The Dead Sea is a terminal lake of one of the largest hydrological systems in the Levant and may thus be viewed as a large rain gauge for the region. Variations of its level are indicative of the climate variations in the region. Here, we present the decadal- to centennial-resolution Holocene lake-level curve of the Dead Sea. Then we determine the regional hydroclimatology that affected level variations. To achieve this goal we compare modern natural lake-level variations and instrumental rainfall records and quantify the hydrology relative to lake-level rise, fall, or stability. To quantify that relationship under natural conditions, rainfall data pre-dating the artificial Dead Sea level drop since the 1960s are used. In this respect, Jerusalem station offers the longest uninterrupted pre-1960s rainfall record and Jerusalem rains serve as an adequate proxy for the Dead Sea headwaters rainfall. Principal component analysis indicates that temporal variations of annual precipitation in all stations in Israel north of the current 200 mm yr−1 average isohyet during 1940–1990 are largely synchronous and in phase (∼70% of the total variance explained by PC1). This station also represents well northern Jordan and the area all the way to Beirut, Lebanon, especially during extreme drought and wet spells. We (a) determine the modern, and propose the past regional hydrology and Eastern Mediterranean (EM) climatology that affected the severity and length of droughts/wet spells associated with multiyear episodes of Dead Sea level falls/rises and (b) determine that EM cyclone tracks were different in average number and latitude in wet and dry years in Jerusalem. The mean composite sea level pressure and 500-mb height anomalies indicate that the potential causes for wet and dry episodes span the entire EM and are rooted in the larger-scale northern hemisphere atmospheric circulation. We also identified remarkably close association (within radiocarbon resolution) between climatic changes in the Levant, reflected by level changes, and culture shifts in this region.

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Venetoclax is a specific B cell lymphoma 2 (BCL-2) inhibitor with promising activity against acute myeloid leukemia (AML), but its clinical efficacy as a single agent or in combination with hypomethylating agents (HMAs), such as azacitidine, is hampered by intrinsic and acquired resistance. Here, we performed a genome-wide CRISPR knockout screen and found that inactivation of genes involved in mitochondrial translation restored sensitivity to venetoclax in resistant AML cells. Pharmacologic inhibition of mitochondrial protein synthesis with antibiotics that target the ribosome, including tedizolid and doxycycline, effectively overcame venetoclax resistance. Mechanistic studies showed that both tedizolid and venetoclax suppressed mitochondrial respiration, with the latter demonstrating inhibitory activity against complex I [nicotinamide adenine dinucleotide plus hydrogen (NADH) dehydrogenase] of the electron transport chain (ETC). The drugs cooperated to activate a heightened integrated stress response (ISR), which, in turn, suppressed glycolytic capacity, resulting in adenosine triphosphate (ATP) depletion and subsequent cell death. Combination treatment with tedizolid and venetoclax was superior to either agent alone in reducing leukemic burden in mice engrafted with treatment-resistant human AML. The addition of tedizolid to azacitidine and venetoclax further enhanced the killing of resistant AML cells in vitro and in vivo. Our findings demonstrate that inhibition of mitochondrial translation is an effective approach to overcoming venetoclax resistance and provide a rationale for combining tedizolid, azacitidine, and venetoclax as a triplet therapy for AML.

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