First evidence of pulsations in Vega? Results of today's most extensive spectroscopic search

The impact of rapid rotation on stellar evolution theory remains poorly understood as of today. Vega is a special object in this context as spectroscopic and interferometric studies have shown that it is a rapid rotator seen nearly pole one, a rare orientation particularly interesting for seismic studies. In this paper we present a first systematic search for pulsations in Vega. The goal of the present work is to detect for the first time pulsations in a rapidly rotating star seen nearly pole-on. Vega was monitored in quasi-continuous high-resolution echelle spectroscopy. A total of 4478 spectra were obtained within 3 individual runs in 2008, 2009 and 2010 at high resolution. This data set should represent the most extensive high S/N, high resolution quasi-continuous survey obtained on Vega as of today. Equivalent photospheric absorption profiles were calculated for the stellar spectrum, but also for the telluric lines acting as a radial velocity reference. Residual velocities were analysed and periodic low amplitude variations, potentially indicative of stellar pulsations, detected. All three data sets revealed the presence of residual periodic variations: 5.32 and 9.19 c/d, (A approx 6 m/s) in 2008, 12.71 and 13.25 c/d, (A approx 8 m/s) in 2009 and 5.42 and 10.82 c/d, (A approx 3-4 m/s) in 2010. A Lomb-Scargle periodogram of each velocity bin of the equivalent profile was performed for the 2010 run, not showing the presence of any higher order nrp mode. It is too early to conclude that the variations are due to stellar pulsations, and a confirmation of the detection with a highly stable spectrograph is a necessary next step. If pulsations are confirmed, their very small amplitudes show that the star would belong to a category of very "quiet" pulsators

A coaching program to improve dietary intake of patients with CKD: ENTICE-CKD

The dietary self-management of CKD is challenging. Telehealth interventions may provide an effective delivery method to facilitate sustained dietary change.This pilot, randomized, controlled trial evaluated secondary and exploratory outcomes after a dietitian-led telehealth coaching intervention to improve diet quality in people with stage 3-4 CKD. The intervention group received phone calls every 2 weeks for 3 months (with concurrent, tailored text messages for 3 months), followed by 3 months of tailored text messages without telephone coaching, to encourage a diet consistent with CKD guidelines. The control group received usual care for 3 months, followed by nontailored, educational text messages for 3 months.Eighty participants (64% male), aged 62±12 years, were randomized to the intervention or control group. Telehealth coaching was safe, with no adverse events or changes to serum biochemistry at any time point. At 3 months, the telehealth intervention, compared with the control, had no detectable effect on overall diet quality on the Alternative Health Eating Index (3.2 points, 95% confidence interval, -1.3 to 7.7), nor at 6 months (0.5 points, 95% confidence interval, -4.6 to 5.5). There was no change in clinic BP at any time point in any group. There were significant improvements in several exploratory diet and clinical outcomes, including core food group consumption, vegetable servings, fiber intake, and body weight.Telehealth coaching was safe, but appeared to have no effect on the Alternative Healthy Eating Index or clinic BP. There were clinically significant changes in several exploratory diet and clinical outcomes, which require further investigation.Evaluation of Individualized Telehealth Intensive Coaching to Promote Healthy Eating and Lifestyle in CKD (ENTICE-CKD), ACTRN12616001212448

Diabetes Mellitus and Mortality after Acute Coronary Syndrome as a First or Recurrent Cardiovascular Event

