Probing Dynein and Kinesin Stepping with Mechanical Manipulation in a Living Cell

Molecular motors: By combining optical tweezers and high-speed particle tracking, individual steps of microtubule motor proteins transporting organelles can be detected under known force loads in living mammalian cells (see figure). We report a label-free assay for simultaneous optical manipulation and tracking of endogenous lipid droplets as actively transported cargoes in a living mammalian cell with sub-millisecond time resolution. Using an EM-CCD camera as a highly sensitive quadrant detector, we can detect steps of dynein- and kinesin-driven cargoes under known force loads. We can distinguish single and multiple motor-driven cargoes and show that the stall forces for inward and outward transported cargoes are similar. By combining the stall force observable with the ability to detect individual steps, we can characterize kinesin- and dynein-driven active transport in different force regimes.Chemistry and Chemical Biolog

A Bayesian Calibration Framework for EDGES

We develop a Bayesian model that jointly constrains receiver calibration, foregrounds and cosmic 21cm signal for the EDGES global 21\,cm experiment. This model simultaneously describes calibration data taken in the lab along with sky-data taken with the EDGES low-band antenna. We apply our model to the same data (both sky and calibration) used to report evidence for the first star formation in 2018. We find that receiver calibration does not contribute a significant uncertainty to the inferred cosmic signal (<1%), though our joint model is able to more robustly estimate the cosmic signal for foreground models that are otherwise too inflexible to describe the sky data. We identify the presence of a significant systematic in the calibration data, which is largely avoided in our analysis, but must be examined more closely in future work. Our likelihood provides a foundation for future analyses in which other instrumental systematics, such as beam corrections and reflection parameters, may be added in a modular manner.Comment: 18 pages + 3 for appendices. 13 figures. Accepted to MNRA

Analytic approximations of scattering effects on beam chromaticity in 21-cm global experiments

Scattering from objects near an antenna produce correlated signals from strong compact radio sources in a manner similar to those used by the Sea Interferometer to measure the radio source positions using the fine frequency structure in the total power spectrum of a single antenna. These fringes or ripples due to correlated signal interference are present at a low level in the spectrum of any single antenna and are a major source of systematics in systems used to measure the global redshifted 21-cm signal from the early universe. In the Sea Interferometer a single antenna on a cliff above the sea is used to add the signal from the direct path to the signal from the path reflected from the sea thereby forming an interferometer. This was used for mapping radio sources with a single antenna by Bolton and Slee in the 1950s. In this paper we derive analytic expressions to determine the level of these ripples and compare these results in a few simple cases with electromagnetic modeling software to verify that the analytic calculations are sufficient to obtain the magnitude of the scattering effects on the measurements of the global 21-cm signal. These analytic calculations are needed to evaluate the magnitude of the effects in cases that are either too complex or take too much time to be modeled using software

Low-Frequency Radio Recombination Lines Away From the Inner Galactic Plane

Diffuse radio recombination lines (RRLs) in the Galaxy are possible foregrounds for redshifted 21~cm experiments. We use EDGES drift scans centered at $-26.7^o$~declination to characterize diffuse RRLs across the southern sky. We find RRLs averaged over the large antenna beam ($72^o \times 110^o$) reach minimum amplitudes between right ascensions~2-6~h. In this region, the C$\alpha$ absorption amplitude is $33\pm11$~mK (1$\sigma$) averaged over 50-87~MHz ($27\gtrsim z \gtrsim15$ for the 21~cm line) and increases strongly as frequency decreases. C$\beta$ and H$\alpha$ lines are consistent with no detection with amplitudes of $13\pm14$ and $12\pm10$~mK (1$\sigma$), respectively. At 108-124.5~MHz ($z\approx11$) in the same region, we find no evidence for carbon or hydrogen lines at the noise level of 3.4~mK (1$\sigma$). Conservatively assuming observed lines come broadly from the diffuse interstellar medium, as opposed to a few compact regions, these amplitudes provide upper limits on the intrinsic diffuse lines. The observations support expectations that Galactic RRLs can be neglected as significant foregrounds for a large region of sky until redshifted 21~cm experiments, particularly those targeting Cosmic Dawn, move beyond the detection phase. We fit models of the spectral dependence of the lines averaged over the large beam of EDGES, which may contain multiple line sources with possible line blending, and find that including degrees of freedom for expected smooth, frequency-dependent deviations from local thermodynamic equilibrium (LTE) is preferred over simple LTE assumptions for C$\alpha$ and H$\alpha$ lines. For C$\alpha$ we estimate departure coefficients $0.79<b_n\beta_n<4.5$ along the inner Galactic Plane and $0<b_n\beta_n<2.3$ away from the inner Galactic Plane.Comment: 25 pages, 14 figures, 3 tables, submitted to AA

