Induction of SOCS-3 is insufficient to confer IRS-1 protein degradation in 3T3-L1 adipocytes

Insulin receptor substrate (IRS)-1 is a key protein in insulin signaling. Several studies have shown that the expression of IRS-1 can be modulated by protein degradation via the proteasome and the degradation of IRS-1 can be related to insulin-resistant states. The degradation of IRS-1 has been shown to be induced by SOCS-1 and SOCS-3 via the ubiquitin pathway. The goal of our study was to determine if the induction of SOCS-3 correlated with increased IRS-1 degradation in cultured 3T3-L1 adipocytes. Interestingly, our studies have shown that there is little correlation between the induction in SOCS-3 expression and the degradation of IRS-1 in mature 3T3-L1 adipocytes. Our results clearly demonstrate that treatment with leukemia inhibitory factor (LIF) or cardiotrophin (CT)-1 strongly induces the expression of SOCS-3 in mature 3T3-L1 adipocytes, but does not affect the degradation of IRS-1. On the contrary, tumor necrosis factor (TNF) α and insulin, which very weakly induce SOCS-3 expression, have profound effects on IRS-1 degradation. In summary, our results indicate that the expression of SOCS-3 does not correlate with the degradation of IRS-1 proteins in fat cells. © 2006 Elsevier Inc. All rights reserved

Adjusting for genetic confounders in transcriptome-wide association studies improves discovery of risk genes of complex traits

Many methods have been developed to leverage expression quantitative trait loci (eQTL) data to nominate candidate genes from genome-wide association studies. These methods, including colocalization, transcriptome-wide association studies (TWAS) and Mendelian randomization-based methods; however, all suffer from a key problem—when assessing the role of a gene in a trait using its eQTLs, nearby variants and genetic components of other genes’ expression may be correlated with these eQTLs and have direct effects on the trait, acting as potential confounders. Our extensive simulations showed that existing methods fail to account for these ‘genetic confounders’, resulting in severe inflation of false positives. Our new method, causal-TWAS (cTWAS), borrows ideas from statistical fine-mapping and allows us to adjust all genetic confounders. cTWAS showed calibrated false discovery rates in simulations, and its application on several common traits discovered new candidate genes. In conclusion, cTWAS provides a robust statistical framework for gene discovery

Tumour-derived leukaemia inhibitory factor is a major driver of cancer cachexia and morbidity in C26 tumour-bearing mice

BACKGROUND: Cancer cachexia is a metabolic wasting syndrome that is strongly associated with a poor prognosis. The initiating factors causing fat and muscle loss are largely unknown. Previously, we found that leukaemia inhibitory factor (LIF) secreted by C26 colon carcinoma cells was responsible for atrophy in treated myotubes. In the present study, we tested whether C26 tumour‐derived LIF is required for cancer cachexia in mice by knockout of Lif in C26 cells. METHODS: A C26 Lif null tumour cell line was made using CRISPR‐Cas9. Measurements of cachexia were compared in mice inoculated with C26 vs. C26^Lif−/− tumour cells, and atrophy was compared in myotubes treated with medium from C26 vs. C26^Lif−/− tumour cells. Levels of 25 cytokines/chemokines were compared in serum of mice bearing C26 vs. C26^Lif−/− tumours and in the medium from these tumour cell lines. RESULTS: At study endpoint, C26 mice showed outward signs of sickness while mice with C26^Lif−/− tumours appeared healthy. Mice with C26^Lif−/− tumours showed a 55–75% amelioration of body weight loss, muscle loss, fat loss, and splenomegaly compared with mice with C26 tumours (P < 0.05). The heart was not affected by LIF levels because the loss of cardiac mass was the same in C26 and C^26Lif−/− tumour‐bearing mice. LIF levels in mouse serum was entirely dependent on secretion from the tumour cells. Serum levels of interleukin‐6 and G‐CSF were increased by 79‐fold and 68‐fold, respectively, in C26 mice but only by five‐fold and two‐fold, respectively, in C26^Lif−/− mice, suggesting that interleukin‐6 and G‐CSF increases are dependent on tumour‐derived LIF. CONCLUSIONS: This study shows the first use of CRISPR‐Cas9 knockout of a candidate cachexia factor in tumour cells. The results provide direct evidence for LIF as a major cachexia initiating factor for the C26 tumour in vivo. Tumour‐derived LIF was also a regulator of multiple cytokines in C26 tumour cells and in C26 tumour‐bearing mice. The identification of tumour‐derived factors such as LIF that initiate the cachectic process is immediately applicable to the development of therapeutics to treat cachexia. This is a proof of principle for studies that when carried out in human cells, will make possible an understanding of the factors causing cachexia in a patient‐specific manner.This work was supported by NIAMS R01AR060217 to S. C. K. and R. W. J. and NIAMS R01 R01AR060209 to A. R. J., and by the Dudley Allen Sargent Research Fund. The authors certify that they comply with the ethical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle: update 2017.40 (R01AR060217 - NIAMS; R01 R01AR060209 - NIAMS; Dudley Allen Sargent Research Fund)Published versio

