Past climates and environments experienced by the Saharo-Arabian desert belt are of prime importance for palaeoclimatic and palaeoanthropological research. On orbital timescales transformations of the desert into a savannah-like landscape in response to higher precipitation provided "windows of opportunity" for hominin dispersal from Africa into Eurasia. On long timescales, palaeoenvironmental reconstructions for the region are predominantly derived from marine sediments and available terrestrial records from the Arabian Peninsula are limited to 450 ka before present (BP). Here, we present a new stalagmite-based palaeoclimate record from Mukalla Cave in Yemen which extends back to ~1.1 million years BP or Marine Isotope Stage (MIS) 31, as determined by Uranium-lead dating. Stalagmite Y99 grew only during peak interglacial periods and warm substages back to ~1.1 Ma. Stalagmite calcite oxygen isotope (δ 18 O) values show that every past interglacial humid period was wetter than the Holocene, a period in which large lakes formed in the now arid areas of southern Arabia. Carbon isotope (δ 13 C) values indicate habitable savannah-like environments developed during these pluvial periods. A total of 21 pluvial periods with precipitation of more than 300 mm yr -1 occurred since ~1.1 Ma and thus numerous opportunities for hominin dispersals occurred throughout the Pleistocene. New determinations of hydrogen (δDFI) and oxygen (δ 18 OFI) isotopes in stalagmite fluid inclusion water demonstrates that enhanced precipitation in Southern Arabia was brought by the African and Indian Summer Monsoons. When combined with subannual calcite analysis of δ 18 O and δ 13 C, these data reveal a distinct wet (summer) and dry (winter) seasonality. Highlights • Pluvial periods recorded in stalagmites from Southern Arabia up to 1.073 Ma (MIS 31) • Speleothem growth in Yemen only occurred during interglacial maxima and warm substages • The African Summer Monsoon (ASM) and Indian Summer Monsoon (ISM) increased precipitation to Southwestern Arabia • Monsoonal rainfall increased precipitation to south-eastern Arabia • All Pleistocene pluvial periods were wetter than the Holocene pluvial period • Grassland environments formed during peak interglacials • Interglacial grasslands provided "windows of opportunity" for hominin occupation of the now arid Arabian interior and dispersals from Africa.

Oral cancer patients report sensitivity to spicy foods and liquids. The mechanism responsible for chemosensitivity induced by oral cancer is not known. We simulate oral cancer-induced chemosensitivity in a xenograft oral cancer mouse model using two-bottle choice drinking and conditioned place aversion assays. An anatomic basis of chemosensitivity is shown in increased expression of TRPV1 in anatomically relevant trigeminal ganglion (TG) neurons in both the xenograft and a carcinogen (4-nitroquinoline 1-oxide)-induced oral cancer mouse models. The percent of retrograde labeled TG neurons that respond to TRPV1 agonist, capsaicin, is increased along with the magnitude of response as measured by calcium influx, in neurons from the cancer models. To address the possible mechanism of TRPV1 sensitivity in tongue afferents, we study the role of PAR2, which can sensitize the TRPV1 channel. We show co-expression of TRPV1 and PAR2 on tongue afferents and using a conditioned place aversion assay, demonstrate that PAR2 mediates oral cancer-induced, TRPV1-evoked sensitivity in an oral cancer mouse model. The findings provide insight into oral cancer-mediated chemosensitivity.

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Supplemental Digital Content is Available in the Text.Oral cancer mouse models were used to demonstrate that sympathetic neurotransmission modulates oral cancer pain and tumor growth through adrenergic signaling in the tumor microenvironment.