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1.  Pitchfork Regulates Primary Cilia Dizsassembly and Left-Right Asymmetry 
Developmental cell  2010;19(1):66-77.
SUMMARY
A variety of developmental disorders have been associated with ciliary defects, yet the controls that govern cilia disassembly are largely unknown. Here we report a mouse embryonic node gene, which we named Pitchfork (Pifo). Pifo associates with ciliary targeting complexes and accumulates at the basal body during cilia disassembly. Haploinsufficiency causes a unique node cilia duplication phenotype, left-right asymmetry defects, and heart failure. This phenotype is likely relevant in humans, because we identified a heterozygous R80K PIFO mutation in a fetus with situs inversus and cystic liver and kidneys, and in patient with double-outflow right ventricle. We show that PIFO, but not R80K PIFO, is sufficient to activate Aurora A, a protooncogenic kinase that induces cilia retraction, and that Pifo/PIFO mutation causes cilia retraction, basal body liberation, and overreplication defects. Thus, the observation of a disassembly phenotype in vivo provides an entry point to understand and categorize ciliary disease.
doi:10.1016/j.devcel.2010.06.005
PMCID: PMC3671612  PMID: 20643351
2.  CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs 
Nature genetics  2010;43(1):72-78.
Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by recurrent infections of the upper and lower respiratory tract, reduced fertility in males and situs inversus in about 50% of affected individuals (Kartagener syndrome). It is caused by motility defects in the respiratory cilia that are responsible for airway clearance, the flagella that propel sperm cells and the nodal monocilia that determine left-right asymmetry1. Recessive mutations that cause PCD have been identified in genes encoding components of the outer dynein arms, radial spokes and cytoplasmic pre-assembly factors of axonemal dyneins, but these mutations account for only about 50% of cases of PCD. We exploited the unique properties of dog populations to positionally clone a new PCD gene, CCDC39. We found that loss-of-function mutations in the human ortholog underlie a substantial fraction of PCD cases with axonemal disorganization and abnormal ciliary beating. Functional analyses indicated that CCDC39 localizes to ciliary axonemes and is essential for assembly of inner dynein arms and the dynein regulatory complex.
doi:10.1038/ng.726
PMCID: PMC3509786  PMID: 21131972
3.  Validity of Self-Reported Solar UVR Exposure Compared to Objectively Measured UVR Exposure 
Background
Reliance on verbal self-report of solar exposure in skin cancer prevention and epidemiologic studies may be problematic if self-report data are not valid due to systematic errors in recall, social desirability bias, or other reasons.
Methods
This study examines the validity of self-reports of exposure to ultraviolet radiation (UVR) compared to objectively measured exposure among children and adults in outdoor recreation settings in four regions of the United States. Objective UVR exposures of 515 participants were measured using polysulfone film badge UVR dosimeters on two days. The same subjects provided self-reported UVR exposure data on surveys and 4-day sun exposure diaries, for comparison to their objectively measured exposure.
Results
Dosimeter data showed that lifeguards had the greatest UVR exposure (24.5% of weekday ambient UVR), children the next highest exposures (10.3% ambient weekday UVR) and parents had the lowest (6.6% ambient weekday UVR). Similar patterns were observed in self-report data. Correlations between diary reports and dosimeter findings were fair to good and were highest for lifeguards (r = 0.38 – 0.57), followed by parents (r = 0.28 – 0.29) and children (r = 0.18 – 0.34). Correlations between survey and diary measures were moderate to good for lifeguards (r = 0.20 – 0.54) and children (r = 0.35 – 0.53).
Conclusions
This is the largest study of its kind to date, and supports the utility of self-report measures of solar UVR exposure.
Impact
Overall, self-reports of sun exposure produce valid measures of UVR exposure among parents, children, and lifeguards who work outdoors.
doi:10.1158/1055-9965.EPI-10-0709
PMCID: PMC3005549  PMID: 20940277
skin cancer; sun exposure; UVR; dosimeters; validation; biomarkers
4.  Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes 
Nature genetics  2010;42(7):619-625.