Optimal algorithms for haplotype assembly from whole-genome sequence data

Motivation: Haplotype inference is an important step for many types of analyses of genetic variation in the human genome. Traditional approaches for obtaining haplotypes involve collecting genotype information from a population of individuals and then applying a haplotype inference algorithm. The development of high-throughput sequencing technologies allows for an alternative strategy to obtain haplotypes by combining sequence fragments. The problem of ‘haplotype assembly’ is the problem of assembling the two haplotypes for a chromosome given the collection of such fragments, or reads, and their locations in the haplotypes, which are pre-determined by mapping the reads to a reference genome. Errors in reads significantly increase the difficulty of the problem and it has been shown that the problem is NP-hard even for reads of length 2. Existing greedy and stochastic algorithms are not guaranteed to find the optimal solutions for the haplotype assembly problem

Faecal immunochemical test for patients with 'high-risk' bowel symptoms: a large prospective cohort study and updated literature review

Background: We evaluated whether faecal immunochemical testing (FIT) can rule out colorectal cancer (CRC) among patients presenting with ‘high-risk’ symptoms requiring definitive investigation. Methods: Three thousand five hundred and ninety-six symptomatic patients referred to the standard urgent CRC pathway were recruited in a multi-centre observational study. They completed FIT in addition to standard investigations. CRC miss rate (percentage of CRC cases with low quantitative faecal haemoglobin [f-Hb] measurement) and specificity (percentage of patients without cancer with low f-Hb) were calculated. We also provided an updated literature review. Results: Ninety patients had CRC. At f-Hb < 10 µg/g, the miss rate was 16.7% (specificity 80.1%). At f-Hb < 4 µg/g, the miss rate was 12.2% (specificity 73%), which became 3.3% if low FIT plus the absence of anaemia and abdominal pain were considered (specificity 51%). Within meta-analyses of 9 UK studies, the pooled miss rate was 7.2% (specificity 74%) for f-Hb < 4 µg/g. Discussion: FIT alone as a triage tool would miss an estimated 1 in 8 cases in our study (1 in 14 from meta-analysis), while many people without CRC could avoid investigations. FIT can focus secondary care diagnostic capacity on patients most at risk of CRC, but more work on safety netting is required before incorporating FIT triage into the urgent diagnostic pathway

Quantitative faecal immunochemical test for patients with 'high risk' bowel symptoms: a prospective cohort study

