We search for the signature of parity-violating physics in the cosmic microwave background, called cosmic birefringence, using the Planck data release 4. We initially find a birefringence angle of ...β=0.30°±0.11° (68% C.L.) for nearly full-sky data. The values of β decrease as we enlarge the Galactic mask, which can be interpreted as the effect of polarized foreground emission. Two independent ways to model this effect are used to mitigate the systematic impact on β for different sky fractions. We choose not to assign cosmological significance to the measured value of β until we improve our knowledge of the foreground polarization.
The importance of serine metabolism in cancer Mattaini, Katherine R; Sullivan, Mark R; Vander Heiden, Matthew G
The Journal of cell biology,
08/2016, Letnik:
214, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Serine metabolism is frequently dysregulated in cancers; however, the benefit that this confers to tumors remains controversial. In many cases, extracellular serine alone is sufficient to support ...cancer cell proliferation, whereas some cancer cells increase serine synthesis from glucose and require de novo serine synthesis even in the presence of abundant extracellular serine. Recent studies cast new light on the role of serine metabolism in cancer, suggesting that active serine synthesis might be required to facilitate amino acid transport, nucleotide synthesis, folate metabolism, and redox homeostasis in a manner that impacts cancer.
Background The ideal age to introduce egg into the infant diet has been debated for the past 2 decades in the context of rising rates of egg allergy. Objective We sought to determine whether regular ...consumption of egg protein from age 4 to 6 months reduces the risk of IgE-mediated egg allergy in infants with hereditary risk, but without eczema. Methods Infants aged 4 to 6 months were randomly allocated to receive daily pasteurized raw whole egg powder (n = 407) or a color-matched rice powder (n = 413) to age 10 months. All infants followed an egg-free diet and cooked egg was introduced to both groups at age 10 months. The primary outcome was IgE-mediated egg allergy defined by a positive pasteurized raw egg challenge and egg sensitization at age 12 months. Results There was no difference between groups in the percentage of infants with IgE-mediated egg allergy (egg 7.0% vs control 10.3%; adjusted relative risk, 0.75; 95% CI, 0.48-1.17; P = .20). A higher proportion of participants in the egg group stopped taking the study powder because of a confirmed allergic reaction (25 of 407 6.1% compared with 6 of 413 1.5%). Egg-specific IgG4 levels were substantially higher in the egg group at 12 months (median, 1.22 mgA /L vs control 0.07 mgA /L; P < .0001). Conclusions We found no evidence that regular egg intake from age 4 to 6 months substantially alters the risk of egg allergy by age 1 year in infants who are at hereditary risk of allergic disease and had no eczema symptoms at study entry.
Mycobacterium abscessus
is the most common rapidly growing non-tuberculous mycobacteria to cause pulmonary disease in patients with impaired lung function such as cystic fibrosis.
M
.
abscessus
...displays high intrinsic resistance to common antibiotics and inducible resistance to macrolides like clarithromycin. As such,
M
.
abscessus
is clinically resistant to the entire regimen of front-line
M
.
tuberculosis
drugs, and treatment with antibiotics that do inhibit
M
.
abscessus
in the lab results in cure rates of 50% or less. Here, we identified epetraborole (EPT) from the MMV pandemic response box as an inhibitor against the essential protein leucyl-tRNA synthetase (LeuRS) in
M
.
abscessus
. EPT protected zebrafish from lethal
M
.
abscessus
infection and did not induce self-resistance nor against clarithromycin. Contrary to most antimycobacterials, the whole-cell activity of EPT was greater against
M
.
abscessus
than
M
.
tuberculosis
, but crystallographic and equilibrium binding data showed that EPT binds LeuRS
Mabs
and LeuRS
Mtb
with similar residues and dissociation constants. Since EPT-resistant
M
.
abscessus
mutants lost LeuRS editing activity, these mutants became susceptible to misaminoacylation with leucine mimics like the non-proteinogenic amino acid norvaline. Proteomic analysis revealed that when
M
.
abscessus
LeuRS mutants were fed norvaline, leucine residues in proteins were replaced by norvaline, inducing the unfolded protein response with temporal changes in expression of GroEL chaperonins and Clp proteases. This supports our
in vitro
data that supplementation of media with norvaline reduced the emergence of EPT mutants in both
M
.
abscessus
and
M
.
tuberculosis
. Furthermore, the combination of EPT and norvaline had improved
in vivo
efficacy compared to EPT in a murine model of
M
.
abscessus
infection. Our results emphasize the effectiveness of EPT against the clinically relevant cystic fibrosis pathogen
M
.
abscessus
, and these findings also suggest norvaline adjunct therapy with EPT could be beneficial for
M
.
abscessus
and other mycobacterial infections like tuberculosis.
