Amoeba predation of Cryptococcus: A quantitative and population genomic evaluation of the accidental pathogen hypothesis.

The "Amoeboid Predator-Fungal Animal Virulence Hypothesis" posits that interactions with environmental phagocytes shape the evolution of virulence traits in fungal pathogens. In this hypothesis, selection to avoid predation by amoeba inadvertently selects for traits that contribute to fungal escape from phagocytic immune cells. Here, we investigate this hypothesis in the human fungal pathogens Cryptococcus neoformans and Cryptococcus deneoformans. Applying quantitative trait locus (QTL) mapping and comparative genomics, we discovered a cross-species QTL region that is responsible for variation in resistance to amoeba predation. In C. neoformans, this same QTL was found to have pleiotropic effects on melanization, an established virulence factor. Through fine mapping and population genomic comparisons, we identified the gene encoding the transcription factor Bzp4 that underlies this pleiotropic QTL and we show that decreased expression of this gene reduces melanization and increases susceptibility to amoeba predation. Despite the joint effects of BZP4 on amoeba resistance and melanin production, we find no relationship between BZP4 genotype and escape from macrophages or virulence in murine models of disease. Our findings provide new perspectives on how microbial ecology shapes the genetic architecture of fungal virulence, and suggests the need for more nuanced models for the evolution of pathogenesis that account for the complexities of both microbe-microbe and microbe-host interactions.

Search for a Neutron Dark Decay in

Neutron dark decays have been suggested as a solution to the discrepancy between bottle and beam experiments, providing a dark matter candidate that can be searched for in halo nuclei. The free neutron in the final state following the decay of ^{6}He into ^{4}He+n+χ provides an exceptionally clean detection signature when combined with a high efficiency neutron detector. Using a high-intensity ^{6}He^{+} beam at Grand Accélérateur National d'Ions Lourds, a search for a coincident neutron signal resulted in an upper limit on a dark decay branching ratio of Br_{χ}≤4.0×10^{-10} (95% C.L.). Using the dark neutron decay model proposed originally by Fornal and Grinstein, we translate this into an upper bound on a dark neutron branching ratio of O(10^{-5}), improving over global constraints by one to several orders of magnitude depending on m_{χ}.

Cognitive and psychiatric outcomes in the GALAXY trial: effect of anaesthesia in deep brain stimulation.

BACKGROUND: This study aims: (1) To compare cognitive and psychiatric outcomes after bilateral awake versus asleep subthalamic nucleus (STN) deep brain stimulation (DBS) surgery for Parkinson's disease (PD). (2) To explore the occurrence of psychiatric diagnoses, cognitive impairment and quality of life after surgery in our whole sample. (3) To validate whether we can predict postoperative cognitive decline. METHODS: 110 patients with PD were randomised to receive awake (n=56) or asleep (n=54) STN DBS surgery. At baseline and 6-month follow-up, all patients underwent standardised assessments testing several cognitive domains, psychiatric symptoms and quality of life. RESULTS: There were no differences on neuropsychological composite scores and psychiatric symptoms between the groups, but we found small differences on individual tests and cognitive domains. The asleep group performed better on the Rey Auditory Verbal Learning Test delayed memory test (f=4.2, p=0.04), while the awake group improved on the Rivermead Behavioural Memory Test delayed memory test. (f=4.4, p=0.04). The Stroop III score was worse for the awake group (f=5.5, p=0.02). Worse scores were present for Stroop I (Stroop word card) (f=6.3, p=0.01), Stroop II (Stroop color card) (f=46.4, p<0.001), Stroop III (Stroop color-word card) (f=10.8, p=0.001) and Trailmaking B/A (f=4.5, p=0.04). Improvements were seen on quality of life: Parkinson's Disease Questionnaire-39 (f=24.8, p<0.001), and psychiatric scales: Hamilton Depression Rating Scale (f=6.2, p=0.01), and Hamilton Anxiety Rating Scale (f=5.5, p=0.02). CONCLUSIONS: This study suggests that the choice between awake and asleep STN DBS does not affect cognitive, mood and behavioural adverse effects, despite a minor difference in memory. STN DBS has a beneficial effect on quality of life, mood and anxiety symptoms. TRIAL REGISTRATION NUMBER: NTR5809.

