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Research advances from the National Institutes of Health (NIH) Intramural Research Program (IRP) are often published in high-impact journals. Read some of our recent articles:

Authors: Zhou Q, Yu X, Demirkaya E, Deuitch N, Stone D, Tsai WL, Kuehn HS, Wang H, Yang D, Park YH, Ombrello AK, Blake M, Romeo T, Remmers EF, Chae JJ, Mullikin JC, Güzel F, Milner JD, Boehm M, Rosenzweig SD, Gadina M, Welch SB, Özen S, Topaloglu R, Abinun M, Kastner DL, Aksentijevich I

Journal: Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):10127-32. doi: 10.1073/pnas.1612594113. Epub 2016 Aug 24.

Systemic autoinflammatory diseases are caused by mutations in genes that function in innate immunity. Here, we report an autoinflammatory disease caused by loss-of-function mutations in OTULIN (FAM105B), encoding a deubiquitinase with linear linkage specificity. We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency. HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with WT OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients' fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. This discovery adds to the emerging spectrum of human diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies.

Authors: LeDoux JE, Pine DS

Journal: Am J Psychiatry. 2016 Sep 9:appiajp201616030353.

Tremendous progress has been made in basic neuroscience in recent decades. One area that has been especially successful is research on how the brain detects and responds to threats. Such studies have demonstrated comparable patterns of brain-behavior relationships underlying threat processing across a range of mammalian species, including humans. This would seem to be an ideal body of information for advancing our understanding of disorders in which altered threat processing is a key factor, namely, fear and anxiety disorders. But research on threat processing has not led to significant improvements in clinical practice. The authors propose that in order to take advantage of this progress for clinical gain, a conceptual reframing is needed. Key to this conceptual change is recognition of a distinction between circuits underlying two classes of responses elicited by threats: 1) behavioral responses and accompanying physiological changes in the brain and body and 2) conscious feeling states reflected in self-reports of fear and anxiety. This distinction leads to a "two systems" view of fear and anxiety. The authors argue that failure to recognize and consistently emphasize this distinction has impeded progress in understanding fear and anxiety disorders and hindered attempts to develop more effective pharmaceutical and psychological treatments. The two-system view suggests a new way forward.

Authors: Xi L, Pham T, Payabyab EC, Sherry RM, Rosenberg SA, Raffeld M

Journal: Clin Cancer Res. 2016 Aug 1. pii: clincanres.0613.2016. [Epub ahead of print]

PURPOSE: Adoptive transfer of activated autologous tumor-infiltrating lymphocytes (TIL) can mediate complete, durable regressions in patients with metastatic melanoma (MM). Responding patients generally do not have significant changes in non-cutaneous RECIST targets before 30-60 days following TIL infusion, and complete responses are often not confirmed for 1-2 years. There is a critical need for a biomarker that can provide early information regarding the likelihood and duration of a response to enable rational decisions about altering therapy. We wished to evaluate the role of ctDNA in separating responding from non-responding patients.

EXPERIMENTAL DESIGN: We studied BRAF V600E ctDNA levels by a sensitive allele specific PCR assay in 388 serum samples from 48 patients who received TIL immunotherapy at the National Cancer Institute, and correlated differences in the dynamic patterns of their ctDNA measurements with response outcomes.

RESULTS: A strong correlation was found between the presence or absence of an early serum peak of V600E ctDNA, and the likelihood of an objective response. Furthermore, patients that developed an early ctDNA peak and cleared their serum of V600E ctDNA were highly likely to achieve a complete response over the next 1-2 years. Patients that showed no peak of V600E ctDNA failed to achieve an objective response, with one exception.

CONCLUSIONS: We show that the dynamic changes occurring in BRAF V600E ctDNA levels within the first month following T-cell transfer immunotherapy in MM can be used to rapidly identify responding from non-responding patients, potentially allowing clinicians to make critical treatment-related decisions in a more timely manner. These data also suggest that the majority of tumor killing by TIL occurs very early after the initiation of therapy.

Authors: Ghazizadeh A, Griggs W, Hikosaka O

Journal: Front Neurosci. 2016 Aug 19;10:378. doi: 10.3389/fnins.2016.00378. eCollection 2016.

