Two atmospheric circulation systems, the mid-latitude Westerlies and the Asian summer monsoon (ASM), play key roles in northern-hemisphere climatic changes. However, the variability of the Westerlies in Asia and their relationship to the ASM remain unclear. Here, we present the longest and highest-resolution drill core from Lake Qinghai on the northeastern Tibetan Plateau (TP), which uniquely records the variability of both the Westerlies and the ASM since 32 ka, reflecting the interplay of these two systems. These records document the anti-phase relationship of the Westerlies and the ASM for both glacial-interglacial and glacial millennial timescales. During the last glaciation, the influence of the Westerlies dominated; prominent dust-rich intervals, correlated with Heinrich events, reflect intensified Westerlies linked to northern high-latitude climate. During the Holocene, the dominant ASM circulation, punctuated by weak events, indicates linkages of the ASM to orbital forcing, North Atlantic abrupt events, and perhaps solar activity changes.

Rifampin is a cornerstone of modern antituberculosis therapy. However, rifampin's half-life of 3 h is believed to limit its utility for intermittent therapy, so new congeners with long half-lives are being developed. Using an in vitro pharmacokinetic-pharmacodynamic model of tuberculosis, we examined the relationships between rifampin exposure, microbial killing of log-phase-growth Mycobacterium tuberculosis, and suppression of resistance. Rifampin's microbial killing was linked to the area under the concentration-time curve-to-MIC ratio. The suppression of resistance was associated with the free peak concentration (C max )-to-MIC ratio and not the duration that the rifampin concentration was above MIC. Rifampin prevented resistance to itself at a free C max /MIC ratio of >175. The postantibiotic effect duration was >5.2 days and was most closely related to the C max /MIC ratio (r 2 ‫؍‬ 0.96). To explain rifampin's concentration-dependent effect, we examined the kinetics of rifampin entry into M. tuberculosis. Rifampin achieved concentration-dependent intracellular steady-state concentrations within 15 min. Our results suggest that doses of rifampin higher than those currently employed would optimize the effect of rifampin, if patients could tolerate them. Another major implication is that in the design of new rifampin congeners for intermittent therapy, the important properties may include (i) the efficient entry of the rifamycin into M. tuberculosis, (ii) the achievement of a free C max /MIC of >175 that can be tolerated by patients, and (iii) a long postantibiotic effect duration.Tuberculosis (TB) is arguably the most important infectious disease to have confronted humankind. Currently, Mycobacterium tuberculosis infects 2 billion of the 6 billion people worldwide (50). The discovery of rifampin 40 years ago (31) was revolutionary in allowing the creation of potent combination drug regimens against this ancient nemesis. Rifampin is the backbone of modern anti-TB chemotherapy by virtue of being active against M. tuberculosis in exponential growth phase as well as possessing activity against nonreplicating persistent bacilli. Major limitations to rifampin use are believed to include its short half-life (t 1/2 ), which allows cycles of M. tuberculosis regrowth and resistance emergence.It has been the belief for almost half a century that if a drug such as rifampin was given once a week in the initial phase of therapy, its short serum t 1/2 of 3 h would allow short periods of microbial killing followed by regrowth between doses (33, 37). The inference is that the length of time that rifampin is above a certain threshold concentration is the most important index associated with M. tuberculosis killing and the prevention of resistance. Thus, one of the strategic goals of the World Health Organization, the pharmaceutical industry, and research scientists has been to develop rifampin congeners with long t 1/2 s, such as rifapentine, which would make intermittent dosing more effective (3,9,24,26).It is widely believed...

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