Objectives: To evaluate whether quantitative measurement of faecal haemoglobin (f-Hb) using faecal immunochemical testing (FIT) can be used to rule out colorectal cancer (CRC) for patients who present to primary care with ‘high risk’ symptoms defined by national guidelines for urgent referral for suspected cancer (NICE NG12). / Design: Prospective cohort study carried out between April 2017 and March 2019. / Setting: 59 GP practices in London and 24 hospitals in England. / Participants: Symptomatic patients in England referred to the urgent CRC pathway who provided a faecal sample for FIT in addition to standard investigations for cancer. / Main outcome measures: CRC was confirmed by established clinical and histopathology procedures. f-Hb (μg per gram of stool) was measured in a central laboratory blinded to cancer outcome. We calculated sensitivity (percentage of patients with CRC who have f-Hb exceeding specified cut-offs); false-positive rate [FPR] (percentage of patients without CRC whose f-Hb exceeds the same cut-offs); and positive predictive value [PPV] (percentage of all patients with f-Hb above the cut-offs who have CRC). / Results: 4676 patients were recruited of whom 3596 patients were included (had a valid FIT test and a known definitive diagnosis). Among the 3596, median age was 67 years, 53% were female and 78% had colonoscopy. 90 patients were diagnosed with CRC, 7 with other cancers, and 3499 with no cancer found. f-Hb did not correlate with age, sex or ethnicity. Using f-Hb ≥4μg/g (lowest limit of detection), sensitivity, FPR and PPV were 87.8%, 27.0% and 7.7% respectively. Using f-Hb ≥10μg/g, the corresponding measures were 83.3%, 19.9% and 9.7%. 15 patients with CRC had f-Hb below 10μg/g. If FIT had been used at thresholds of 10μg/g or 4μg/g, 1 in 6 or 1 in 8 patients with cancer respectively would have been missed. If the absence of anaemia or abdominal pain is used alongside f-Hb 10 μg/g, only 1 in 18 cancers would be missed but 56% of people without CRC could potentially avoid further investigations including colonoscopies. / Conclusions: In our study, if FIT alone had been used to determine urgent referral for patients with ‘high risk’ symptoms for definitive cancer investigation, some patients with bowel cancer would not have been diagnosed. If used in conjunction with clinical features, particularly in the absence of anaemia, the efficacy of FIT is significantly improved. With appropriate safety netting, FIT could be used to focus secondary care diagnostic capacity on patients most at risk of CRC

Global health crises are also information crises: A call to action

Association for Information Science & Technology published a piece from Bo Xie and others about the Misinformation/disinformation particularly during global health crises on March 13, 2020.Office of the VP for Researc

Entropy bounds in terms of the w parameter

In a pair of recent articles [PRL 105 (2010) 041302 - arXiv:1005.1132; JHEP 1103 (2011) 056 - arXiv:1012.2867] two of the current authors have developed an entropy bound for equilibrium uncollapsed matter using only classical general relativity, basic thermodynamics, and the Unruh effect. An odd feature of that bound, S <= A/2, was that the proportionality constant, 1/2, was weaker than that expected from black hole thermodynamics, 1/4. In the current article we strengthen the previous results by obtaining a bound involving the (suitably averaged) w parameter. Simple causality arguments restrict this averaged parameter to be <= 1. When equality holds, the entropy bound saturates at the value expected based on black hole thermodynamics. We also add some clarifying comments regarding the (net) positivity of the chemical potential. Overall, we find that even in the absence of any black hole region, we can nevertheless get arbitrarily close to the Bekenstein entropy.Comment: V1: 14 pages. V2: One reference added. V3: This version accepted for publication in JHE

Sex-biased parental care and sexual size dimorphism in a provisioning arthropod

The diverse selection pressures driving the evolution of sexual size dimorphism (SSD) have long been debated. While the balance between fecundity selection and sexual selection has received much attention, explanations based on sex-specific ecology have proven harder to test. In ectotherms, females are typically larger than males, and this is frequently thought to be because size constrains female fecundity more than it constrains male mating success. However, SSD could additionally reflect maternal care strategies. Under this hypothesis, females are relatively larger where reproduction requires greater maximum maternal effort – for example where mothers transport heavy provisions to nests. To test this hypothesis we focussed on digger wasps (Hymenoptera: Ammophilini), a relatively homogeneous group in which only females provision offspring. In some species, a single large prey item, up to 10 times the mother’s weight, must be carried to each burrow on foot; other species provide many small prey, each flown individually to the nest. We found more pronounced female-biased SSD in species where females carry single, heavy prey. More generally, SSD was negatively correlated with numbers of prey provided per offspring. Females provisioning multiple small items had longer wings and thoraxes, probably because smaller prey are carried in flight. Despite much theorising, few empirical studies have tested how sex-biased parental care can affect SSD. Our study reveals that such costs can be associated with the evolution of dimorphism, and this should be investigated in other clades where parental care costs differ between sexes and species