A small number of peptide growth factor ligands are used repeatedly in development and homeostasis to drive programs of cell differentiation and function. Cells and tissues must integrate inputs from ...these diverse signals correctly, while failure to do so leads to pathology, reduced fitness, or death. Previous work using the nematode C. elegans identified an interaction between the bone morphogenetic protein (BMP) and insulin/IGF-1-like signaling (IIS) pathways in the regulation of lipid homeostasis. The molecular components required for this interaction, however, were not fully understood. Here we report that INS-4, one of 40 insulin-like peptides (ILPs), is regulated by BMP signaling to modulate fat accumulation. Furthermore, we find that the IIS transcription factor DAF-16/FoxO, but not SKN-1/Nrf, acts downstream of BMP signaling in lipid homeostasis. Interestingly, BMP activity alters sensitivity of these two transcription factors to IIS-promoted cytoplasmic retention in opposite ways. Finally, we probe the extent of BMP and IIS interactions by testing additional IIS functions including dauer formation, aging, and autophagy induction. Coupled with our previous work and that of other groups, we conclude that BMP and IIS pathways have at least three modes of interaction: independent, epistatic, and antagonistic. The molecular interactions we identify provide new insight into mechanisms of signaling crosstalk and potential therapeutic targets for IIS-related pathologies such as diabetes and metabolic syndrome.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An outbreak of severe acute respiratory syndrome coronavirus 2 infection occurred among church attendees after an infectious chorister sang at multiple services. We detected 12 secondary ...case-patients. Video recordings of the services showed that case-patients were seated in the same section, up to 15 m from the primary case-patient, without close physical contact, suggesting airborne transmission.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
To examine racial differences in the distribution of histological subtypes of renal cell carcinoma (RCC) and associations with established RCC risk factors by subtype.
Materials and ...Methods
Tumours from 1532 consecutive patients with RCC who underwent nephrectomy at Vanderbilt University Medical Center (1998–2012) were classified as clear‐cell, papillary, chromophobe and other subtypes. In pairwise comparisons, we used multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between race, sex, age, end‐stage renal disease (ESRD) and body mass index at diagnosis according to histological subtype.
Results
The RCC subtype distribution was significantly different in black people from that in white people (P < 0.001), with a substantially higher proportion of patients with papillary RCC among black people than white people (35.7 vs 13.8%). In multivariate analyses, compared with clear‐cell RCC, people with papillary RCC were significantly more likely to be black (OR 4.15; 95% CI 2.64–6.52) and less likely to be female (OR 0.60; 95% CI 0.43–0.83). People with chromophobe RCC were significantly more likely to be female (OR 2.32; 95% CI 1.44–3.74). Both people with papillary RCC (OR 6.26; 95% CI 2.75–14.24) and those with chromophobe RCC (OR 7.07; 95% CI 2.13–23.46) were strongly and significantly more likely to have ESRD, compared with those with clear‐cell RCC.
Conclusion
We observed marked racial differences in the proportional subtype distribution of RCCs diagnosed at a large tertiary care academic centre. To our knowledge, no previous study has examined racial differences in the distribution of RCC histologies while adjusting for ESRD, which was the factor most strongly associated with papillary and chromophobe RCC compared with clear‐cell RCC.
This paper presents insights and action proposals to better harness technological innovation for sustainable development. We begin with three key insights from scholarship and practice. First, ...technological innovation processes do not follow a set sequence but rather emerge from complex adaptive systems involving many actors and institutions operating simultaneously from local to global scales. Barriers arise at all stages of innovation, from the invention of a technology through its selection, production, adaptation, adoption, and retirement. Second, learning from past efforts to mobilize innovation for sustainable development can be greatly improved through structured cross-sectoral comparisons that recognize the socio-technical nature of innovation systems. Third, current institutions (rules, norms, and incentives) shaping technological innovation are often not aligned toward the goals of sustainable development because impoverished, marginalized, and unborn populations too often lack the economic and political power to shape innovation systems to meet their needs. However, these institutions can be reformed, and many actors have the power to do so through research, advocacy, training, convening, policymaking, and financing. We conclude with three practice-oriented recommendations to further realize the potential of innovation for sustainable development: (i) channels for regularized learning across domains of practice should be established; (ii) measures that systematically take into account the interests of underserved populations throughout the innovation process should be developed; and (iii) institutions should be reformed to reorient innovation systems toward sustainable development and ensure that all innovation stages and scales are considered at the outset.