Among many objects around us, some are more salient than others (i.e., attract our attention automatically). Some objects may be inherently salient (e.g., brighter), while others may become salient by virtue of their ecological relevance through experience. However, the role of ecologicalexperience in automatic attention has not been studied systematically. To address this question, we let subjects (macaque monkeys) view a large number of complex objects (>300), each experienced repeatedly (>5 days) with rewarding, aversive or no outcome association (mere-perceptual exposure). Test of salience was done on separate days using free viewing with no outcome. We found that gaze was biased among the objects from the outset, affecting saccades to objects or fixations within objects. When the outcome was rewarding, gaze preference was stronger (i.e., positive) for objects with larger or equal but uncertain rewards. The effects of aversive outcomes were variable. Gaze preference was positive for some outcome associations (e.g., airpuff), but negative for others (e.g., time-out), possibly due to differences in threat levels. Finally, novel objects attracted gaze, but mere perceptual exposure of objects reduced their salience (learned negative salience). Our results show that, in primates, object salience is strongly influenced by previous ecological experience and is supported by a large memory capacity. Owing to such high capacity for learned salience, the ability to rapidly choose important objects can grow during the entire life to promote biological fitness.

Authors: Shin HY, Willi M, Yoo KH, Zeng X, Wang C, Metser G, Hennighausen L

Journal: Nat Genet. 2016 Aug;48(8):904-11. doi: 10.1038/ng.3606. Epub 2016 Jul 4.

Super-enhancers comprise dense transcription factor platforms highly enriched for active chromatin marks. A paucity of functional data led us to investigate the role of super-enhancers in the mammary gland, an organ characterized by exceptional gene regulatory dynamics during pregnancy. ChIP-seq analysis for the master regulator STAT5A, the glucocorticoid receptor, H3K27ac and MED1 identified 440 mammary-specific super-enhancers, half of which were associated with genes activated during pregnancy. We interrogated the Wap super-enhancer, generating mice carrying mutations in STAT5-binding sites within its constituent enhancers. Individually, the most distal site displayed the greatest enhancer activity. However, combinatorial mutation analysis showed that the 1,000-fold induction in gene expression during pregnancy relied on all enhancers. Disabling the binding sites of STAT5, NFIB and ELF5 in the proximal enhancer incapacitated the entire super-enhancer. Altogether, these data suggest a temporal and functional enhancer hierarchy. The identification of mammary-specific super-enhancers and the mechanistic exploration of the Wap locus provide insights into the regulation of cell-type-specific expression of hormone-sensing genes.

Authors: Parr CL, Magnus MC, Karlstad Ø, Haugen M, Refsum H, Ueland PM, McCann A, Nafstad P, Håberg SE, Nystad W, London SJ.

Journal: Am J Respir Crit Care Med. 2016 Aug 12.

RATIONALE: A potential adverse effect of high folate intake during pregnancy on children's asthma development remains controversial.

OBJECTIVES: To prospectively investigate folate intake from both food and supplements during pregnancy and asthma at age seven years when the diagnosis is more reliable than at preschool age.

METHODS: This study included eligible children born 2002-2006 from the Norwegian Mother and Child Cohort Study, a population-based pregnancy cohort, linked to the Norwegian Prescription Database. Current asthma at age seven was defined by asthma medications dispensed at least twice in the year (1,901 cases, n=39,846) or by maternal questionnaire report (1,624 cases, n=28,872). Maternal folate intake was assessed with a food frequency questionnaire validated against plasma folate. We used log-binomial and multinomial regression to calculate adjusted relative risks with 95% confidence intervals.

MEASUREMENTS AND MAIN RESULTS: Risk of asthma was increased in the highest vs. lowest quintile of total folate intake with an adjusted relative risk of 1.23 (95% confidence interval 1.06 to 1.44) that was similar for maternally reported asthma. Mothers in the highest quintile had a relatively high intake of food folate (median 308, interquartile range 241-366 μg/day) and nearly all took at least 400 μg/day of supplemental folic acid (median 500, interquartile range 400-600).

CONCLUSIONS: In this large prospective population based cohort with essentially complete follow-up, pregnant women taking supplemental folic-acid at or above the recommended dose, combined with a diet rich in folate, reach a total folate intake level that may slightly increase risk of asthma in children.

Authors: Hussain S, Ji Z, Taylor AJ, DeGraff LM, George M, Tucker CJ, Chang CH, Li R, Bonner JC, Garantziotis S

Journal: ACS Nano. 2016 Aug 23;10(8):7675-88. doi: 10.1021/acsnano.6b03013.

Commercialization of multiwalled carbon nanotubes (MWCNT)-based applications has been hampered by concerns regarding their lung toxicity potential. Hyaluronic acid (HA) is a ubiquitously found polysaccharide, which is anti-inflammatory in its native high molecular weight form. HA-functionalized smart MWCNTs have shown promise as tumor-targeting drug delivery agents and can enhance bone repair and regeneration. However, it is unclear whether HA functionalization could reduce the pulmonary toxicity potential of MWCNTs. Using in vivo and in vitro approaches, we investigated the effectiveness of MWCNT functionalization with HA in increasing nanotube biocompatibility and reducing lung inflammatory and fibrotic effects. We utilized three-dimensional cultures of differentiated primary human bronchial epithelia to translate findings from rodent assays to humans. We found that HA functionalization increased stability and dispersion of MWCNTs and reduced postexposure lung inflammation, fibrosis, and mucus cell metaplasia compared with nonfunctionalized MWCNTs. Cocultures of fully differentiated bronchial epithelial cells (cultivated at air-liquid interface) and human lung fibroblasts (submerged) displayed significant reduction in injury, oxidative stress, as well as pro-inflammatory gene and protein expression after exposure to HA-functionalized MWCNTs compared with MWCNTs alone. In contrast, neither type of nanotubes stimulated cytokine production in primary human alveolar macrophages. In aggregate, our results demonstrate the effectiveness of HA functionalization as a safer design approach to eliminate MWCNT-induced lung injury and suggest that HA functionalization works by reducing MWCNT-induced epithelial injury.

Authors: Boritz EA, Darko S, Swaszek L, Wolf G, Wells D, Wu X, Henry AR, Laboune F, Hu J, Ambrozak D, Hughes MS, Hoh R, Casazza JP, Vostal A, Bunis D, Nganou-Makamdop K, Lee JS, Migueles SA, Koup RA, Connors M, Moir S, Schacker T, Maldarelli F, Hughes SH, Deeks SG, Douek DC

Journal: Cell. 2016 Jul 20. pii: S0092-8674(16)30810-8. doi: 10.1016/j.cell.2016.06.039.

Targeted HIV cure strategies require definition of the mechanisms that maintain the virus. Here, we tracked HIV replication and the persistence of infected CD4 T cells in individuals with natural virologic control by sequencing viruses, T cell receptor genes, HIV integration sites, and cellular transcriptomes. Our results revealed three mechanisms of HIV persistence operating within distinct anatomic and functional compartments. In lymph node, we detected viruses with genetic and transcriptional attributes of active replication in both T follicular helper (TFH) cells and non-TFH memory cells. In blood, we detected inducible proviruses of archival origin among highly differentiated, clonally expanded cells. Linking the lymph node and blood was a small population of circulating cells harboring inducible proviruses of recent origin. Thus, HIV replication in lymphoid tissue, clonal expansion of infected cells, and recirculation of recently infected cells act together to maintain the virus in HIV controllers despite effective antiviral immunity.

Authors: Liu S, Liu J, Ma Q, Cao L, Fattah RJ, Yu Z, Bugge TH, Finkel T, Leppla SH

JournalProc Natl Acad Sci U S A. 2016 Jul 12;113(28):E4079-87. doi: 10.1073/pnas.1600982113.

Engineered tumor-targeted anthrax lethal toxin proteins have been shown to strongly suppress growth of solid tumors in mice. These toxins work through the native toxin receptors tumor endothelium marker-8 and capillary morphogenesis protein-2 (CMG2), which, in other contexts, have been described as markers of tumor endothelium. We found that neither receptor is required for tumor growth. We further demonstrate that tumor cells, which are resistant to the toxin when grown in vitro, become highly sensitive when implanted in mice. Using a range of tissue-specific loss-of-function and gain-of-function genetic models, we determined that this in vivo toxin sensitivity requires CMG2 expression on host-derived tumor endothelial cells. Notably, engineered toxins were shown to suppress the proliferation of isolated tumor endothelial cells. Finally, we demonstrate that administering an immunosuppressive regimen allows animals to receive multiple toxin dosages and thereby produces a strong and durable antitumor effect. The ability to give repeated doses of toxins, coupled with the specific targeting of tumor endothelial cells, suggests that our strategy should be efficacious for a wide range of solid tumors.

Authors: Ding H, Smith RG, Poleg-Polsky A, Diamond JS, Briggman KL

Journal: Nature. 2016 Jul 7;535(7610):105-10.

Directionally tuned signalling in starburst amacrine cell (SAC) dendrites lies at the heart of the circuit that detects the direction of moving stimuli in the mammalian retina. The relative contributions of intrinsic cellular properties and network connectivity to SAC direction selectivity remain unclear. Here we present a detailed connectomic reconstruction of SAC circuitry in mouse retina and describe two previously unknown features of synapse distributions along SAC dendrites: input and output synapses are segregated, with inputs restricted to proximal dendrites; and the distribution of inhibitory inputs is fundamentally different from that observed in rabbit retina. An anatomically constrained SAC network model suggests that SAC–SAC wiring differences between mouse and rabbit retina underlie distinct contributions of synaptic inhibition to velocity and contrast tuning and receptive field structure. In particular, the model indicates that mouse connectivity enables SACs to encode lower linear velocities that account for smaller eye diameter, thereby conserving angular velocity tuning. These predictions are confirmed with calcium imaging of mouse SAC dendrites responding to directional stimuli.