There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

The transcription factor NF-kappaB has been the focus of intense investigation for nearly two decades. Over this period, considerable progress has been made in determining the function and regulation of NF-kappaB, although there are nuances in this important signaling pathway that still remain to be understood. The challenge now is to reconcile the regulatory complexity in this pathway with the complexity of responses in which NF-kappaB family members play important roles. In this review, we provide an overview of established NF-kappaB signaling pathways with focus on the current state of research into the mechanisms that regulate IKK activation and NF-kappaB transcriptional activity.

/pdf/signaling-to-nf-kappab-1zyb7vgt7s.pdf

Signaling to NF-kappaB.

Transforming growth factor-β utilizes a multitude of intracellular signaling pathways in addition to Smads to regulate a wide array of cellular functions. These non-canonical, non-Smad pathways are activated directly by ligand-occupied receptors to reinforce, attenuate, or otherwise modulate downstream cellular responses. These non-Smad pathways include various branches of MAP kinase pathways, Rho-like GTPase signaling pathways, and phosphatidylinositol-3-kinase/AKT pathways. This review focuses on recent advances in the understanding of the molecular and biochemical mechanisms of non-Smad pathways. In addition, functions of these non-Smad pathways are also discussed.

/pdf/non-smad-pathways-in-tgf-b-signaling-1mlq9nzj3e.pdf

Non-Smad pathways in TGF-β signaling

Transforming growth factor-beta (TGFbeta) signalling regulates cancer through mechanisms that function either within the tumour cell itself or through host-tumour cell interactions. Studies of tumour-cell-autonomous TGFbeta effects show clearly that TGFbeta signalling has a mechanistic role in tumour suppression and tumour promotion. In addition, factors in the tumour microenvironment, such as fibroblasts, immune cells and the extracellular matrix, influence the ability of TGFbeta to promote or suppress carcinoma progression and metastasis. The complex nature of TGFbeta signalling and crosstalk in the tumour microenvironment presents a unique challenge, and an opportunity to develop therapeutic intervention strategies for targeting cancer.

Tumour microenvironment: TGFβ: the molecular Jekyll and Hyde of cancer

Recent studies have demonstrated that mitogen-activated protein kinases (MAPKs), including Jun N-terminus kinase (JNK), p38 and Erk, play crucial roles in cell migration. JNK, for example, regulates cell migration by phosphorylating paxillin, DCX, Jun and microtubule-associated proteins. Studies of p38 show that this MAPK modulates migration by phosphorylating MAPK-activated protein kinase 2/3 (MAPKAP 2/3), which appears to be important for directionality of migration. Erk governs cell movement by phosphorylating myosin light chain kinase (MLCK), calpain or FAK. Thus, the different kinases in the MAPK family all seem able to regulate cell migration but by distinct mechanisms.

MAP kinases and cell migration

MEKK1-deficient mice show an eye open at birth phenotype caused by impairment in embryonic eyelid closure. MEK kinase 1 (MEKK1) is highly expressed in the growing tip of the eyelid epithelium, which displays loose cell–cell contacts and prominent F-actin fibers in wild-type mice, but compact cell contacts, lack of polymerized actin and a concomitant impairment in c-Jun N-terminal phosphorylation in MEKK1-deficient mice. In cultured keratinocytes, MEKK1 is essential for JNK activation by TGF-β and activin, but not by TGF-α. MEKK1-driven JNK activation is required for actin stress fiber formation, c-Jun phosphorylation and cell migration. However, MEKK1 ablation does not impair other TGF-β/activin functions, such as nuclear translocation of Smad4. These results establish a specific role for the MEKK1–JNK cascade in transmission of TGF-β and activin signals that control epithelial cell movement, providing the mechanistic basis for the regulation of eyelid closure by MEKK1. This study also suggests that the signaling mechanisms that control eyelid closure in mammals and dorsal closure in Drosophila are evolutionarily conserved.

/pdf/a-role-for-mek-kinase-1-in-tgf-b-activin-induced-epithelium-4wrq4mazvg.pdf

A role for MEK kinase 1 in TGF-β/activin-induced epithelium movement and embryonic eyelid closure

Keratocan, a Cornea-specific Keratan Sulfate Proteoglycan, Is Regulated by Lumican

AIM—To report the success of vitrectomy in eliminating cystoid macular oedema and improving vision in three eyes of two patients with diabetic cystoid macular oedema. In all of the eyes there was no ophthalmoscopic evidence of traction from a posterior hyaloid membrane or from proliferative tissue.
METHODS—Pars plana vitrectomy was performed on three eyes of two patients with diabetic cystoid macular oedema who did not show traction upon examination with a slit lamp biomicroscope and a scanning laser ophthalmoscope.
RESULTS—Cystoid changes disappeared 1, 3, and 5 days, postoperatively, and diffuse macular oedema resolved within 2 weeks. The visual acuity was improved and maintained.
CONCLUSION—Vitrectomy can be effective in some patients with diabetic cystoid macular oedema even in patients who lack evidence of traction by ophthalmoscopy.

Keywords: diabetic retinopathy; cystoid macular oedema; pars plana vitrectomy

https://bjo.bmj.com/content/bjophthalmol/83/1/12.full.pdf

Vitrectomy for cystoid macular oedema with attached posterior hyaloid membrane in patients with diabetes

Improved visual acuity following pars plana vitrectomy for diabetic cystoid macular edema and detached posterior hyaloid.

It remains elusive as to what bone marrow (BM) cell types infiltrate into injured and/or diseased tissues and subsequently differentiate to assume the phenotype of residential cells, for example, neurons, cardiac myocytes, keratocytes, etc., to repair damaged tissue. Here, we examined the possibility of whether BM cell invasion via circulation into uninjured and injured corneas could assume a keratocyte phenotype, using chimeric mice generated by transplantation of enhanced green fluorescent protein (EGFP)+ BM cells into keratocan null (Kera−/−) and lumican null (Lum−/−) mice. EGFP+ BM cells assumed dendritic cell morphology, but failed to synthesize corneal-specific keratan sulfate proteoglycans, that is KS-lumican and KS-keratocan. In contrast, some EGFP+ BM cells introduced by intrastromal transplantation assumed keratocyte phenotypes. Furthermore, BM cells were isolated from Kera-Cre/ZEG mice, a double transgenic mouse line in which cells expressing keratocan become EGFP+ due to the synthesis of Cre driven by keratocan promoter. Three days after corneal and conjunctival transplantations of such BM cells into Kera−/− mice, green keratocan positive cells were found in the cornea, but not in conjunctiva. It is worthy to note that transplanted BM cells were rejected in 4 weeks. MSC isolated from BM were used to examine if BM mesenchymal stem cells (BM-MSC) could assume keratocyte phenotype. When BM-MSC were intrastromal-transplanted into Kera−/− mice, they survived in the cornea without any immune and inflammatory responses and expressed keratocan in Kera−/− mice. These observations suggest that corneal intrastromal transplantation of BM-MSC may be an effective treatment regimen for corneal diseases involving dysfunction of keratocytes.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1582-4934.2011.01418.x

Yasuhito Hayashi

Papers

A role for MEK kinase 1 in TGF-β/activin-induced epithelium movement and embryonic eyelid closure

Keratocan, a Cornea-specific Keratan Sulfate Proteoglycan, Is Regulated by Lumican

Vitrectomy for cystoid macular oedema with attached posterior hyaloid membrane in patients with diabetes

Improved visual acuity following pars plana vitrectomy for diabetic cystoid macular edema and detached posterior hyaloid.

Bone marrow mesenchymal stem cells can differentiate and assume corneal keratocyte phenotype