Diabetes Mellitus (DM) is associated with adverse cardiovascular prognosis. However, the risk associated with DM may vary between individuals according to their overall cardiovascular risk burden. Therefore, we aimed to determine whether DM is associated with poor outcome in patients presenting with Acute Coronary Syndrome (ACS) according to the index episode being a first or recurrent cardiovascular event.We conducted a retrospective analysis of a prospective cohort study involving 2499 consecutively admitted patients with confirmed ACS in 11 UK hospitals during 2003. Usual care was provided for all participants. Demographic factors, co-morbidity and treatment (during admission and at discharge) factors were recorded. The primary outcome was all cause mortality (median 2 year follow up), compared for cohorts with and without DM according to their prior cardiovascular disease (CVD) disease status. Adjusted analyses were performed with Cox proportional hazards regression analysis. Within the entire cohort, DM was associated with an unadjusted 45% increase in mortality. However, in patients free of a history of CVD, mortality of those with and without DM was similar (18.8% and 19.7% respectively; p = 0.74). In the group with CVD, mortality of patients with DM was significantly higher than those without DM (46.7% and 33.2% respectively; p<0.001). The age and sex adjusted interaction between DM and CVD in predicting mortality was highly significant (p = 0.002) and persisted after accounting for comorbidities and treatment factors (p = 0.006). Of patients free of CVD, DM was associated with smaller elevation of Troponin I (p<0.001). However in patients with pre-existing CVD Troponin I was similar (p = 0.992).DM is only associated with worse outcome after ACS in patients with a pre-existing history of CVD. Differences in the severity of myocyte necrosis may account for this. Further investigation is required, though our findings suggest that aggressive primary prevention of CVD in patients with DM may have beneficially modified their first presentation with (and mortality after) ACS

Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification

A Study of Pi Aquarii During a Quasi-normal Star Phase: Refined Fundamental Parameters and Evidence for Binarity

We present the results of recent multicolor photometric and high-resolution spectroscopic observations of the bright Be star Pi Aquarii. Observational data collected from the literature were used to study the star's variations over the last four decades. The star is identified with the IR sources F22227+0107 in the IRAS Faint Point Source catalog and MSX5_G066.0066-44.7392 in the MSX catalog. The variations in near-IR brightness of Pi Aqr are found to be among the largest reported for Be stars. Since 1996, the star has shown only weak signs of circumstellar emission, which has allowed us to refine the fundamental stellar parameters: A_V=0.15 mag., T_eff=24000K, log g=3.9, and M_V=-2.95 mag. A weak emission component of the H-alpha line has been detected during the recent quasi-normal star phase. From analysis of the H-alpha line profiles, we find anti-phased radial velocity variations of the emission component and the photospheric absorption, with a period of 84.1 days and semi-amplitudes of 101.4 and 16.7 km/s, respectively. This result suggests that Pi Aqr may be a binary system consisting of stars with masses of M_1 sin^{3}i = 12.4 M_sun, M_2 sin^{3}i = 2.0 M_sun. We also estimate the orbital inclination angle to be between 50 and 75 degrees. We suggest that the photometric, spectroscopic, and polarimetric variations observed during the second half of the 20th century may be due to variable mass transfer between the binary components.Comment: 26 pages (including 8 figs, 2 tables), accepted by Ap

Cyclic AMP Control Measured in Two Compartments in HEK293 Cells: Phosphodiesterase KM Is More Important than Phosphodiesterase Localization

The intracellular second messenger cyclic AMP (cAMP) is degraded by phosphodiesterases (PDE). The knowledge of individual families and subtypes of PDEs is considerable, but how the different PDEs collaborate in the cell to control a cAMP signal is still not fully understood. In order to investigate compartmentalized cAMP signaling, we have generated a membrane-targeted variant of the cAMP Bioluminiscence Resonance Energy Transfer (BRET) sensor CAMYEL and have compared intracellular cAMP measurements with it to measurements with the cytosolic BRET sensor CAMYEL in HEK293 cells. With these sensors we observed a slightly higher cAMP response to adenylyl cyclase activation at the plasma membrane compared to the cytosol, which is in accordance with earlier results from Fluorescence Resonance Energy Transfer (FRET) sensors. We have analyzed PDE activity in fractionated lysates from HEK293 cells using selective PDE inhibitors and have identified PDE3 and PDE10A as the major membrane-bound PDEs and PDE4 as the major cytosolic PDE. Inhibition of membrane-bound or cytosolic PDEs can potentiate the cAMP response to adenylyl cyclase activation, but we see no significant difference between the potentiation of the cAMP response at the plasma membrane and in cytosol when membrane-bound and cytosolic PDEs are inhibited. When different levels of stimulation were tested, we found that PDEs 3 and 10 are mainly responsible for cAMP degradation at low intracellular cAMP concentrations, whereas PDE4 is more important for control of cAMP at higher concentrations

A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease

Purpose: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. Methods: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. Results: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. Conclusion: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration

PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.

OBJECTIVE: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. METHODS: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. RESULTS: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. INTERPRETATION: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225-240