The zinc cluster protein Sut1 contributes to filamentation in Saccharomyces cerevisiae

Copyright © 2013, American Society for Microbiology. All Rights ReservedSut1 is a transcriptional regulator of the Zn(II)(2)Cys(6) family in the budding yeast Saccharomyces cerevisiae. The only function that has been attributed to Sut1 is sterol uptake under anaerobic conditions. Here, we show that Sut1 is also expressed in the presence of oxygen, and we identify a novel function for Sut1. SUT1 overexpression blocks filamentous growth, a response to nutrient limitation, in both haploid and diploid cells. This inhibition by Sut1 is independent of its function in sterol uptake. Sut1 downregulates the expression of GAT2, HAP4, MGA1, MSN4, NCE102, PRR2, RHO3, and RHO5. Several of these Sut1 targets (GAT2, HAP4, MGA1, RHO3, and RHO5) are essential for filamentation in haploids and/or diploids. Furthermore, the expression of the Sut1 target genes, with the exception of MGA1, is induced during filamentous growth. We also show that SUT1 expression is autoregulated and inhibited by Ste12, a key transcriptional regulator of filamentation. We propose that Sut1 partially represses the expression of GAT2, HAP4, MGA1, MSN4, NCE102, PRR2, RHO3, and RHO5 when nutrients are plentiful. Filamentation-inducing conditions relieve this repression by Sut1, and the increased expression of Sut1 targets triggers filamentous growth.The project was supported by Deutsche Forschungsgemeinschaft grant HO 2098/

The association between baseline persistent pain and weight change in patients attending a specialist weight management service

To quantify the influence of baseline pain levels on weight change at one-year follow-up in patients attending a National Health Service specialist weight management programme.We compared one-year follow-up weight (body mass) change between patient sub-groups of none-to-mild, moderate, and severe pain at baseline. A mean sub-group difference in weight change of ≥5kg was considered clinically relevant.Of the 141 complete cases, n = 43 (30.5%) reported none-to-mild pain, n = 44 (31.2%) reported moderate pain, and n = 54 (38.3%) reported severe pain. Covariate-adjusted mean weight loss (95%CI) was similar for those with none-to-mild (8.1kg (4.2 to 12.0kg)) and moderate pain (8.3kg (4.9 to 11.7kg). The mean weight loss of 3.0kg (-0.4 to 6.4kg) for the severe pain group was 5.1kg (-0.6 to 10.7, p = 0.08) lower than the none-to-mild pain group and 5.3kg (0.4 to 10.2kg, p = 0.03) lower than the moderate pain group.Patients with severe pain upon entry to a specialist weight management service in England achieve a smaller mean weight loss at one-year follow-up than those with none-to-moderate pain. The magnitude of the difference in mean weight loss was clinically relevant, highlighting the importance of addressing severe persistent pain in obese patients undertaking weight management programmes

Weight-loss interventions for adults with overweight/obesity and chronic musculoskeletal pain: a mixed methods systematic review

Worldwide prevalence of adult overweight and obesity is a growing public health issue. Adults with overweight/obesity often have chronic musculoskeletal pain (CMP). Using a mixed-methods review, we aimed to quantify the effectiveness and explore the appropriateness of weight loss interventions for this population. Electronic databases were searched for studies published between 01/01/90 and 01/07/16. The review included 14 randomized controlled trials that reported weight and pain outcomes, and three qualitative studies that explored perceptions of adults with co-existing overweight/obesity and CMP. The random-effects pooled mean weight loss was 4.9kg (95%CI:2.9,6.8) greater for intervention vs control. The pooled mean reduction in pain was 7.3/100units (95%CI:4.1,10.5) greater for intervention vs control. Study heterogeneity was substantial for weight loss (I 2 =95%, tau= plus-minus 3.5kg) and pain change (I 2 =67%, tau= plus-minus 4.1%). Meta-regression slopes for the predictors of study quality, mean age and baseline mean weight on mean study weight reduction were shallow and not statistically significant (P > 0.05). The meta-regression slope between mean pain reduction and mean weight lost was shallow, and not statistically significant, −0.09kg per unit pain score change (95%CI:−0.21,0.40, P=0.54). Meta-synthesis of qualitative findings resulted in two synthesized findings; the importance of healthcare professionals understanding the effects of pain on ability to control weight and developing management/education programmes that address co-morbidity

Influence of Race on Microsatellite Instability and CD8+ T Cell Infiltration in Colon Cancer

