Activating transcription factor 4 (ATF4) is a multifunctional transcription regulatory protein in the basic leucine zipper superfamily. ATF4 can be expressed in most if not all mammalian cell types, ...and it can participate in a variety of cellular responses to specific environmental stresses, intracellular derangements, or growth factors. Because ATF4 is involved in a wide range of biological processes, its roles in human health and disease are not yet fully understood. Much of our current knowledge about ATF4 comes from investigations in cultured cell models, where ATF4 was originally characterized and where further investigations continue to provide new insights. ATF4 is also an increasingly prominent topic of in vivo investigations in fully differentiated mammalian cell types, where our current understanding of ATF4 is less complete. Here, we review some important high-level concepts and questions concerning the basic biology of ATF4. We then discuss current knowledge and emerging questions about the in vivo role of ATF4 in one fully differentiated cell type, mammalian skeletal muscle fibers.
We discuss an alternative scheme for including effective range corrections in pionless effective field theory. The standard approach treats range terms as perturbative insertions in the
T
-matrix. In ...a finite volume this scheme can lead to singular behavior close to the unperturbed energies. We consider an alternative scheme that resums the effective range but expands the spurious pole of the
T
-matrix created by this resummation. We test this alternative expansion for several model potentials and observe good convergence.
Commensal bacteria in the colon may play a role in colorectal cancer (CRC) development. Recent studies from North America showed that
Fusobacterium nucleatum
(
Fn
) infection is over-represented in ...disease tissue versus matched normal tissue in CRC patients. Using quantitative real-time polymerase chain reaction (qPCR) of DNA extracted from colorectal tissue biopsies and surgical resections of three European cohorts totalling 122 CRC patients, we found an over-abundance of
Fn
in cancerous compared to matched normal tissue (
p
< 0.0001). To determine whether
Fn
infection is an early event in CRC development, we assayed
Fn
in colorectal adenoma (CRA) tissue from 52 Irish patients. While for all CRAs the
Fn
level was not statistically significantly higher in disease versus normal tissue (
p
= 0.06), it was significantly higher for high-grade dysplasia (
p
= 0.015). As a secondary objective, we determined that CRC patients with low
Fn
levels had a significantly longer overall survival time than patients with moderate and high levels of the bacterium (
p
= 0.008). The investigation of
Fn
as a potential non-invasive biomarker for CRC screening showed that, while
Fn
was more abundant in stool samples from CRC patients compared to adenomas or controls, the levels in stool did not correlate with cancer or adenoma tissue levels from the same individuals. This is the first study examining
Fn
in the colonic tissue and stool of European CRC and CRA patients, and suggests
Fn
as a novel risk factor for disease progression from adenoma to cancer, possibly affecting patient survival outcomes. Our results highlight the potential of
Fn
detection as a diagnostic and prognostic determinant in CRC patients.
During its orbit around the four million solar mass black hole Sagittarius A* the star S2 experiences significant changes in gravitational potential. We use this change of potential to test one part ...of the Einstein equivalence principle: the local position invariance (LPI). We study the dependency of different atomic transitions on the gravitational potential to give an upper limit on violations of the LPI. This is done by separately measuring the redshift from hydrogen and helium absorption lines in the stellar spectrum during its closest approach to the black hole. For this measurement we use radial velocity data from 2015 to 2018 and combine it with the gravitational potential at the position of S2, which is calculated from the precisely known orbit of S2 around the black hole. This results in a limit on a violation of the LPI of |β_{He}-β_{H}|=(2.4±5.1)×10^{-2}. The variation in potential that we probe with this measurement is six magnitudes larger than possible for measurements on Earth, and a factor of 10 larger than in experiments using white dwarfs. We are therefore testing the LPI in a regime where it has not been tested before.
Skeletal muscle atrophy is a common and debilitating condition that lacks a pharmacologic therapy. To develop a potential therapy, we identified 63 mRNAs that were regulated by fasting in both human ...and mouse muscle, and 29 mRNAs that were regulated by both fasting and spinal cord injury in human muscle. We used these two unbiased mRNA expression signatures of muscle atrophy to query the Connectivity Map, which singled out ursolic acid as a compound whose signature was opposite to those of atrophy-inducing stresses. A natural compound enriched in apples, ursolic acid reduced muscle atrophy and stimulated muscle hypertrophy in mice. It did so by enhancing skeletal muscle insulin/IGF-I signaling and inhibiting atrophy-associated skeletal muscle mRNA expression. Importantly, ursolic acid's effects on muscle were accompanied by reductions in adiposity, fasting blood glucose, and plasma cholesterol and triglycerides. These findings identify a potential therapy for muscle atrophy and perhaps other metabolic diseases.
