Elucidating the structure and function of the nucleus-The NIH Common Fund 4D Nucleome program.

Genomic architecture appears to play crucial roles in health and a variety of diseases. How nuclear structures reorganize over different timescales is elusive, partly because the tools needed to probe and perturb them are not as advanced as needed by the field. To fill this gap, the National Institutes of Health Common Fund started a program in 2015, called the 4D Nucleome (4DN), with the goal of developing and ultimately applying technologies to interrogate the structure and function of nuclear organization in space and time.

Validation of antibodies: Lessons learned from the Common Fund Protein Capture Reagents Program.

Large-scale generation of protein capture reagents remains a technical challenge, but their generation is just the beginning. Validation is a critical, iterative process that yields different results for different uses. Independent, community-based validation offers the possibility of transparent data sharing, with use case­specific results made broadly available. This type of resource, which can grow as new validation data are obtained for an expanding group of reagents, provides a community resource that should accompany future reagent-generating efforts. To address a pressing need for antibodies or other reagents that recognize human proteins, the National Institutes of Health Common Fund launched the Protein Capture Reagents Program in 2010 as a pilot to target human transcription factors. Here, we describe lessons learned from this program concerning generation and validation of research reagents, which we believe are generally applicable for future research endeavors working in a similar space.

Erythema Ab Igne and Malignant Transformation to Squamous Cell Carcinoma.

Erythema ab igne (EAI) is a cutaneous reaction resulting from prolonged exposure to an infrared heat source at temperatures insufficient to cause a burn. It is most commonly reported on the lower extremities and back, and it presents with persistent areas of reticular erythema associated with hyperpigmentation, epidermal atrophy, and telangiectases. Erythema ab igne traditionally is associated with chronic exposure to open fires and coal stoves. More recently, other implicated causes include heating pads, laptop computers, heated furniture, and electric space heaters. Histologic features of squamous atypia with basal layer crowding and loss of maturation throughout the epidermis can be seen in later stages of EAI. Therefore, although EAI is predominantly a chronic pigmentary disorder, a percentage of patients might be at increased risk for cutaneous malignant transformation, including squamous cell carcinoma (SCC).

A Blueprint for Characterizing Senescence.

Given the heterogeneity of senescent cells, our knowledge of both the drivers and consequences of cellular senescence in tissues and organs remains limited, as is our understanding of how this process could be harnessed for human health. Here we identified five broad areas that would help propel the field forward.

A perianal subcutaneous metastasis as the presenting sign for lung cancer.

Metastases to soft tissues are rarely reported in the initial presentation and diagnosis of lung cancer. We report a case of a 77-year-old white man who presented with a 9-day history of a painful, rapidly growing mass on his left buttock in the gluteal cleft. The deep dermal location of the neoplasm and the lack of epidermal involvement led to suspicion of a metastatic carcinoma. Imaging showed a lung lesion suspected to be a primary malignancy with distant liver and gastric fundus metastases. Lung pathology showed primarily adenocarcinoma with squamous differentiation, whereas the skin biopsy showed poorly differentiated squamous cell carcinoma. Clinically, we concluded the skin carcinoma was a metastasis of a primary lung adenocarcinoma with squamous differentiation. This case highlights the importance of appropriate preventative screening.

The NIH Common Fund/Roadmap Epigenomics Program: Successes of a comprehensive consortium.

The NIH Roadmap Epigenomics Program was launched to deliver reference epigenomic data from human tissues and cells, develop tools and methods for analyzing the epigenome, discover novel epigenetic marks, develop methods to manipulate the epigenome, and determine epigenetic contributions to diverse human diseases. Here, we comment on the outcomes from this program: the scientific contributions made possible by a consortium approach and the challenges, benefits, and lessons learned from this group science effort.

Atypical cutaneous and histological presentation of adult-onset Still's disease.

Adult-onset Still's disease (AOSD), the adult variant of systemic juvenile idiopathic arthritis, is a rare auto-inflammatory condition that presents with characteristic skin findings. There is no specific test available; diagnosis is usually based on the symptoms and evanescent rash found in patients. More recently, however, descriptions of atypical cutaneous and histological manifestations of AOSD have been published. We describe a case of atypical AOSD and discuss recent literature on this different cutaneous and histological presentation. Our results add to the growing discussion on atypical AOSD and suggest that this presentation may have been underreported and more common than previously thought.

Accelerating a paradigm shift: The Common Fund Single Cell Analysis Program.

It has become exceedingly important to understand the precise molecular profiles of the nearly 40 trillion cells in an adult human because of their role in determining health, disease, and therapeutic outcome. The National Institutes of Health (NIH) Common Fund-supported Single Cell Analysis Program (SCAP) was designed to address this challenge. In this review, we outline the original program goals and provide a perspective on the impact of the program as a catalyst for exploration of heterogeneity of human tissues at the cellular level. We believe that the technological advances in single-cell RNA sequencing and multiplexed imaging combined with computational methods made by this program will undoubtedly have an impact on broad and robust applications of single-cell analyses in both health and disease research.

Spectrum of orocutaneous disease associations: Immune-mediated conditions.

There are a number of diseases that manifest both on the skin and the oral mucosa, and therefore the importance for dermatologists in clinical practice to be aware of these associations is paramount. In the following continuing medical education series, we outline orocutaneous disease associations with both immunologic and inflammatory etiologies.

Spectrum of orocutaneous disease associations: Genodermatoses and inflammatory conditions.

The oral cavity and cutaneous organ systems share a close embryologic origin. Therefore, there are numerous dermatologic conditions presenting with concomitant oral findings of which the dermatologist must be aware. The second article in this continuing medical education series reviews inflammatory orocutaneous conditions and a number of genodermatoses. It is essential for dermatologists to be familiar with oral cavity manifestations associated with dermatologic diseases for prompt diagnosis, management, and appropriate referral to stomatology and dentistry.

Ustekinumab treatment for psoriasis in 119 patients maintained on therapy for a minimum of one year: a review.

Ustekinumab is a human IgG1κ monoclonal antibody that binds with high affinity and specificity to the p40 protein subunit shared by both the interleukin-12 and interleukin-23 cytokines. This study reviews clinical response and adverse events in 119 psoriasis patients who have received ustekinumab for a minimum of 1 year. The medical records of 119 psoriasis patients treated with ustekinumab at our referral clinic in Dallas between 2009 and 2013 were reviewed for response rates, side effects, and concomitant therapies. Of 119 patients, 117 (98%) had plaque type psoriasis, with 40 (34%) patients having psoriasis affecting either their palms and/or soles. Forty-four (37%) patients had psoriatic arthritis. The median follow-up period was 31 months. Fifty-six (47%) of the 119 patients obtained near complete clearance (response of more than 90% of initial body surface area involvement) upon the final follow-up visit or at the time of ustekinumab treatment discontinuation. Concomitant systemic treatments, primarily methotrexate, were given to 59 (50%) patients. Twenty-three (19%) patients discontinued treatment, primarily for sub-optimal response or loss of response. Fifty (42%) patients required either an increase in the dose of ustekinumab to 90 mg and/or administration more frequently than every 12 weeks to achieve and maintain psoriasis clearance.

NMR characterization of the formation kinetics and structure of di-O-benzylidene sorbitol gels self-assembled in organic solvents.

The molecule 1,3:2,4-di-O-benzylidene sorbitol (DBS) is a common "gelator" that forms thermally reversible gels in diverse organic solvents. Solid-state (13)C and (1)H NMR techniques, along with electron microscopy, are utilized in an exploratory study of DBS in the gelled state where we consider both in situ and dried gels. The gels were formed in either acetone or benzene, with the former being a better solvent for DBS. We find the in situ or dried DBS gels to be composed of rigid twisted nanofibrils (∼15 to 21 nm in diameter). The fibrils show local molecular ordering, but not crystalline order, and they contain no trapped solvent. The molecular mobility at the fibril surface is modestly enhanced, and all the free hydroxyl groups of the sorbitol moiety are involved in strong hydrogen bonding. We also attempted to find a truly crystalline form of DBS whose structure, as judged by the similarity of (13)C spectra, is close to that of the fibrils. We partially succeeded in this quest, employing melt crystallization followed by slow cooling. However, this sample was a mixed crystal having small domains, where only one type of domain was structurally similar to the fibrils. We also investigated the long-time evolution of the in situ DBS gel network. Specifically, high-resolution NMR kinetic studies were performed over periods of days where the residual concentration of DBS in acetone solution was monitored during and after gel formation. The DBS concentration on these long timescales evolved slowly, and we introduce a simple mathematical model and equation to describe this phenomenon.

Lobster attack induces sensitization in the sea hare, Aplysia californica.

Studies of the neural mechanisms of learning, especially of sensitization, have benefitted from extensive research on the model species, Aplysia californica (hereafter Aplysia). Considering this volume of literature on mechanisms, it is surprising that our understanding of the ecological context of sensitization in Aplysia is completely lacking. Indeed, the widespread use of strong electric shock to induce sensitization (an enhancement of withdrawal reflexes following noxious stimulation) is completely unnatural and leaves unanswered the question of whether this simple form of learning has any ecological relevance. We hypothesized that sublethal attack by a co-occurring predator, the spiny lobster, Panulirus interruptus, might be a natural sensitizing stimulus. We tested reflex withdrawal of the tail-mantle and head of individual Aplysia before and after attack by lobsters. Lobster attack significantly increased the amplitude of both reflexes, with a temporal onset that closely matched that observed with electric shock. This result suggests that electric shock may indeed mimic at least one naturally occurring sensitizing stimulus, suggesting, for the first time, an ecological context for this well studied form of learning.