Perfluorobutanesulfonic acid (PFBS) is used as the replacement of perfluorooctanesulfonic acid (PFOS) since 2000 because of the concern on PFOS’ persistence in the environment and the bioaccumulation ...in animals. Accumulating evidence has shown the correlation between the exposure to perfluorinated compounds and enhanced adipogenesis. There is no report, however, of the effect of PFBS on adipogenesis. Therefore, the present work aimed to investigate the role of PFBS in adipogenesis using 3T3-L1 adipocytes. PFBS treatment for 6 days extensively promoted the differentiation of 3T3-L1 preadipocytes to adipocytes, resulting in significantly increased triglyceride levels. In particular, the treatments of PFBS at the early adipogenic differentiation period (day 0–2) were positively correlated with increased the triglyceride accumulation on day 6. PFBS treatments significantly increased the protein and mRNA levels of the master transcription factors in adipocyte differentiation; CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor gamma (PPARγ), along with acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), the key proteins in lipogenesis. PFBS significantly activated the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) after 4-h treatment, and PFBS′ effect on triglyceride was abolished by U0126, a specific MAPK/ERK kinase (MEK) inhibitor. In conclusion, PFBS increased the adipogenesis of 3T3-L1 adipocytes, in part, via MEK/ERK-dependent pathway.
•Perfluorobutanesulfonic acid (PFBS) promoted the adipogenesis in 3T3-L1 cells.•PFBS targets early adipogenesis in 3T3-L1 cells.•Effects of PFBS on adipogenesis is in part via MAPK/ERK-mediated mechanism.
The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates ...concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.
ObjectivePsychological treatments for posttraumatic stress disorder (PTSD) are usually delivered once or twice a week over several months. It is unclear whether they can be successfully delivered ...over a shorter period of time. This clinical trial had two goals: to investigate the acceptability and efficacy of a 7-day intensive version of cognitive therapy for PTSD and to investigate whether cognitive therapy has specific treatment effects by comparing intensive and standard weekly cognitive therapy with an equally credible alternative treatment.MethodPatients with chronic PTSD (N=121) were randomly allocated to 7-day intensive cognitive therapy for PTSD, 3 months of standard weekly cognitive therapy, 3 months of weekly emotion-focused supportive therapy, or a 14-week waiting list condition. The primary outcomes were change in PTSD symptoms and diagnosis as measured by independent assessor ratings and self-report. The secondary outcomes were change in disability, anxiety, depression, and quality of life. Evaluations were conducted at the baseline assessment and at 6 and 14 weeks (the posttreatment/wait assessment). For groups receiving treatment, evaluations were also conducted at 3 weeks and follow-up assessments at 27 and 40 weeks after randomization. All analyses were intent-to-treat.ResultsAt the posttreatment/wait assessment, 73% of the intensive cognitive therapy group, 77% of the standard cognitive therapy group, 43% of the supportive therapy group, and 7% of the waiting list group had recovered from PTSD. All treatments were well tolerated and were superior to waiting list on nearly all outcome measures; no difference was observed between supportive therapy and waiting list on quality of life. For primary outcomes, disability, and general anxiety, intensive and standard cognitive therapy were superior to supportive therapy. Intensive cognitive therapy achieved faster symptom reduction and comparable overall outcomes to standard cognitive therapy.ConclusionsCognitive therapy for PTSD delivered intensively over little more than a week was as effective as cognitive therapy delivered over 3 months. Both had specific effects and were superior to supportive therapy. Intensive cognitive therapy for PTSD is a feasible and promising alternative to traditional weekly treatment.