N=16 Magicity Revealed at the Proton Drip Line through the Study of

The last proton bound calcium isotope ^{35}Ca has been studied for the first time, using the ^{37}Ca(p,t)^{35}Ca two neutron transfer reaction. The radioactive ^{37}Ca nuclei, produced by the LISE spectrometer at GANIL, interacted with the protons of the liquid hydrogen target CRYPTA, to produce tritons t that were detected in the MUST2 detector array, in coincidence with the heavy residues Ca or Ar. The atomic mass of ^{35}Ca and the energy of its first 3/2^{+} state are reported. A large N=16 gap of 4.61(11) MeV is deduced from the mass measurement, which together with other measured properties, makes ^{36}Ca a doubly magic nucleus. The N=16 shell gaps in ^{36}Ca and ^{24}O are of similar amplitude, at both edges of the valley of stability. This feature is discussed in terms of nuclear forces involved, within state-of-the-art shell model calculations. Even though the global agreement with data is quite convincing, the calculations underestimate the size of the N=16 gap in ^{36}Ca by 840 keV.

Structure of

Detailed spectroscopy of the neutron-deficient nucleus ^{36}Ca was obtained up to 9 MeV using the ^{37}Ca(p,d)^{36}Ca and the ^{38}Ca(p,t)^{36}Ca transfer reactions. The radioactive nuclei, produced by the LISE spectrometer at GANIL, interacted with the protons of the liquid hydrogen target CRYPTA, to produce light ejectiles (the deuteron d or triton t) that were detected in the MUST2 detector array, in coincidence with the heavy residues identified by a zero-degree detection system. Our main findings are (i) a similar shift in energy for the 1_{1}^{+} and 2_{1}^{+} states by about -250 keV, as compared with the mirror nucleus ^{36}S; (ii) the discovery of an intruder 0_{2}^{+} state at 2.83(13) MeV, which appears below the first 2^{+} state, in contradiction with the situation in ^{36}S; and (iii) a tentative 0_{3}^{+} state at 4.83(17) MeV, proposed to exhibit a bubble structure with two neutron vacancies in the 2s_{1/2} orbit. The inversion between the 0_{2}^{+} and 2_{1}^{+} states is due to the large mirror energy difference (MED) of -516(130) keV for the former. This feature is reproduced by shell model calculations, using the sd-pf valence space, predicting an almost pure intruder nature for the 0_{2}^{+} state, with two protons (neutrons) being excited across the Z=20 magic closure in ^{36}Ca (^{36}S). This mirror system has the largest MEDs ever observed, if one excludes the few cases induced by the effect of the continuum.

Apathy Induced by Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease: A Meta-Analysis.

Apathy, the loss of motivation, is a common problem in Parkinson's disease (PD) and often observed following deep brain stimulation (DBS) of the subthalamic nucleus (STN). The aim of this meta-analysis was to determine the occurrence of apathy following STN DBS in literature. Relevant articles were searched in PubMed/Medline, SCOPUS, EMBASE, and Web of Sciences electronic databases. Studies were included if they reported apathy scores pre- and post-DBS or the cross-sectional difference between PD patients receiving STN DBS and patients receiving medication only. Thirty-three articles were included in the meta-analyses from 6,658 screened articles by two authors independently. A total of 1,286 patients were included with a mean age (±standard deviation [SD]) of 58.4 ± 8.5 years and a disease duration of 11.0 ± 5.8 years. The apathy score measured by means of the Apathy Evaluation Scale (AES), Starkstein Apathy Scale (SAS), and the Lille Apathy Rating Scale (LARS) was significantly higher after DBS than pre-operatively (g = 0.34, 95% confidence interval [CI] = 0.19-0.48, P < 0.001). An equal, significant difference in severity of apathy was found between STN DBS and medication only (g = 0.36, 95% CI = 0.03-0.65; P = 0.004). Statistical heterogeneity was moderately high, but the effects stood strong after multiple analyses and were independent of tapering off dopaminergic medication. The findings of this meta-analysis indicate that apathy is increased after STN DBS compared to the pre-operative state and to medication only (systematic review registration number: PROSPERO CRD42019133932). © 2020 Universiteit van Amsterdam. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Timing and predictors of severe rotavirus gastroenteritis among unvaccinated infants in low- and middle-income countries.

