Faculty Bibliography

Hair thinning and loss are prominent aging phenotypes but have an unknown mechanism. We show that hair follicle stem cell (HFSC) aging causes the stepwise miniaturization of hair follicles and eventual hair loss in wild-type mice and in humans. In vivo fate analysis of HFSCs revealed that the DNA damage response in HFSCs causes proteolysis of type XVII collagen (COL17A1/BP180), a critical molecule for HFSC maintenance, to trigger HFSC aging, characterized by the loss of stemness signatures and by epidermal commitment. Aged HFSCs are cyclically eliminated from the skin through terminal epidermal differentiation, thereby causing hair follicle miniaturization. The aging process can be recapitulated by Col17a1 deficiency and prevented by the forced maintenance of COL17A1 in HFSCs, demonstrating that COL17A1 in HFSCs orchestrates the stem cell-centric aging program of the epithelial mini-organ.

KCNQ (voltage-gated K(+) channel family 7 (Kv7)) channels control cellular excitability and underlie the K(+) current sensitive to muscarinic receptor signaling (the M current) in sympathetic neurons. Here we show that the novel anti-epileptic drug retigabine (RTG) modulates channel function of pore-only modules (PMs) of the human Kv7.2 and Kv7.3 homomeric channels and of Kv7.2/3 heteromeric channels by prolonging the residence time in the open state. In addition, the Kv7 channel PMs are shown to recapitulate the single-channel permeation and pharmacological specificity characteristics of the corresponding full-length proteins in their native cellular context. A mutation (W265L) in the reconstituted Kv7.3 PM renders the channel insensitive to RTG and favors the conductive conformation of the PM, in agreement to what is observed when the Kv7.3 mutant is heterologously expressed. On the basis of the new findings and homology models of the closed and open conformations of the Kv7.3 PM, we propose a structural mechanism for the gating of the Kv7.3 PM and for the site of action of RTG as a Kv7.2/Kv7.3 K(+) current activator. The results validate the modular design of human Kv channels and highlight the PM as a high-fidelity target for drug screening of Kv channels.

Complex regulatory networks regulate stem cell behavior and contributions to tissue growth, repair, and homeostasis. A full understanding of the networks controlling stem cell self-renewal and differentiation, however, has not yet been realized. To systematically dissect these networks and identify their components, we performed an unbiased, transcriptome-wide in vivo RNAi screen in female Drosophila germline stem cells (GSCs). Based on characterized cellular defects, we classified 646 identified genes into phenotypic and functional groups and unveiled a comprehensive set of networks regulating GSC maintenance, survival, and differentiation. This analysis revealed an unexpected role for ribosomal assembly factors in controlling stem cell cytokinesis. Moreover, our data show that the transition from self-renewal to differentiation relies on enhanced ribosome biogenesis accompanied by increased protein synthesis. Collectively, these results detail the extensive genetic networks that control stem cell homeostasis and highlight the intricate regulation of protein synthesis during differentiation.

White adipose tissue (WAT) is essential for maintaining metabolic function, especially during obesity. The intronic microRNAs miR-33a and miR-33b, located within the genes encoding sterol-regulatory element-binding proteins, SREBP-2 and SREBP-1 respectively, are transcribed in concert with their host genes and function alongside them to regulate cholesterol, fatty acid, and glucose metabolism. SREBP-1 is highly expressed in mature WAT and plays a critical role in promoting in-vitro adipocyte differentiation. It is unknown whether miR-33b is induced during or involved in adipogenesis. This is in part due to loss of miR-33b in rodents, precluding in-vivo assessment of the impact of miR-33b using standard mouse models. This work demonstrates that miR-33b is highly induced upon differentiation of human pre-adipocytes, along with SREBP-1. We further report that miR-33b is an important regulator of adipogenesis, as inhibition of miR-33b enhanced lipid droplet accumulation. Conversely, overexpression of miR-33b impaired pre-adipocyte proliferation, and reduced lipid droplet formation and the induction of PPARgamma target genes during differentiation. These effects may be mediated by targeting of HMGA2, CDK6 and other predicted miR-33b targets. Together, these findings demonstrate a novel role of miR-33b in the regulation of adipocyte differentiation, with important implications for the development of obesity and metabolic disease.

We present a game theoretic framework that models strategic interactions among humans and things that are assumed to be interconnected by a social-technological network, as in an internet of humans and things (IOHT). Often a pair of agents in the network interacts in order for an informed sender-agent to signal an uninformed receiver-agent to take an action that benefits each of the players; the benefits to the pair of agents are modeled by two separate utility functions, both depending on the sender"™s private information, the signal exchanged, and the receiver"™s revealed (and also possibly unrevealed) action. In general, the two agents"™ utilities may not be aligned and may encourage deceptive behavior. For example, a sender, aware of his/her own private "state of ignorance", may seek useful information from a receiver who owns powerful computational resources to search a large corpus of webpages; the sender does so by sending a signal to the receiver in the form of a keyword. Obvious examples of deceptiveness here range from attempts to hide one"™s intentions to auctioning the keywords on an ad exchange through real-time bidding. A rather troublesome situation occurs when deceptions are employed to breach the security of the system, thus making the entire social-technological network unreliable. Earlier, we proposed a signaling-game-theoretic framework to alleviate this problem. This paper further enhances that framework by reconfiguring signals to possess more complex structures (epistatic signals to represent attack and defense options over a given set of vulnerabilities). We explore two augmentations to the original evolutionary signaling game by first enhancing mutation bias toward strategies performing well in previous populations and second allowing the parameters of the utility functions to depend on population preferences giving rise to a minority game with epistatic signaling. The resulting game systems are empirically studied through extensive computer simulation.

