Tumor pH is physiologically important since it influences a number of processes relevant to tumorigenesis and therapy. Hence, knowledge of localized pH within tumors would contribute to understanding these processes. The destructiveness, poor spatial resolution, and poor signal-to-noise ratio (SNR) of current technologies (e.g., microelectrodes, 31 P magnetic resonance spectroscopy) have limited such studies. An extrinsic chemical extracellular pH (pH e ) probe is described that is used in combination with 1 H magnetic resonance spectroscopic imaging to yield pH e maps with a spatial resolution of 1 ؋ 1 ؋ 4 mm 3 . Since the discovery of lactic acid production in tumors more than 50 years ago (1), it has generally been assumed that the pH of tumors is acidic. Indeed, numerous microelectrode measurements have shown that extracellular tumor pH (pH e ) is acidic (2). This acidic pH e of tumors has been confirmed with less invasive 31 P magnetic resonance spectroscopy (MRS) measurements (3). Although the intracellular pH (pH i ) of tumors remains neutral to alkaline (4,5), it is somewhat influenced by the pH e (6).An acidic pH e of tumors is physiologically important since it influences a number of processes relevant to carcinogenesis and therapy. Knowledge of localized pH within tumors, both intra-and extracellular, would allow more detailed study of these processes and relate them to intratumoral pH heterogeneity. For example, it has been found that low pH e in vitro causes tumorigenic transformation of primary Syrian hamster embryo cells (7) and can lead to chromosomal rearrangements in Chinese hamster embryo cells (8,9). Furthermore, culturing cells at low pH causes them to be more invasive in vitro (10) and metastatic in vivo (11). Finally, the orientation of the pH gradient across the cell membrane may influence cell drug resistance (6,12) Previously reported measurements of extracellular pH using either microelectrodes or 31 P MRS of 3-aminopropylphosphonate (3-APP) (3) have drawbacks. Microelectrodes are invasive and can destroy the membrane integrity, thereby disrupting the mechanism for maintaining the pH e . 31 P MRS does not suffer this drawback and has the additional advantage of permitting simultaneous measurements of intracellular pH. However, the limited sensitivity of 31 P MRS allows measurements of pH e only from relatively large tissue volumes. Hence, 31 P MRS provides measurements of pH ranges rather than different pH values for discrete spatial locations (13).The use of 1 H MRS, inherently more sensitive than 31 P MRS, would allow measurements of pH over smaller tissue volumes. For example, the imidazole protons of histidine have long been useful as intracellular pH indicators in NMR (14,15).Rabenstein and Isab (16) first proposed using imidazoles as extrinsic pH e indicators. Gil et al (17) suggested several modifications of the basic structure of the imidazole molecule to improve its performance as an extrinsic pH probe. To date, the most promising candidate for a 1 H nuclear magnetic resonance ...

The insect wing is a key evolutionary innovation that was essential for insect diversification. Yet despite its importance, there is still debate about its evolutionary origins. Two main hypotheses have been proposed: the paranotal hypothesis, which suggests that wings evolved as an extension of the dorsal thorax, and the gill-exite hypothesis, which proposes that wings were derived from a modification of a pre-existing branch at the dorsal base (subcoxa) of the leg. Here, we address this question by studying how wing fates are initially specified during Drosophila embryogenesis, by characterizing a cis-regulatory module (CRM) from the snail (sna) gene, sna-DP (for dorsal primordia). sna-DP specifically marks the early primordia for both the wing and haltere, collectively referred to as the DP. We found that the inputs that activate sna-DP are distinct from those that activate Distalless, a marker for leg fates. Further, in genetic backgrounds in which the leg primordia are absent, the DP are still partially specified. However, lineage-tracing experiments demonstrate that cells from the early leg primordia contribute to both ventral and dorsal appendage fates. Together, these results suggest that the wings of Drosophila have a dual developmental origin: two groups of cells, one ventral and one more dorsal, give rise to the mature wing. We suggest that the dual developmental origins of the wing may be a molecular remnant of the evolutionary history of this appendage, in which cells of the subcoxa of the leg coalesced with dorsal outgrowths to evolve a dorsal appendage with motor control.