Delays in rotavirus vaccine schedule could improve performance in low- and middle-income countries (LMICs). However, delaying the first dose could be detrimental if infants experience severe rotavirus gastroenteritis (RVGE) early in life. Our objective was to describe the timing and predictors of severe RVGE in unvaccinated children in LMICs. We analysed the placebo arms from two clinical trials (cohort 1: NCT00241644; cohort 2: NCT00362648). We estimated the rate, cumulative incidence (per 1000 infants) and age distribution of severe RVGE episodes. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals (CI) for the association between baseline factors and severe RVGE. Cumulative incidence at 6 months of age was 23/1000 (95% CI 15-30) in cohort 1 and 6/1000 (95% CI 3-8) in cohort 2. Early antibiotic use (compared with no use) was associated with 2.03 (95% CI 1.18-3.48) and 1.41 (95% CI 0.80-2.51) times the rate of severe RVGE in cohorts 1 and 2, respectively. The cumulative incidence of severe RVGE was low at 6 months of age, suggesting that a 4-week delay in the vaccination schedule may not result in a large number of severe RVGE episodes prior to vaccine receipt.

Observation of the ß-delayed γ-proton decay of (56)Zn and its impact on the Gamow-Teller strength evaluation.

We report the observation of a very exotic decay mode at the proton drip line, the ß-delayed γ-proton decay, clearly seen in the ß decay of the T_{z}=-2 nucleus ^{56}Zn. Three γ-proton sequences have been observed after the ß decay. Here this decay mode, already observed in the sd shell, is seen for the first time in the fp shell. Both γ and proton decays have been taken into account in the estimation of the Fermi and Gamow-Teller strengths. Evidence for fragmentation of the Fermi strength due to strong isospin mixing is found.

Measurement of the isoscalar monopole response in the neutron-rich nucleus 68Ni.

The isoscalar monopole response has been measured in the unstable nucleus (68)Ni using inelastic alpha scattering at 50A MeV in inverse kinematics with the active target MAYA at GANIL. The isoscalar giant monopole resonance (ISGMR) centroid was determined to be 21.1 ± 1.9 MeV and indications for a soft monopole mode are provided for the first time at 12.9 ± 1.0 MeV. Analysis of the corresponding angular distributions using distorted-wave-born approximation with random-phase approximation transition densities indicates that the L = 0 multipolarity dominates the cross section for the ISGMR and significantly contributes to the low-energy mode. The L=0 part of this low-energy mode, the soft monopole mode, is dominated by neutron excitations. This demonstrates the relevance of inelastic alpha scattering in inverse kinematics in order to probe both the ISGMR and isoscalar soft modes in neutron-rich nuclei.

Experimental study of the two-body spin-orbit force in nuclei.

Energies and spectroscopic factors of the first 7/2-, 3/2-, 1/2-, and 5/2- states in the (35)Si21 nucleus were determined by means of the (d, p) transfer reaction in inverse kinematics at GANIL using the MUST2 and EXOGAM detectors. By comparing the spectroscopic information on the Si35 and S37 isotones, a reduction of the p3/2-p1/2 spin-orbit splitting by about 25% is proposed, while the f7/2-f5/2 spin-orbit splitting seems to remain constant. These features, derived after having unfolded nuclear correlations using shell model calculations, have been attributed to the properties of the two-body spin-orbit interaction, the amplitude of which is derived for the first time in an atomic nucleus. The present results, remarkably well reproduced by using several realistic nucleon-nucleon forces, provide a unique touchstone for the modeling of the spin-orbit interaction in atomic nuclei.

Changes in physical activity, sedentary behaviour and sleep following pulmonary rehabilitation: a systematic review and network meta-analysis.