Significance: Chronic wounds remain a significant public health problem. Alterations in normal physiological processes caused by aging or diabetes lead to impaired tissue repair and the development of chronic and nonhealing wounds. Understanding the unique features of the wound environment will be required to develop new therapeutics that impact these disabling conditions. New drug-delivery systems (DDSs) may enhance current and future therapies for this challenging clinical problem. Recent Advances: Historically, physical barriers and biological degradation limited the efficacy of DDSs in wound healing. In aiming at improving and optimizing drug delivery, recent data suggest that combinations of delivery mechanisms, such as hydrogels, small molecules, RNA interference (RNAi), as well as growth factor and stem cell-based therapies (biologics), could offer exciting new opportunities for improving tissue repair. Critical Issues: The lack of effective therapeutic approaches to combat the significant disability associated with chronic wounds has become an area of increasing clinical concern. However, the unique challenges of the wound environment have limited the development of effective therapeutic options for clinical use. Future Directions: New platforms presented in this review may provide clinicians and scientists with an improved understanding of the alternatives for drug delivery in wound care, which may facilitate the development of new therapeutic approaches for patients.

Formyl peptide receptor 1 (FPR1) targeting multimodal probe cFLFLFK-MHI-DOTA for leukocyte based inflammation imaging is described. The compound consists of three domains, (a) cFLFLF peptide for FPR1 recognition and binding for activated leukocyte, (b) heptamethine cyanine dye (MHI) for near infrared fluorescence (NIRF) detection and imaging, and (c) metal chelator DOTA ligand that could form complex with a radiometal for nuclear (PET/SPECT) imaging or with a paramagnetic metal for MRI imaging. Detailed synthesis, characterization and in vitro evaluation are reported. The availability of dual mode inflammation imaging probe would allow in vivo gross level imaging of inflammation foci as well as ex vivo microscopic level cellular imaging for role played by innate immune cells in inflamed tissue.

Previous National Council on Radiation Protection and Measurements (NCRP) publications have addressed the issues of risk and dose limitation in radiation protection and included guidance on specific organs and the lens of the eye. NCRP decided to prepare an updated commentary intended to enhance the previous recommendations provided in earlier reports. The NCRP Scientific Committee 1-23 (SC 1-23) is charged with preparing a commentary that will evaluate recent studies on the radiation dose response for the development of cataracts and also consider the type and severity of the cataracts as well as the dose rate; provide guidance on whether existing dose limits to the lens of the eye should be changed in the United States; and suggest research needs regarding radiation effects on and dose limits to the lens of the eye. A status of the ongoing work of SC 1-23 was presented at the Annual Meeting, "Changing Regulations and Radiation Guidance: What Does the Future Hold?" The following represents a synopsis of a few main points in the current draft commentary. It is likely that several changes will be forthcoming as SC 1-23 responds to subject matter expert review and develops a final document, expected by mid 2016.

Interventions that lead to reductions in soil-transmitted helminths (STHs) include chemotherapy with anthelmintic drugs and improvements in water, sanitation, and hygiene (WASH). In this opinion article we aim to determine the evidence for optimal approaches for STH control. First we explore the evidence for the above interventions. We then appraise two integration strategies: current chemotherapy-oriented integrated neglected tropical disease (NTD) control and expanded 'multicomponent integration', which includes integrated chemotherapy, WASH, and other intervention strategies. While multicomponent integrated control may be an effective approach to sustainably reduce STH transmission, there is a need for evidence to prove the feasibility of this approach.

BACKGROUND: Systemic antibiotics are used widely to treat moderate to severe acne, but increasing antibiotic resistance makes appropriate use a priority. OBJECTIVE: We sought to determine the duration of systemic antibiotic use in patients with inflammatory/nodulocystic acne who eventually required isotretinoin. METHODS: We performed a retrospective, single-site chart review of patients with acne diagnostic codes evaluated January 1, 2005 to December 31, 2014, at a dermatology practice in an academic medical center. Included patients were prescribed isotretinoin during the study period and received 30 days or more of antibiotics. RESULTS: The average duration of antibiotic use was 331.3 days. In all, 21 patients (15.3%) were prescribed antibiotics for 3 months or less, 88 patients (64.2%) for 6 months or more, and 46 patients (33.6%) for 1 year or longer. Patients treated only at the study site had a mean duration of antibiotic treatment of 283.1 days whereas patients who also received antibiotics from another institution had a mean duration of 380.2 days. This difference approached statistical significance (P = .054). LIMITATIONS: This study was limited to a single center. CONCLUSION: Expert guidelines recommend responsible use of antibiotics in acne in light of emerging resistance. We found that patients who eventually received isotretinoin had extended exposure to antibiotics, exceeding recommendations. Early recognition of antibiotic failure and the need for isotretinoin can curtail antibiotic use.