Abstract
Improved observational constraints on the orbital parameters of the low-mass X-ray binary Scorpius X-1 were recently published in Killestein et al. In the process, errors were corrected in ...previous orbital ephemerides, which have been used in searches for continuous gravitational waves from Sco X-1 using data from the Advanced LIGO detectors. We present the results of a reanalysis of LIGO detector data from the third observing run of Advanced LIGO and Advanced Virgo using a model-based cross-correlation search. The corrected region of parameter space, which was not covered by previous searches, was about 1/3 as large as the region searched in the original O3 analysis, reducing the required computing time. We have confirmed that no detectable signal is present over a range of gravitational-wave frequencies from 25 to 1600 Hz, analogous to the null result of Abbott et al. Our search sensitivity is comparable to that of Abbott et al., who set upper limits corresponding, between 100 and 200 Hz, to an amplitude
h
0
of about 10
−25
when marginalized isotropically over the unknown inclination angle of the neutron star’s rotation axis, or less than 4 × 10
−26
assuming the optimal orientation.
High-mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is passively released from damaged and necrotic cells, and actively released from immune cells. In contrast, cytochrome c is ...released from mitochondria in apoptotic cells, and is considered a reliable biomarker of apoptosis. Thus, HMGB1 and cytochrome c may in part reflect the degree of necrosis and apoptosis present after traumatic brain injury (TBI), where both are felt to contribute to cell death and neurological morbidity. Ventricular cerebrospinal fluid (CSF) was obtained from children admitted to the intensive care unit (ICU) after TBI (n=37). CSF levels of HMGB1 and cytochrome c were determined at four time intervals (0-24 h, 25-48 h, 49-72 h, and>72 h after injury) using enzyme-linked immunosorbent assay (ELISA). Lumbar CSF from children without TBI served as controls (n=12). CSF HMGB1 levels were: control=1.78±0.29, 0-24 h=5.73±1.45, 25-48 h=5.16±1.73, 49-72 h=4.13±0.75,>72 h=3.80±0.90 ng/mL (mean±SEM). Peak HMGB1 levels were inversely and independently associated with favorable Glasgow Outcome Scale (GOS) scores at 6 mo (0.49 0.24-0.97; OR 5-95% CI). CSF cytochrome c levels were: control=0.37±0.10, 0-24 h=0.69±0.15, 25-48 h=0.82±0.48, 49-72 h=1.52±1.08,>72 h=1.38±1.02 ng/mL (mean±SEM). Peak cytochrome c levels were independently associated with abusive head trauma (AHT; 24.29 1.77-334.03) and inversely and independently associated with favorable GOS scores (0.42 0.18-0.99). In conclusion, increased CSF levels of HMGB1 and cytochrome c were associated with poor outcome after TBI in infants and children. These data are also consistent with the designation of HMGB1 as a "danger signal." Distinctly increased CSF cytochrome c levels in infants and children with AHT and poor outcome suggests that apoptosis may play an important role in this unique patient population.
Elevated glucose consumption is fundamental to cancer, but selectively targeting this pathway is challenging. We develop a high-throughput assay for measuring glucose consumption and use it to screen ...non-small-cell lung cancer cell lines against bioactive small molecules. We identify Milciclib that blocks glucose consumption in H460 and H1975, but not in HCC827 or A549 cells, by decreasing SLC2A1 (GLUT1) mRNA and protein levels and by inhibiting glucose transport. Milciclib blocks glucose consumption by targeting cyclin-dependent kinase 7 (CDK7) similar to other CDK7 inhibitors including THZ1 and LDC4297. Enhanced PIK3CA signaling leads to CDK7 phosphorylation, which promotes RNA Polymerase II phosphorylation and transcription. Milciclib, THZ1, and LDC4297 lead to a reduction in RNA Polymerase II phosphorylation on the SLC2A1 promoter. These data indicate that our high-throughput assay can identify compounds that regulate glucose consumption and that CDK7 is a key regulator of glucose consumption in cells with an activated PI3K pathway.
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