COVER A long-exposure photograph shows the Clepsydra Geyser erupting on a moonlit night in Yellowstone National Park’s Lower Geyser Basin. Geysers and other hydrothermal features in Yellowstone National Park are fueled by heat from a magma reservoir in Earth’s upper crust. New seismic imaging of Yellowstone has provided further insight into the volume and distribution of magma in the subsurface. See pages 945 and 1001.

Photo: Paul D. Stewart/NPL/Minden Pictures

ONLINE COVER A smart dual hormone microneedle patch for blood glucose control. Insulin and glucagon secreted from the pancreas are essential for regulating blood glucose levels. Inspired by the dual-responsive mechanism, Yang et al. developed a glucose-responsive microneedle patch that enables closed-loop delivery of both insulin and glucagon for diabetes treatment. In a Type 1 diabetic pig model, the patch kept blood glucose levels within normal range and minimized the risk of hypoglycemia.

ONLINE COVER IL-2 Mutein Passes an Acid Test. This month’s cover depicts a glycolytic tumor releasing lactic acid molecules, establishing an acidic tumor microenvironment (TME). The low pH of the TME suppresses antitumor immune responses and favors tumor growth. Gaggero and Martinez-Fabregas et al. report that cytokines are extremely sensitive to the acidic pH found in tumors and lymph nodes. The activity of IL-2, a cytokine central to T cell responses, is highly limited at acidic pH. Using in vitro evolution, they identify a new IL-2 variant, Switch-2, that exhibits enhanced activity at acidic pH but, surprisingly, exhibits reduced activity at the neutral pH found in healthy tissue. Switch-2 therapy in mice triggered potent antitumor responses while avoiding the severe systemic toxicity associated with current high-dose IL-2 therapies.

ONLINE COVER Bionics replicate biomechanics. Lower-limb prostheses are often heavy, consume a lot of energy, and do not replicate the natural gait. Tran et al. have developed a powered prosthesis for above-knee amputees that possesses knee, ankle, and toe joints to replicate the biomechanics of the leg. The device is lightweight and capable of regenerating energy during walking to extend its battery life. The researchers validated their design with preclinical studies on above-knee amputees showing the ability to ambulate on level ground and on stairs. This month’s cover is a photograph of the prosthesis device: Utah Bionic Leg.

ONLINE COVER This week, Shen et al. report that the GTPase-activating protein TSC2 limits the mechanosensitive and cell growth signaling that drives pulmonary arterial hypertension, a condition that currently lacks effective treatment options. The image shows a lung tissue section from a patient with pulmonary arterial hypertension stained for TSC2 (magenta), smooth muscle α-actin (green), and DAPI (blue).

ONLINE COVER Ketones Rekindle Megakaryocytes. The transmission electron microscopy micrograph shows a murine primary megakaryocyte, a bone marrow cell that produces platelets. Chemotherapy can reduce platelet counts in patients undergoing cancer treatment, which can in turn limit treatment efficacy. Xie et al. found that a ketogenic diet boosted platelet production in mouse models of thrombocytopenia by increasing circulating β-hydroxybutyrate, leading to altered histone acetylation of platelet biogenesis genes in megakaryocytes. A ketogenic diet modestly increased platelet counts in healthy volunteers, and, in a separate cohort of patients with cancer, a ketogenic lifestyle was associated with reduced chemotherapy-induced thrombocytopenia, suggesting this treatment strategy may translate to humans.