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► We determined mRNA expression signatures of skeletal muscle atrophy in humans ► Muscle atrophy signatures negatively correlated with the signature of ursolic acid ► Ursolic acid reduced muscle atrophy and induced muscle hypertrophy in mice ► Although ursolic acid increased skeletal muscle mass, it reduced adiposity
Zusammenfassung
Die Nachsorge gastrointestinaler Karzinome ist häufig unzureichend definiert. Prospektive Untersuchungen, die einen Vorteil der regelmäßigen Nachsorge zeigen, fehlen weitgehend. Meist ...wird eine rein symptomorientierte Nachsorge empfohlen, die zusätzlich die Beurteilung des Ernährungsstatus und eine mögliche psychoonkologische Mitbetreuung beinhaltet. Während in den frühen Stadien eine lokale Nachsorge sinnvoll und effektiv erscheint, ist die Rolle der Nachsorge bei lokal fortgeschrittenen Tumoren deutlich schwieriger zu beurteilen. Dieses Defizit beruht vor allem auf den fehlenden therapeutischen Konsequenzen bei einem Rezidiv. Eine kurative Behandlung ist dann meist nicht mehr möglich und die meisten Studien konnten keinen Überlebensvorteil einer standardisierten Nachsorge nach kurativer Therapie nachweisen. Angesichts der sich ändernden therapeutischen Optionen und des Erfolgs der Therapie rezidivierender kolorektaler Karzinome ist jedoch eine aktuelle Standortbestimmung sinnvoll.
Zusammenfassung
Die Nachsorge gastrointestinaler Karzinome ist häufig unzureichend definiert. Prospektive Untersuchungen, die einen Vorteil der regelmäßigen Nachsorge zeigen, fehlen weitgehend. Meist ...wird eine rein symptomorientierte Nachsorge empfohlen, die zusätzlich die Beurteilung des Ernährungsstatus und eine mögliche psychoonkologische Mitbetreuung beinhaltet. Während in den frühen Stadien eine lokale Nachsorge sinnvoll und effektiv erscheint, ist die Rolle der Nachsorge bei lokal fortgeschrittenen Tumoren deutlich schwieriger zu beurteilen. Dieses Defizit beruht vor allem auf den fehlenden therapeutischen Konsequenzen bei einem Rezidiv. Eine kurative Behandlung ist dann meist nicht mehr möglich und die meisten Studien konnten keinen Überlebensvorteil einer standardisierten Nachsorge nach kurativer Therapie nachweisen. Angesichts der sich ändernden therapeutischen Optionen und des Erfolgs der Therapie rezidivierender kolorektaler Karzinome ist jedoch eine aktuelle Standortbestimmung sinnvoll.
Background The formation of blood vessels within solid tumors directly contributes to cancer growth and metastasis. Until recently, tumor vasculature was thought to occur exclusively via endothelial ...cell (EC) lined structures (i.e. angiogenesis), but a second source of tumor vasculature arises from the cancer cells themselves, a process known as vasculogenic mimicry (VM). While it is generally understood that the function of VM vessels is the same as that of EC-lined vessels (i.e. to supply oxygen and nutrients to the proliferating cancer cells), the molecular mechanisms underpinning VM are yet to be fully elucidated. Methods Human VM-competent melanoma cell lines were examined for their VM potential using the in vitro angiogenesis assays (Matrigel), together with inhibition studies using small interfering RNA and blocking monoclonal antibodies. Invasion assays and adhesion assays were used to examine cancer cell function. Results Herein we demonstrate that CD36, a cell surface glycoprotein known to promote angiogenesis by ECs, also supports VM formation by human melanoma cancer cells. In silico analysis of CD36 expression within the melanoma cohort of The Cancer Genome Atlas suggests that melanoma patients with high expression of CD36 have a poorer clinical outcome. Using in vitro 'angiogenesis' assays and CD36-knockdown approaches, we reveal that CD36 supports VM formation by human melanoma cells as well as adhesion to, and invasion through, a cancer derived extracellular matrix substrate. Interestingly, thrombospondin-1 (TSP-1), a ligand for CD36 on ECs that inhibits angiogenesis, has no effect on VM formation. Further investigation revealed a role for laminin, but not collagen or fibronectin, as ligands for CD36 expressing melanoma cells. Conclusions Taken together, this study suggests that CD36 is a novel regulator of VM by melanoma cancer cells that is facilitated, at least in part, via integrin-alpha.sub.3 and laminin. Unlike angiogenesis, VM is not perturbed by the presence of TSP-1, thus providing new information on differences between these two processes of tumor vascularization which may be exploited to combat cancer progression. Keywords: CD36, Vasculogenic mimicry, Melanoma, Tumor microenvironment, Thrombospondin, Laminin, Integrin
A large field experiment of the Saharan Mineral Dust Experiment (SAMUM) was performed in Praia, Cape Verde, in January and February 2008. The aerosol at Praia is a superposition of mineral dust, ...sea-salt, sulphates and soot. Particles smaller than 500 nm are mainly mineral dust, mineral dust-sulphate mixtures, sulphates and soot-sulphate mixtures. Particles larger then 2.5μm consist of mineral dust, sea-salt and few mineral dust-sulphate mixtures. A transition range exists in between. The major internal mixtures are mineral dust-sulphate and soot-sulphate. Mineral dust-sea-salt mixtures occur occasionally, mineral dust-soot mixtures were not observed. The aspect ratio was 1.3-1.4 for dry particles smaller than 500 nm and 1.6-1.7 for larger ones. Parameterizations are given for dry and humid state. Although the real part of the refractive index showed low variation (1.55-1.58 at 532 nm), a multi-modal imaginary part was detected as function of particle size, reflecting the complex composition. Soot mainly influences the absorption for wavelengths longer than the haematite absorption edge, whereas for shorter wavelengths dust is dominating. The refractive index of the aerosol depends on the source region of the mineral dust and on the presence/absence of a marine component.
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