A Bayesian approach to modelling spectrometer data chromaticity corrected using beam factors -- I. Mathematical formalism

Accurately accounting for spectral structure in spectrometer data induced by instrumental chromaticity on scales relevant for detection of the 21-cm signal is among the most significant challenges in global 21-cm signal analysis. In the publicly available EDGES low-band data set, this complicating structure is suppressed using beam-factor based chromaticity correction (BFCC), which works by dividing the data by a sky-map-weighted model of the spectral structure of the instrument beam. Several analyses of this data have employed models that start with the assumption that this correction is complete. However, while BFCC mitigates the impact of instrumental chromaticity on the data, given realistic assumptions regarding the spectral structure of the foregrounds, the correction is only partial. This complicates the interpretation of fits to the data with intrinsic sky models (models that assume no instrumental contribution to the spectral structure of the data). In this paper, we derive a BFCC data model from an analytic treatment of BFCC and demonstrate using simulated observations that, in contrast to using an intrinsic sky model for the data, the BFCC data model enables unbiased recovery of a simulated global 21-cm signal from beam-factor chromaticity corrected data in the limit that the data is corrected with an error-free beam-factor model.Comment: 26 pages, 8 figures; accepted for publication in MNRA

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial

BACKGROUND: Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. METHODS: ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. FINDINGS: Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89–1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87–1·20], p=0·77). INTERPRETATION: In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. FUNDING: UK National Institute for Health and Care Research

Linking protective GAB2 variants, increased cortical GAB2 expression and decreased Alzheimer's Disease pathology

GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimer’s disease (LOAD) with reported odds ratios (ORs) ranging from 0.75–0.85. We tested eight GAB2 variants in four North American Caucasian case-control series (2,316 LOAD, 2,538 controls) for association with LOAD. Meta-analyses revealed ORs ranging from (0.61–1.20) with no significant association (all p>0.32). Four variants were hetergeneous across the populations (all p<0.02) due to a potentially inflated effect size (OR = 0.61–0.66) only observed in the smallest series (702 LOAD, 209 controls). Despite the lack of association in our series, the previously reported protective association for GAB2 remained after meta-analyses of our data with all available previously published series (11,952-22,253 samples; OR = 0.82–0.88; all p<0.04). Using a freely available database of lymphoblastoid cell lines we found that protective GAB2 variants were associated with increased GAB2 expression (p = 9.5×10−7−9.3×10−6). We next measured GAB2 mRNA levels in 249 brains and found that decreased neurofibrillary tangle (r = −0.34, p = 0.0006) and senile plaque counts (r = −0.32, p = 0.001) were both good predictors of increased GAB2 mRNA levels albeit that sex (r = −0.28, p = 0.005) may have been a contributing factor. In summary, we hypothesise that GAB2 variants that are protective against LOAD in some populations may act functionally to increase GAB2 mRNA levels (in lymphoblastoid cells) and that increased GAB2 mRNA levels are associated with significantly decreased LOAD pathology. These findings support the hypothesis that Gab2 may protect neurons against LOAD but due to significant population heterogeneity, it is still unclear whether this protection is detectable at the genetic level

Multi-ancestry genome-wide association study accounting for gene-psychosocial factor interactions identifies novel loci for blood pressure traits

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP, taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from five ancestry groups. In the combined meta-analyses of stages 1 and 2, we identified 59 loci (p value &lt; 5e−8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel&nbsp;loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A and PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5 and CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations