Exome sequencing and in vitro studies identified podocalyxin as a candidate gene for focal and segmental glomerulosclerosis

Our understanding of focal and segmental glomerulosclerosis (FSGS) has advanced significantly from the studies of rare, monogenic forms of the disease. These studies have demonstrated the critical roles of multiple aspects of podocyte function in maintaining glomerular function. A substantial body of research has suggested that the integral membrane protein podocalyxin (PODXL) is required for proper function of podocytes, possibly by preserving the patency of the slit diaphragm by negative charge-based repulsion. Exome sequencing of affected cousins from an autosomal dominant pedigree with FSGS identified a co-segregating private variant, PODXL p.L442R, affecting the transmembrane region of the protein. Of the remaining 11 shared gene variants, two segregated with disease but their gene products were not detected in the glomerulus. In comparison to wild type, this disease-segregating PODXL variant facilitated dimerization. By contrast, this change does not alter protein stability, extracellular domain glycosylation, cell surface expression, global subcellular localization, or interaction with its intracellular binding partner ezrin. Thus, a variant form of PODXL remains the most likely candidate causing FSGS in one family with autosomal dominant inheritance, but its full effect on protein function remains unknown. Our work highlights the challenge faced in the clinical interpretation of whole exome data for small pedigrees with autosomal dominant diseases

An extended study on addressing defender teamwork while accounting for uncertainty in attacker defender games using iterative Dec-MDPs

Multi-agent teamwork and defender-attacker security games are two areas that are currently receiving significant attention within multi-agent systems research. Unfortunately, despite the need for effective teamwork among multiple defenders, little has been done to harness the teamwork 1 research in security games. The problem that this paper seeks to solve is the coordination of decentralized defender agents in the presence of uncer-tainty while securing targets against an observing adversary. To address this problem, we offer the following novel contributions in this paper: (i) New model of security games with defender teams that coordinate under uncertainty; (ii) New algorithm based on column generation that uti-lizes Decentralized Markov Decision Processes (Dec-MDPs) to generate defender strategies that incorporate uncertainty; (iii) New techniques to handle global events (when one or more agents may leave the system) during defender execution; (iv) Heuristics that help scale up in the num-ber of targets and agents to handle real-world scenarios; (v) Exploration of the robustness of randomized pure strategies. The paper opens the door to a potentially new area combining computational game theory and multi-agent teamwork.

Effects of Age, Race, and Ethnicity on the Optic Nerve and Peripapillary Region Using Spectral-Domain OCT 3D Volume Scans

Purpose: To evaluate the effects of age, race, and ethnicity on the optic nerve and peripapillary retina using spectral-domain optical coherence tomography (SD-OCT) three-dimensional (3D) volume scans in normal subjects. Methods: This is a cross-sectional study performed at a single institution in Boston. All patients received retinal nerve fiber layer (RNFL) scans and an optic nerve 3D volume scan. The SD-OCT software calculated peripapillary RNFL thickness, retinal thickness (RT), and retinal volume (RV). Custom-designed software calculated neuroretinal rim minimum distance band (MDB) thickness and area. Results: There were 272 normal subjects, including 175 whites, 40 blacks, 40 Asians, and 17 Hispanics. Rates of age-related decline were 2.3%, 2.0%, 1.7%, 3.3%, and 4.3% per decade for RNFL, RT, RV, MDB neuroretinal rim thickness, and MDB area, respectively. The RNFL was most affected by racial and ethnic variations, with Asians having thicker global, superior, and inferior RNFL, Hispanics having thicker inferior RNFL, and blacks having thinner temporal RNFL, compared to whites. For MDB thickness and area, Asians had smaller nasal values and blacks had smaller temporal values. Peripapillary RT and RV parameters were not influenced by race and ethnicity. Conclusions: All of the parameters exhibited age-related declines. RNFL, MDB thickness, and MDB area demonstrated racial and ethnic variations, while peripapillary RT and RV did not. Translational Relevance: This study demonstrates that both normal aging and ethnicity affect several novel 3D OCT parameters used to diagnose and monitor glaucoma (i.e., RT, RV, and MDB), and this should be factored in when making clinical decisions based on these parameters

Effects of Age, Race, and Ethnicity on the Optic Nerve and Peripapillary Region Using Spectral-Domain OCT 3D Volume Scans

Purpose: To evaluate the effects of age, race, and ethnicity on the optic nerve and peripapillary retina using spectral-domain optical coherence tomography (SD-OCT) three-dimensional (3D) volume scans in normal subjects. Methods: This is a cross-sectional study performed at a single institution in Boston. All patients received retinal nerve fiber layer (RNFL) scans and an optic nerve 3D volume scan. The SD-OCT software calculated peripapillary RNFL thickness, retinal thickness (RT), and retinal volume (RV). Custom-designed software calculated neuroretinal rim minimum distance band (MDB) thickness and area. Results: There were 272 normal subjects, including 175 whites, 40 blacks, 40 Asians, and 17 Hispanics. Rates of age-related decline were 2.3%, 2.0%, 1.7%, 3.3%, and 4.3% per decade for RNFL, RT, RV, MDB neuroretinal rim thickness, and MDB area, respectively. The RNFL was most affected by racial and ethnic variations, with Asians having thicker global, superior, and inferior RNFL, Hispanics having thicker inferior RNFL, and blacks having thinner temporal RNFL, compared to whites. For MDB thickness and area, Asians had smaller nasal values and blacks had smaller temporal values. Peripapillary RT and RV parameters were not influenced by race and ethnicity. Conclusions: All of the parameters exhibited age-related declines. RNFL, MDB thickness, and MDB area demonstrated racial and ethnic variations, while peripapillary RT and RV did not. Translational Relevance: This study demonstrates that both normal aging and ethnicity affect several novel 3D OCT parameters used to diagnose and monitor glaucoma (i.e., RT, RV, and MDB), and this should be factored in when making clinical decisions based on these parameters