Joubert syndrome (JBTS), related disorders (JSRD) and Meckel syndrome (MKS) are ciliopathies. We now report that MKS2 and JBTS2 loci are allelic and due to mutations in TMEM216, encoding an uncharacterized tetraspan transmembrane protein. JBTS2 patients displayed frequent nephronophthisis and polydactytly, and two cases conformed to the Oro-Facio-Digital type VI phenotype, whereas skeletal dysplasia was common in MKS fetuses. A single p.R73L mutation was identified in all patients of Ashkenazi Jewish descent (n=10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in patient fibroblasts or following siRNA knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 complexed with Meckelin, encoded by a gene also mutated in JSRD and MKS. Abrogation of tmem216 expression in zebrafish led to gastrulation defects that overlap with other ciliary morphants. The data implicate a new family of proteins in the ciliopathies, and further support allelism between ciliopathy disorders.
doi:10.1038/ng.594
PMCID: PMC2894012  PMID: 20512146
5.  Training for and Dissemination of the Nutrition Environment Measures Surveys (NEMS) 
Preventing Chronic Disease  2010;7(6):A126.
Introduction
Researchers believe that nutrition environments contribute to obesity and may explain some health disparities. The Nutrition Environment Measures Surveys (NEMS) are valid and reliable observational measures of the nutrition environment. This article describes the dissemination of the measures, including the development, implementation, and evaluation of training workshops, and a follow-up survey of training participants.
Methods
To disseminate the NEMS measures, we developed a 2-day intensive, participatory workshop. We used an immediate postcourse evaluation and a structured telephone follow-up interview to evaluate the workshops and the dissemination strategy. Topics included use of the NEMS measures, reactions to the workshops, and participants' training others on the measures.
Results
During the study period, 173 people participated in 14 workshops. Participants indicated a high level of satisfaction with the training workshops. Almost two-thirds of respondents reported using the measures to train an additional 292 people and to rate more than 3,000 food outlets. The measures have been used in diverse locations across the United States for various purposes. Respondents have reported NEMS results in peer-reviewed journals, master's theses, newspaper articles, and presentations.
Conclusion
The NEMS measures are the only nutrition environment measures that have been packaged for distribution and widely disseminated. The measures fill a need in the worlds of research and community action, and dissemination was successful in accelerating diffusion and promoting adoption of the measures. The use of an ongoing, continual process to improve workshops and measures contributes to the usefulness of the surveys and accelerates their adoption and continued use.
PMCID: PMC2995598  PMID: 20950533
6.  Postinflammatory Hyperpigmentation 
Postinflammatory hyperpigmentation is a common sequelae of inflammatory dermatoses that tends to affect darker skinned patients with greater frequency and severity. Epidemiological studies show that dyschromias, including postinflammatory hyperpigmentation, are among the most common reasons darker racial/ethnic groups seek the care of a dermatologist. The treatment of postinflammatory hyperpigmentation should be started early to help hasten its resolution and begins with management of the initial inflammatory condition. First-line therapy typically consists of topical depigmenting agents in addition to photoprotection including a sunscreen. Topical tyrosinase inhibitors, such as hydroquinone, azelaic acid, kojic acid, arbutin, and certain licorice extracts, can effectively lighten areas of hypermelanosis. Other depigmenting agents include retinoids, mequinol, ascorbic acid, niacinamide, N-acetyl glucosamine, and soy with a number of emerging therapies on the horizon. Topical therapy is typically effective for epidermal postinflammatory hyperpigmentation; however, certain procedures, such as chemical peeling and laser therapy, may help treat recalcitrant hyperpigmentation. It is also important to use caution with all of the above treatments to prevent irritation and worsening of postinflammatory hyperpigmentation.
PMCID: PMC2921758  PMID: 20725554
7.  A Review of Acne in Ethnic Skin 
Acne vulgaris is one of the most common conditions for which all patients, including those with skin of color (Fitzpatrick skin types IV–VI), seek dermatological care. The multifactorial pathogenesis of acne appears to be the same in ethnic patients as in Caucasians. However, there is controversy over whether certain skin biology characteristics, such as sebum production, differ in ethnic patients. Clinically, acne lesions can appear the same as those seen in Caucasians; however, histologically, all types of acne lesions in African Americans can be associated with intense inflammation including comedones, which can also have some degree of inflammation. It is the sequelae of the disease that are the distinguishing characteristics of acne in skin of color, namely postinflammatory hyperpigmentation and keloidal or hypertrophic scarring. Although the medical and surgical treatment options are the same, it is these features that should be kept in mind when designing a treatment regimen for acne in skin of color.
PMCID: PMC2921746  PMID: 20725545
9.  Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy  
The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1–NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are “ciliopathies”. Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyses also revealed a likely cilia-related function; suppression of zebrafish xpnpep3 phenocopied the developmental phenotypes of ciliopathy morphants, and this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal. Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish. Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways.
doi:10.1172/JCI40076
PMCID: PMC2827951  PMID: 20179356

Results 1-9 (9)