, and three promoted photoreceptor survival in mouse rd1 retinal explants. Both shared and complementary mechanisms of action were implicated across leads. Shared target tests implicated parp1-dependent cell death in our zebrafish RP model. Complementation tests revealed enhanced and additive/synergistic neuroprotective effects of paired drug combinations in mouse photoreceptor cultures and zebrafish, respectively. These results highlight the value of cross-species/multi-model phenotypic drug discovery and suggest combinatorial drug therapies may provide enhanced therapeutic benefits for RP patients.

Genomic rearrangements associated with speciation often result in variation in chromosome number among closely related species. Malassezia species show variable karyotypes ranging between six and nine chromosomes. Here, we experimentally identified all eight centromeres in M. sympodialis as 3–5-kb long kinetochore-bound regions that span an AT-rich core and are depleted of the canonical histone H3. Centromeres of similar sequence features were identified as CENP-A-rich regions in Malassezia furfur, which has seven chromosomes, and histone H3 depleted regions in Malassezia slooffiae and Malassezia globosa with nine chromosomes each. Analysis of synteny conservation across centromeres with newly generated chromosome-level genome assemblies suggests two distinct mechanisms of chromosome number reduction from an inferred nine-chromosome ancestral state: (a) chromosome breakage followed by loss of centromere DNA and (b) centromere inactivation accompanied by changes in DNA sequence following chromosome–chromosome fusion. We propose that AT-rich centromeres drive karyotype diversity in the Malassezia species complex through breakage and inactivation.

Background: Clozapine is a key antipsychotic drug for treatment-resistant schizophrenia but exhibits highly variable pharmacokinetics and a propensity for serious adverse effects. Currently, these challenges are addressed using therapeutic drug monitoring (TDM). This study primarily sought to (i) verify the importance of covariates identified in a prior clozapine population pharmacokinetic (popPK) model in the absence of environmental covariates using physiologically based pharmacokinetic (PBPK) modelling, and then to (ii) evaluate the performance of the popPK model as an adjunct or alternative to TDM-guided dosing in an active TDM population. Methods: A popPK model incorporating age, metabolic activity, sex, smoking status and weight was applied to predict clozapine trough concentrations (Cmin) in a PBPK-simulated population and an active TDM population comprising 142 patients dosed to steady state at Flinders Medical Centre in Adelaide, South Australia. Post hoc analyses were performed to deconvolute the impact of physiological and environmental covariates in the TDM population. Results: Analysis of PBPK simulations confirmed age, cytochrome P450 1A2 activity, sex and weight as physiological covariates associated with variability in clozapine Cmin (R2 = 0.7698; p = 0.0002). Prediction of clozapine Cmin using a popPK model based on these covariates accounted for min in the TDM population. Conclusions: Variability in clozapine exposure was primarily driven by environmental covariates in an active TDM population. Pharmacokinetic modelling can be used as an adjunct to TDM to deconvolute sources of variability in clozapine exposure.