The design of power magnetic components for operation at high frequency (HF, 3-30 MHz) has been hindered by a lack of magnetic material performance data and by the limited design theory in that ...frequency range. To address these deficiencies, we have measured and present core loss data for a variety of commercially available magnetic materials in the HF range. In addition, we extend the theory of performance factor for appropriate use in the HF design. Since magnetic materials suitable for HF applications tend to have low permeability, we also consider the impact of low permeability on design. We conclude that, with appropriate material selection and design, increased frequencies can continue to yield improved power density well into the HF regime.
The mitogen-activated protein kinase (MAPK) pathway is critical to oncogenic signaling in the majority of patients with malignant melanoma. Driver mutations in both NRAS and BRAF have important ...implications for prognosis and treatment. The development of inhibitors to mediators of the MAPK pathway, including those to CRAF, BRAF, and MEK, has led to major advances in the treatment of patients with melanoma. In particular, the selective BRAF inhibitor vemurafenib has been shown to improve overall survival in patients with tumors harboring BRAF mutations. However, the duration of benefit is limited in many patients and highlights the need for understanding the limitations of therapy in order to devise more effective strategies. MEK inhibitors have proven to particularly active in BRAF mutant melanomas also. Emerging knowledge about mechanisms of resistance as well as a more complete understanding of the biology of MAPK pathway signaling provides insight into rational combination regimens and sequences of molecularly targeted therapies.
The accurate repair of DNA is critical for genome stability and cancer prevention. DNA double-strand breaks are one of the most toxic lesions; however, they can be repaired using homologous ...recombination. Homologous recombination is a high-fidelity DNA repair pathway that uses a homologous template for repair. One central HR step is RAD51 nucleoprotein filament formation on the single-stranded DNA ends, which is a step required for the homology search and strand invasion steps of HR. RAD51 filament formation is tightly controlled by many positive and negative regulators, which are collectively termed the RAD51 mediators. The RAD51 mediators function to nucleate, elongate, stabilize, and disassemble RAD51 during repair. In model organisms, RAD51 paralogs are RAD51 mediator proteins that structurally resemble RAD51 and promote its HR activity. New functions for the RAD51 paralogs during replication and in RAD51 filament flexibility have recently been uncovered. Mutations in the human RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and SWSAP1) are found in a subset of breast and ovarian cancers. Despite their discovery three decades ago, few advances have been made in understanding the function of the human RAD51 paralogs. Here, we discuss the current perspective on the in vivo and in vitro function of the RAD51 paralogs, and their relationship with cancer in vertebrate models.
Tumors exhibit altered metabolism compared to normal tissues. Many cancers upregulate expression of serine synthesis pathway enzymes, and some tumors exhibit copy-number gain of the gene encoding the ...first enzyme in the pathway, phosphoglycerate dehydrogenase (PHGDH). However, whether increased serine synthesis promotes tumor growth and how serine synthesis benefits tumors is controversial. Here, we demonstrate that increased PHGDH expression promotes tumor progression in mouse models of melanoma and breast cancer, human tumor types that exhibit PHGDH copy-number gain. We measure circulating serine levels and find that PHGDH expression is necessary to support cell proliferation at lower physiological serine concentrations. Increased dietary serine or high PHGDH expression is sufficient to increase intracellular serine levels and support faster tumor growth. Together, these data suggest that physiological serine availability restrains tumor growth and argue that tumors arising in serine-limited environments acquire a fitness advantage by upregulating serine synthesis pathway enzymes.
Display omitted
•PHGDH expression accelerates mouse models of melanoma and breast cancer•Physiological serine levels can restrain tumor growth in breast cancer•Increased dietary serine levels can accelerate tumor progression•PHGDH expression only benefits tumors in tissues with low serine availability
Nutrient availability can constrain tumor growth. Sullivan et al. demonstrate that in some cancers, physiological levels of the amino acid serine are insufficient to support maximal tumor growth and that melanoma and breast tumors derive a growth advantage by upregulating serine biosynthesis.
PDF
