33 research outputs found
The roles of calcium signaling and ERK1/2 phosphorylation in a Pax6(+/- )mouse model of epithelial wound-healing delay
BACKGROUND: Congenital aniridia caused by heterozygousity at the PAX6 locus is associated with ocular surface disease including keratopathy. It is not clear whether the keratopathy is a direct result of reduced PAX6 gene dosage in the cornea itself, or due to recurrent corneal trauma secondary to defects such as dry eye caused by loss of PAX6 in other tissues. We investigated the hypothesis that reducing Pax6 gene dosage leads to corneal wound-healing defects. and assayed the immediate molecular responses to wounding in wild-type and mutant corneal epithelial cells. RESULTS: Pax6(+/- )mouse corneal epithelia exhibited a 2-hour delay in their response to wounding, but subsequently the cells migrated normally to repair the wound. Both Pax6(+/+ )and Pax6(+/- )epithelia activated immediate wound-induced waves of intracellular calcium signaling. However, the intensity and speed of propagation of the calcium wave, mediated by release from intracellular stores, was reduced in Pax6(+/- )cells. Initiation and propagation of the calcium wave could be largely decoupled, and both phases of the calcium wave responses were required for wound healing. Wounded cells phosphorylated the extracellular signal-related kinases 1/2 (phospho-ERK1/2). ERK1/2 activation was shown to be required for rapid initiation of wound healing, but had only a minor effect on the rate of cell migration in a healing epithelial sheet. Addition of exogenous epidermal growth factor (EGF) to wounded Pax6(+/- )cells restored the calcium wave, increased ERK1/2 activation and restored the immediate healing response to wild-type levels. CONCLUSION: The study links Pax6 deficiency to a previously overlooked wound-healing delay. It demonstrates that defective calcium signaling in Pax6(+/- )cells underlies this delay, and shows that it can be pharmacologically corrected. ERK1/2 phosphorylation is required for the rapid initiation of wound healing. A model is presented whereby minor abrasions, which are quickly healed in normal corneas, transiently persist in aniridic patients, compromising the corneal stroma
Interactions between anti-EGFR therapies and cytotoxic chemotherapy in oesophageal squamous cell carcinoma: why clinical trials might have failed and how they could succeed
Acknowledgements We thank Alice Savage for technical laboratory assistance. Funding The work undertaken was funded by Ninewells Cancer Campaign (Dundee) and Scottish Government Chief Scientist Office (Grant reference TCS/19/18).Peer reviewedPublisher PD
Restricted growth of Schwann cells lacking Cajal bands slows conduction in myelinated nerves
Nerve impulses are propagated at nodes of Ranvier in the
myelinated nerves of vertebrates. Internodal distances have
been proposed to affect the velocity of nerve impulse conduction;
however, direct evidence is lacking, and the cellular mechanisms
that might regulate the length of the myelinated segments
are unknown. Ramon y Cajal described longitudinal and transverse
bands of cytoplasm or trabeculae in internodal Schwann
cells and suggested that they had a nutritive function. Here we
show that internodal growth in wild-type nerves is precisely
matched to nerve extension, but disruption of the cytoplasmic
bands in Periaxin-null mice impairs Schwann cell elongation during nerve growth. By contrast, myelination proceeds normally.
The capacity of wild-type and mutant Schwann cells to
elongate is cell-autonomous, indicating that passive stretching
can account for the lengthening of the internode during limb
growth. As predicted on theoretical grounds, decreased internodal
distances strikingly decrease conduction velocities and so
affect motor function.We propose that microtubule-based transport
in the longitudinal bands of Cajal permits internodal
Schwann cells to lengthen in response to axonal growth, thus
ensuring rapid nerve impulse transmission
Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have
fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in
25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16
regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of
correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP,
while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in
Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium
(LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region.
Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant
enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the
refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa,
an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of
PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent
signals within the same regio
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Thirty-five Oriental Philosophers
These are questions to which oriental thinkers have given a wide range of philosophical answers that are intellectually and imaginatively stimulating.
Thirty-Five Oriental Philosophers is a succinctly informative introduction to the thought of thirty-five important figures in the Chinese, Indian, Arab, Japanese and Tibetan philosophical traditions. Thinkers covered include founders such as Zoroaster, Confucius, Buddha and Muhammed, as well as influential modern figures such as Gandhi, Mao Tse-Tung, Suzuki and Nishida.
The book is divided into sections, in which an introduction to the tradition it covers precedes the essays on its individual philosophers. Notes, further reading lists, and cross-references provide the student with a clear route to further study. There is a glossary of key terms at the end of the book