African American patients with colorectal cancer show higher mortality than their Caucasian counterparts. Biology might play a partial role, and prior studies suggest a higher prevalence for microsatellite instability (MSI) among cancers from African Americans, albeit patients with MSI cancers have improved survival over patients with non-MSI cancers, counter to the outcome observed for African American patients. CD8+ T cell infiltration of colon cancer is postively correlated with MSI tumors, and is also related to improved outcome. Here, we utilized a 503-person, population-based colon cancer cohort comprising 45% African Americans to determine, under blinded conditions from all epidemiological data, the prevalence of MSI and associated CD8+ T cell infiltration within the cancers. Among Caucasian cancers, 14% were MSI, whereas African American cancers demonstrated 7% MSI (P = 0.009). Clinically, MSI cancers between races were similar; among microsatellite stable cancers, African American patients were younger, female, and with proximal cancers. CD8+ T cells were higher in MSI cancers (88.0 vs 30.4/hpf, P<0.0001), but was not different between races. Utilizing this population-based cohort, African American cancers show half the MSI prevalence of Caucasians without change in CD8+ T cell infiltration which may contribute towards their higher mortality from colon cancer

A truncated DNA-damage-signaling response is activated after DSB formation in the G1 phase of Saccharomyces cerevisiae

In Saccharomyces cerevisiae, the DNA damage response (DDR) is activated by the spatio-temporal colocalization of Mec1-Ddc2 kinase and the 9-1-1 clamp. In the absence of direct means to monitor Mec1 kinase activation in vivo, activation of the checkpoint kinase Rad53 has been taken as a proxy for DDR activation. Here, we identify serine 378 of the Rad55 recombination protein as a direct target site of Mec1. Rad55-S378 phosphorylation leads to an electrophoretic mobility shift of the protein and acts as a sentinel for Mec1 activation in vivo. A single double-stranded break (DSB) in G1-arrested cells causes phosphorylation of Rad55-S378, indicating activation of Mec1 kinase. However, Rad53 kinase is not detectably activated under these conditions. This response required Mec1-Ddc2 and loading of the 9-1-1 clamp by Rad24-RFC, but not Rad9 or Mrc1. In addition to Rad55–S378, two additional direct Mec1 kinase targets are phosphorylated, the middle subunit of the ssDNA-binding protein RPA, RPA2 and histone H2A (H2AX). These data suggest the existence of a truncated signaling pathway in response to a single DSB in G1-arrested cells that activates Mec1 without eliciting a full DDR involving the entire signaling pathway including the effector kinases

Light Curves and Colors of the Ejecta from Dimorphos after the DART Impact

On 26 September 2022 the Double Asteroid Redirection Test (DART) spacecraft impacted Dimorphos, a satellite of the asteroid 65803 Didymos. Because it is a binary system, it is possible to determine how much the orbit of the satellite changed, as part of a test of what is necessary to deflect an asteroid that might threaten Earth with an impact. In nominal cases, pre-impact predictions of the orbital period reduction ranged from ~8.8 - 17.2 minutes. Here we report optical observations of Dimorphos before, during and after the impact, from a network of citizen science telescopes across the world. We find a maximum brightening of 2.29 $\pm$ 0.14 mag upon impact. Didymos fades back to its pre-impact brightness over the course of 23.7 $\pm$ 0.7 days. We estimate lower limits on the mass contained in the ejecta, which was 0.3 - 0.5% Dimorphos' mass depending on the dust size. We also observe a reddening of the ejecta upon impact.Comment: Accepted by Natur

Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics

Liquid-liquid phase separation (LLPS) of RNA-binding proteins plays an important role in the formation of multiple membrane-less organelles involved in RNA metabolism, including stress granules. Defects in stress granule homeostasis constitute a cornerstone of ALS/FTLD pathogenesis. Polar residues (tyrosine and glutamine) have been previously demonstrated to be critical for phase separation of ALS-linked stress granule proteins. We now identify an active role for arginine-rich domains in these phase separations. Moreover, arginine-rich dipeptide repeats (DPRs) derived from C9orf72 hexanucleotide repeat expansions similarly undergo LLPS and induce phase separation of a large set of proteins involved in RNA and stress granule metabolism. Expression of arginine-rich DPRs in cells induced spontaneous stress granule assembly that required both eIF2α phosphorylation and G3BP. Together with recent reports showing that DPRs affect nucleocytoplasmic transport, our results point to an important role for arginine-rich DPRs in the pathogenesis of C9orf72 ALS/FTLD