BACKGROUND: The variety of innovations to traditional centre-based pulmonary rehabilitation (CBPR), including different modes of delivery and adjuncts, are likely to lead to differential responses in physical activity, sedentary behaviour and sleep. OBJECTIVES: To examine the relative effectiveness of different pulmonary rehabilitation-based interventions on physical activity, sedentary behaviour and sleep. METHODS: Randomised trials in chronic respiratory disease involving pulmonary rehabilitation-based interventions were systematically searched for. Network meta-analyses compared interventions for changes in physical activity, sedentary behaviour and sleep in COPD. RESULTS: 46 studies were included, and analyses were performed on most common outcomes: steps per day (k=24), time spent in moderate-to-vigorous physical activity (MVPA; k=12) and sedentary time (k=8). There were insufficient data on sleep outcomes (k=3). CBPR resulted in greater steps per day and MVPA and reduced sedentary time compared to usual care. CBPR+physical activity promotion resulted in greater increases in steps per day compared to both usual care and CBPR, with greater increases in MVPA and reductions in sedentary time compared to usual care, but not CBPR. Home-based pulmonary rehabilitation resulted in greater increases in steps per day and decreases in sedentary time compared to usual care. Compared to usual care, CBPR+physical activity promotion was the only intervention where the lower 95% confidence interval for steps per day surpassed the minimal important difference. No pulmonary rehabilitation-related intervention resulted in greater increases in MVPA or reductions in sedentary time compared to CBPR. CONCLUSION: The addition of physical activity promotion to pulmonary rehabilitation improves volume of physical activity, but not intensity, compared to CBPR. High risk of bias and low certainty of evidence suggests that these results should be viewed with caution.

A lipid atlas of human and mouse immune cells provides insights into ferroptosis susceptibility.

The cellular lipidome comprises thousands of unique lipid species. Here, using mass spectrometry-based targeted lipidomics, we characterize the lipid landscape of human and mouse immune cells ( www.cellularlipidatlas.com ). Using this resource, we show that immune cells have unique lipidomic signatures and that processes such as activation, maturation and development impact immune cell lipid composition. To demonstrate the potential of this resource to provide insights into immune cell biology, we determine how a cell-specific lipid trait-differences in the abundance of polyunsaturated fatty acid-containing glycerophospholipids (PUFA-PLs)-influences immune cell biology. First, we show that differences in PUFA-PL content underpin the differential susceptibility of immune cells to ferroptosis. Second, we show that low PUFA-PL content promotes resistance to ferroptosis in activated neutrophils. In summary, we show that the lipid landscape is a defining feature of immune cell identity and that cell-specific lipid phenotypes underpin aspects of immune cell physiology.

Strain heterogeneity in a non-pathogenic fungus highlights factors contributing to virulence.

Fungal pathogens exhibit extensive strain heterogeneity, including variation in virulence. Whether closely related non-pathogenic species also exhibit strain heterogeneity remains unknown. Here, we comprehensively characterized the pathogenic potentials (i.e., the ability to cause morbidity and mortality) of 16 diverse strains of Aspergillus fischeri, a non-pathogenic close relative of the major pathogen Aspergillus fumigatus. In vitro immune response assays and in vivo virulence assays using a mouse model of pulmonary aspergillosis showed that A. fischeri strains varied widely in their pathogenic potential. Furthermore, pangenome analyses suggest that A. fischeri genomic and phenotypic diversity is even greater. Genomic, transcriptomic, and metabolomic profiling identified several pathways and secondary metabolites associated with variation in virulence. Notably, strain virulence was associated with the simultaneous presence of the secondary metabolites hexadehydroastechrome and gliotoxin. We submit that examining the pathogenic potentials of non-pathogenic close relatives is key for understanding the origins of fungal pathogenicity.

Spectroscopy of 26F to probe proton-neutron forces close to the drip line.

A long-lived J(π) = 4(1)(+) isomer, T(1/2) = 2.2(1) ms, has been discovered at 643.4(1) keV in the weakly bound (9)(26)F nucleus. It was populated at Grand Accélérateur National d'Ions Lourds in the fragmentation of a (36)S beam. It decays by an internal transition to the J(π) = 1(1)(+) ground state [82(14)%], by ß decay to (26)Ne, or ß-delayed neutron emission to (25)Ne. From the ß-decay studies of the J(π) =1(1)(+) and J(π) = 4(1)(+) states, new excited states have been discovered in (25,26)Ne. Gathering the measured binding energies of the J(π) = 1(1)(+) -4(1)(+) multiplet in (9)(26)F, we find that the proton-neutron π0d(5/2)ν0d(3/2) effective force used in shell-model calculations should be reduced to properly account for the weak binding of (9)(26)F. Microscopic coupled cluster theory calculations using interactions derived from chiral effective field theory are in very good agreement with the energy of the low-lying 1(1)(+), 2(1)(+), 4(1)(+) states in (26)F. Including three-body forces and coupling to the continuum effects improve the agreement between experiment and theory as compared to the use of two-body forces only.

