How genetic and environmental factors interact in Parkinson disease is poorly understood. We have now compared the patterns of vulnerability and rescue of Caenorhabditis elegans with genetic modifications of three different genetic factors implicated in Parkinson disease (PD). We observed that expressing ␣-synuclein, deleting parkin (K08E3.7), or knocking down DJ-1 (B0432.2) or parkin produces similar patterns of pharmacological vulnerability and rescue. C. elegans lines with these genetic changes were more vulnerable than nontransgenic nematodes to mitochondrial complex I inhibitors, including rotenone, fenperoximate, pyridaben, or stigmatellin. In contrast, the genetic manipulations did not increase sensitivity to paraquat, sodium azide, divalent metal ions (Fe(II) or Cu(II)), or etoposide compared with the nontransgenic nematodes. Each of the PD-related lines was also partially rescued by the antioxidant probucol, the mitochondrial complex II activator, D-␤-hydroxybutyrate, or the anti-apoptotic bile acid tauroursodeoxycholic acid. Complete protection in all lines was achieved by combining D-␤-hydroxybutyrate with tauroursodeoxycholic acid but not with probucol. These results show that diverse PD-related genetic modifications disrupt the mitochondrial function in C. elegans, and they raise the possibility that mitochondrial disruption is a pathway shared in common by many types of familial PD.The etiology of Parkinson disease has both genetic and environmental components (1). Epidemiological studies show that PD 3 is more common in rural areas, and increased rates of PD are associated with the use of agricultural toxins, such as pesticides and herbicides (2). Attention has focused on inhibitors of the mitochondrial electron transport chain because some of the agricultural toxins implicated in PD are complex I inhibitors (2). In addition, ingestion of complex I inhibitors causes syndromes related to PD. The complex I inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively kills dopaminergic neurons in many types of animals (1). Rotenone, another complex I inhibitor, also causes a PD-related syndrome in rats and causes multiple changes in the mitochondria of cultured neurons relevant to PD (3-6). These factors implicate disruption of mitochondrial function, and particularly complex I inhibition, in the etiology of PD.Many of the genes associated with familial cases of PD have been identified, but no clear consensus exists over whether the different disease-related proteins converge onto a common pathway. Mutation of ␣-synuclein (at A53T, A30P, or K46E) or duplication of ␣-synuclein is associated with familial parkinsonisms (7-10). Loss of the putative ubiquitin ligase, parkin, causes autosomal recessive juvenile parkinsonism (11). Mutations in the genes coding for UCH-L1, DJ-1, and PINK1 are also all associated with autosomal recessive PD, and mutations in LRRK2 are associated with autosomal dominant PD (12-15). ␣-Synuclein is a small ubiquitous protein that binds lipids and might regulate ves...

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We present ground-based infrared transit observations for four dynamically interacting Kepler planets, including Kepler-29b, Kepler-36c, KOI-1783.01, and Kepler-177c, obtained using the Wide-field Infrared Camera on the Hale 200" telescope at Palomar Observatory. By utilizing an engineered diffuser and custom guiding software, we mitigate time-correlated telluric and instrumental noise sources in these observations. We achieve an infrared photometric precision comparable to or better than that of space-based observatories such as the Spitzer Space Telescope, and detect transits with greater than 5σ significance for all planets aside from Kepler-36c. For Kepler-177c (J = 13.9) our measurement uncertainties are only 1.2× the photon noise limit and 1.9 times better than the predicted photometric precision for Spitzer IRAC photometry of this same target. We find that a single transit observation obtained 4 − 5 years after the end of the original Kepler mission can reduce dynamical mass uncertainties by as much as a factor of three for these systems. Additionally, we combine our new observations of KOI-1783.01 with information from the literature to confirm the planetary nature of this system. We discuss the implications of our new mass and radius constraints in the context of known exoplanets with low incident fluxes, and we note that Kepler-177c may be a more massive analog to the currently known super-puffs given its core mass (4.2±0.8M ⊕ ) and large gas-to-core ratio (2.5±0.2). Our demonstrated infrared photometric performance opens up new avenues for ground-based observations of transiting exoplanets previously thought to be restricted to space-based investigation.

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Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with one of the worst prognoses worldwide and has an overall 5-year survival rate of only 9%. Although chemotherapy is the recommended treatment for patients with advanced PDAC, its efficacy is not satisfactory. The dense dysplastic stroma of PDAC is a major obstacle to the delivery of chemotherapy drugs and plays an important role in the progression of PDAC. Therefore, stroma-targeting therapy is considered a potential treatment strategy to improve the efficacy of chemotherapy and patient survival. While several preclinical studies have shown encouraging results, the anti-tumor potential of the PDAC stroma has also been revealed, and the extreme depletion might promote tumor progression and undermine patient survival. Therefore, achieving a balance between stromal abundance and depletion might be the further of stroma-targeting therapy. This review summarized the current progress of stroma-targeting therapy in PDAC and discussed the doubleedged sword of its therapeutic effects.

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