Corneal perforation in ocular graft-versus-host disease

PURPOSE: Corneal perforation is a rare, vision-threatening complication of ocular graft-versus-host disease (GVHD) and is not well understood. Our objective was to examine the clinical disease course and histopathologic correlation in patients who progressed to this outcome. METHODS: This study is a retrospective case series from four academic centers in the United States. All patients received a hematopoietic stem cell transplant (HSCT) prior to developing ocular GVHD. Variables of interest included patient demographics, time interval between HSCT and ocular events, visual acuity throughout clinical course, corticosteroid and infection prophylaxis regimens at time of corneal perforation, medical/surgical interventions, and histopathology. RESULTS: Fourteen eyes from 14 patients were analyzed. Most patients were male (86%) and Caucasian (86%), and average age at time of hematopoietic stem cell transplant was 47 years. The mean interval between hematopoietic stem cell transplant and diagnosis of ocular graft-versus-host disease was 9.5 months, and between hematopoietic stem cell transplant and corneal perforation was 37 months. Initial best-corrected visual acuity was 20/40 or better in 9 eyes, and all eyes had moderate or poor visual outcomes despite aggressive management, including corneal gluing in all patients followed by keratoplasty in 8 patients. The mean follow-up after perforation was 34 months (range 2-140 months). Oral prednisone was used prior to perforation in 11 patients (79%). On histopathology, representative specimens in the acute phase demonstrated ulcerative keratitis with perforation but minimal inflammatory cells and no microorganisms, consistent with sterile corneal melt in the setting of immunosuppression; and in the healed phase, filling in of the perforation site with fibrous scar. CONCLUSIONS: In these patients, an extended time interval was identified between the diagnosis of ocular graft-versus-host disease and corneal perforation. This represents a critical window to potentially prevent this devastating outcome. Further study is required to identify those patients at greatest risk as well as to optimize prevention strategies

A global database for metacommunity ecology, integrating species, traits, environment and space

The use of functional information in the form of species traits plays an important role in explaining biodiversity patterns and responses to environmental changes. Although relationships between species composition, their traits, and the environment have been extensively studied on a case-by-case basis, results are variable, and it remains unclear how generalizable these relationships are across ecosystems, taxa and spatial scales. To address this gap, we collated 80 datasets from trait-based studies into a global database for metaCommunity Ecology: Species, Traits, Environment and Space; “CESTES”. Each dataset includes four matrices: species community abundances or presences/absences across multiple sites, species trait information, environmental variables and spatial coordinates of the sampling sites. The CESTES database is a live database: it will be maintained and expanded in the future as new datasets become available. By its harmonized structure, and the diversity of ecosystem types, taxonomic groups, and spatial scales it covers, the CESTES database provides an important opportunity for synthetic trait-based research in community ecology

The Paf oncogene is essential for hematopoietic stem cell function and development

The Paf oncogene is highly expressed in cycling hematopoietic stem cells (HSCs) and is required for the development of long-term HSCs

Immuno-Therapy with Anti-CTLA4 Antibodies in Tolerized and Non-Tolerized Mouse Tumor Models

Monoclonal antibodies specific for cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA4) are a novel form of cancer immunotherapy. While preclinical studies in mouse tumor models have shown anti-tumor efficacy of anti-CTLA4 injection or expression, anti-CTLA4 treatment in patients with advanced cancers had disappointing therapeutic benefit. These discrepancies have to be addressed in more adequate pre-clinical models. We employed two tumor models. The first model is based on C57Bl/6 mice and syngeneic TC-1 tumors expressing HPV16 E6/E7. In this model, the HPV antigens are neo-antigens, against which no central tolerance exists. The second model involves mice transgenic for the proto-oncogen neu and syngeneic mouse mammary carcinoma (MMC) cells. In this model tolerance to Neu involves both central and peripheral mechanisms. Anti-CTLA4 delivery as a protein or expression from gene-modified tumor cells were therapeutically efficacious in the non-tolerized TC-1 tumor model, but had no effect in the MMC-model. We also used the two tumor models to test an immuno-gene therapy approach for anti-CTLA4. Recently, we used an approach based on hematopoietic stem cells (HSC) to deliver the relaxin gene to tumors and showed that this approach facilitates pre-existing anti-tumor T-cells to control tumor growth in the MMC tumor model. However, unexpectedly, when used for anti-CTLA4 gene delivery in this study, the HSC-based approach was therapeutically detrimental in both the TC-1 and MMC models. Anti-CTLA4 expression in these models resulted in an increase in the number of intratumoral CD1d+ NKT cells and in the expression of TGF-β1. At the same time, levels of pro-inflammatory cytokines and chemokines, which potentially can support anti-tumor T-cell responses, were lower in tumors of mice that received anti-CTLA4-HSC therapy. The differences in outcomes between the tolerized and non-tolerized models also provide a potential explanation for the low efficacy of CTLA4 blockage approaches in cancer immunotherapy trials

Acute Muscular Sarcocystosis: An International Investigation Among Ill Travelers Returning From Tioman Island, Malaysia, 2011-2012

A large outbreak of acute muscular sarcocystosis (AMS) among international tourists who visited Tioman Island, Malaysia, is described. Clinicians evaluating travelers returning ill from Malaysia with myalgia, with or without fever, should consider AMS in their differential diagnosi