First measurement of pure electron shakeoff in the ß decay of trapped 6He+ ions.

The electron shakeoff probability of 6Li2+ ions resulting from the ß- decay of 6He+ ions has been measured with high precision using a specially designed recoil ion spectrometer. This is the first measurement of a pure electron shakeoff following nuclear ß decay, not affected by multielectron processes such as Auger cascades. In this ideal textbook case for the application of the sudden approximation, the experimental ionization probability was found to be P(so)(exp)=0.02339(36) in perfect agreement with simple quantum mechanical calculations.

Unveiling the intruder deformed 02(+) state in 34Si.

The 02(+) state in 34Si has been populated at the GANIL-LISE3 facility through the ß decay of a newly discovered 1(+) isomer in 34Al of 26(1) ms half-life. The simultaneous detection of e(+)e(-) pairs allowed the determination of the excitation energy E(02(+))=2719(3) keV and the half-life T(1/2)=19.4(7) ns, from which an electric monopole strength of ρ(2)(E0)=13.0(0.9)×10(-3) was deduced. The 2(1)(+) state is observed to decay both to the 0(1)(+) ground state and to the newly observed 0(2)(+) state [via a 607(2) keV transition] with a ratio R(2(1)(+)→0(1)(+)/2(1)(+)→0(2)(+))=1380(717). Gathering all information, a weak mixing with the 0(1)(+) and a large deformation parameter of ß=0.29(4) are found for the 0(2)(+) state, in good agreement with shell model calculations using a new SDPF-U-MIX interaction allowing np-nh excitations across the N=20 shell gap.

The impact of the meta-analysis of pulmonary rehabilitation by Lacasse and colleagues: transforming pulmonary rehabilitation from "art to science".

#Pulmonaryrehab was transformed in the 1990s into the standard of care for COPD: this article focuses on the impact of the 1996 meta-analysis by Lacasse and colleagues which provided the evidence to silence the sceptics https://bit.ly/3MIntBC.

Streptococcus pneumoniae serotype 6C: an intra- and interclonal complex comparison.

We report the annotated draft genome sequences of four serotype 6C Streptococcus pneumoniae isolates of differing genetic backgrounds. Serotype 6C isolates are increasing in prevalence and becoming progressively more resistant to antibiotics. As a result, these strains are likely to become more important in the near future.

Direct observation of two protons in the decay of 54Zn.

The two protons emitted in the decay of 54Zn have been individually observed for the first time in a time projection chamber. The total decay energy and the half-life measured in this work agree with the results obtained in a previous experiment. Angular and energy correlations between the two protons are determined and compared to theoretical distributions of a three-body model. Within the shell model framework, the relative decay probabilities show a strong contribution of the p2 configuration for the two-proton emission. After 45Fe, the present result on 54Zn constitutes only the second case of a direct observation of the ground state two-proton decay of a long-lived isotope.

4D-imaging of drip-line radioactivity by detecting proton emission from 54mNi pictured with ACTAR TPC.

Proton radioactivity was discovered exactly 50 years ago. First, this nuclear decay mode sets the limit of existence on the nuclear landscape on the neutron-deficient side. Second, it comprises fundamental aspects of both quantum tunnelling as well as the coupling of (quasi)bound quantum states with the continuum in mesoscopic systems such as the atomic nucleus. Theoretical approaches can start either from bound-state nuclear shell-model theory or from resonance scattering. Thus, proton-radioactivity guides merging these types of theoretical approaches, which is of broader relevance for any few-body quantum system. Here, we report experimental measurements of proton-emission branches from an isomeric state in 54mNi, which were visualized in four dimensions in a newly developed detector. We show that these decays, which carry an unusually high angular momentum, ℓ = 5 and ℓ = 7, respectively, can be approximated theoretically with a potential model for the proton barrier penetration and a shell-model calculation for the overlap of the initial and final wave functions.