UV radiation (UV) is classified as a “complete carcinogen” because it is both a mutagen and a non-specific damaging agent and has properties of both a tumor initiator and a tumor promoter. In environmental abundance, UV is the most important modifiable risk factor for skin cancer and many other environmentally-influenced skin disorders. However, UV also benefits human health by mediating natural synthesis of vitamin D and endorphins in the skin, therefore UV has complex and mixed effects on human health. Nonetheless, excessive exposure to UV carries profound health risks, including atrophy, pigmentary changes, wrinkling and malignancy. UV is epidemiologically and molecularly linked to the three most common types of skin cancer, basal cell carcinoma, squamous cell carcinoma and malignant melanoma, which together affect more than a million Americans annually. Genetic factors also influence risk of UV-mediated skin disease. Polymorphisms of the melanocortin 1 receptor (MC1R) gene, in particular, correlate with fairness of skin, UV sensitivity, and enhanced cancer risk. We are interested in developing UV-protective approaches based on a detailed understanding of molecular events that occur after UV exposure, focusing particularly on epidermal melanization and the role of the MC1R in genome maintenance.

Positive behavior support (PBS) and functional behavioral assessment (FBA) are two significant concepts of the 1997 amendments to the Individuals with Disabilities Education Act. These two concepts are not new, but they are important for improving the quality of efforts to educate children and youth with disabilities. The purposes of this article are to describe (a) the context in which PBS and FBA are needed and (b) definitions and features of PBS and FBA. An important message is that positive behavioral interventions and supports involve the whole school, and successful implementation emphasizes the identification, adoption, and sustained use of effective policies, systems, data-based decision making, and practices. Systems-level challenges are also discussed.

Phenol oxidase (PO) was isolated as a proenzyme (pro-phenol oxidase, pro-PO) from the hemolymph of Manduca sexta larvae and purified to homogeneity. Pro-PO exhibits a Mr of 130,000 on gel filtration and two bands with an apparent Mr of -100,000 on SDS/PAGE, as well as sizeexclusion HPLC. Activation of pro-PO was achieved either by specific proteolysis by a cuticular protease or by the detergent cetylpyridinium chloride at a concentration below the critical micellar concentration. A cDNA clone for M. sexta pro-PO was obtained from a larval hemocyte cDNA library. The clone encodes a polypeptide of -80,000 Da that contains two copper-binding sites and shows high sequence similarity to POs, hemocyanins, and storage proteins of arthropods. The M. sexta pro-PO, together with other arthropod pro-POs, contains a short stretch of amino acids with sequence similarity to the thiol ester region of a-macroglobulins and complement proteins C3 and C4.Melanin biosynthesis occurs widely, not only in animals but also in plants and fungi (1). Phenol oxidase (PO), which possesses both tyrosinase activity (monophenol monooxygenase; monophenol, L-dopa:oxygen oxidoreductase; EC 1.14.18.1), as well as o-diphenol oxidase (1,2-benzenediol:oxygen oxidoreductase; EC 1.10.3.1), is responsible for initiating the biosynthesis of melanin (2, 3). In arthropods and especially in insects, PO is uniquely involved in another important biochemical process-cuticular sclerotization (hardening). Sclerotization is vital for the survival of all insects, as it affords protection to the soft invertebrate body (3-8). During sclerotization, PO-generated quinones participate in the quinone tanning process or serve as substrates for quinone isomerases that convert quinones to quinone methides for quinone methide sclerotization (9-13). Certain quinone methides are converted by another cuticular enzyme, quinone methide isomerase, to 1,2-dehydro-N-acyldopamine derivatives (14). These compounds are further oxidized by PO to reactive quinone methide imine amides (15, 16), which serve as the reactive intermediates of a,f3-sclerotization. Quinones, quinone methides, and quinone methide imine amides react with cuticular proteins and chitin, forming eventually cross-linked cuticle.Apart from participating in sclerotization and melanization of cuticle, POs are also known to be involved in two other physiologically important processes-defense reactions (arthropod immunity) and wound healing. During invasion by a foreign organism, pro-phenol oxidase (pro-PO) present in the hemocytes is released and activated to produce melanin pigments for deposition on the intruder (17)(18)(19). The damage that can be caused by the foreign organisms is thus limited by encapsulation and melanization. Similarly during wounding of insect cuticle, PO causes massive deposition of melanin pigment at the wound site to prevent hemolymph loss and to block the entry of opportunistically invading microorganisms (20).Given such important functions, it could be expected that PO would be one o...

Collagen prolyl 4-hydroxylase (P4H) expression and collagen hydroxylation in cancer cells are necessary for breast cancer progression. Here, we show that P4H alpha 1 subunit (P4HA1) protein expression is induced in triple-negative breast cancer (TNBC) and HER2 positive breast cancer. By modulating alpha ketoglutarate (α-KG) and succinate levels P4HA1 expression reduces proline hydroxylation on hypoxia-inducible factor (HIF) 1α, enhancing its stability in cancer cells. Activation of the P4HA/HIF-1 axis enhances cancer cell stemness, accompanied by decreased oxidative phosphorylation and reactive oxygen species (ROS) levels. Inhibition of P4HA1 sensitizes TNBC to the chemotherapeutic agent docetaxel and doxorubicin in xenografts and patient-derived models. We also show that increased P4HA1 expression correlates with short relapse-free survival in TNBC patients who received chemotherapy. These results suggest that P4HA1 promotes chemoresistance by modulating HIF-1-dependent cancer cell stemness. Targeting collagen P4H is a promising strategy to inhibit tumor progression and sensitize TNBC to chemotherapeutic agents.

Without prevention strategies, schools can expect to observe behavioral difficulties in more than 20% of the school population. Using schoolwide systems of positive behavioral support, schools can decrease the number of problem behaviors by students, providing a clearer focus for intervention on the students with the greatest support needs. This article presents a case example of schoolwide positive behavioral support, including its planning, implementation, and outcomes. The entire process of creating schoolwide teams, determining actions, and developing consensus is described in detail with specific examples. Outcomes of school-selected dependent variables indicate large decreases in the number of students excluded from the classroom learning environment for problem behaviors. Details of specific problems and issues are discussed with examples.