Authors: Martin D, Degese MS, Vitale-Cross L, Iglesias-Bartolome R, Valera JLC, Wang Z, Feng X, Yeerna H, Vadmal V, Moroishi T, Thorne RF, Zaida M, Siegele B, Cheong SC, Molinolo AA, Samuels Y, Tamayo P, Guan KL, Lippman SM, Lyons JG, Gutkind JS
Journal: Nat Commun. 2018 Jul 9;9(1):2372. doi: 10.1038/s41467-018-04590-1.
Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes.
Authors: Loftfield E, Cornelis MC, Caporaso N, Yu K, Sinha R, Freedman N
Journal: JAMA Intern Med. 2018 Jul 2. doi: 10.1001/jamainternmed.2018.2425. [Epub ahead of print]
IMPORTANCE: Prospective cohorts in North America, Europe, and Asia show consistent inverse associations between coffee drinking and mortality, including deaths from cardiovascular disease and some cancers. However, concerns about coffee, particularly among people with common genetic polymorphisms affecting caffeine metabolism and among those drinking more than 5 cups per day, remain.
OBJECTIVE: To evaluate associations of coffee drinking with mortality by genetic caffeine metabolism score.
DESIGN, SETTING, AND PARTICIPANTS: The UK Biobank is a population-based study that invited approximately 9.2 million individuals from across the United Kingdom to participate. We used baseline demographic, lifestyle, and genetic data form the UK Biobank cohort, with follow-up beginning in 2006 and ending in 2016, to estimate hazard ratios (HRs) for coffee intake and mortality, using multivariable-adjusted Cox proportional hazards models. We investigated potential effect modification by caffeine metabolism, defined by a genetic score of previously identified polymorphisms in AHR, CYP1A2, CYP2A6, and POR that have an effect on caffeine metabolism. Of the 502 641 participants who consented with baseline data, we included those who were not pregnant and had complete data on coffee intake and smoking status (n = 498 134).
EXPOSURES: Total, ground, instant, and decaffeinated coffee intake.
MAIN OUTCOMES AND MEASURES: All-cause and cause-specific mortality.
RESULTS: The mean age of the participants was 57 years (range, 38-73 years); 271 019 (54%) were female, and 387 494 (78%) were coffee drinkers. Over 10 years of follow-up, 14 225 deaths occurred. Coffee drinking was inversely associated with all-cause mortality. Using non-coffee drinkers as the reference group, HRs for drinking less than 1, 1, 2 to 3, 4 to 5, 6 to 7, and 8 or more cups per day were 0.94 (95% CI, 0.88-1.01), 0.92 (95% CI, 0.87-0.97), 0.88 (95% CI, 0.84-0.93), 0.88 (95% CI, 0.83-0.93), 0.84 (95% CI, 0.77-0.92), and 0.86 (95% CI, 0.77-0.95), respectively. Similar associations were observed for instant, ground, and decaffeinated coffee, across common causes of death, and regardless of genetic caffeine metabolism score. For example, the HRs for 6 or more cups per day ranged from 0.70 (95% CI, 0.53-0.94) to 0.92 (95% CI, 0.78-1.10), with no evidence of effect modification across strata of caffeine metabolism score (P = .17 for heterogeneity).
CONCLUSIONS AND RELEVANCE: Coffee drinking was inversely associated with mortality, including among those drinking 8 or more cups per day and those with genetic polymorphisms indicating slower or faster caffeine metabolism. These findings suggest the importance of noncaffeine constituents in the coffee-mortality association and provide further reassurance that coffee drinking can be a part of a healthy diet.
Authors: Urata S, Kenyon E, Nayak D, Cubitt B, Kurosaki Y, Yasuda J, de la Torre JC, McGavern DB
Journal: PLoS Pathog. 2018 Jul 20;14(7):e1007172. doi: 10.1371/journal.ppat.1007172. [Epub ahead of print]
The interferon inducible protein, BST-2 (or, tetherin), plays an important role in the innate antiviral defense system by inhibiting the release of many enveloped viruses. Consequently, viruses have evolved strategies to counteract the anti-viral activity of this protein. While the mechanisms by which BST-2 prevents viral dissemination have been defined, less is known about how this protein shapes the early viral distribution and immunological defense against pathogens during the establishment of persistence. Using the lymphocytic choriomeningitis virus (LCMV) model of infection, we sought insights into how the in vitro antiviral activity of this protein compared to the immunological defense mounted in vivo. We observed that BST-2 modestly reduced production of virion particles from cultured cells, which was associated with the ability of BST-2 to interfere with the virus budding process mediated by the LCMV Z protein. Moreover, LCMV does not encode a BST-2 antagonist, and viral propagation was not significantly restricted in cells that constitutively expressed BST-2. In contrast to this very modest effect in cultured cells, BST-2 played a crucial role in controlling LCMV in vivo. In BST-2 deficient mice, a persistent strain of LCMV was no longer confined to the splenic marginal zone at early times post-infection, which resulted in an altered distribution of LCMV-specific T cells, reduced T cell proliferation / function, delayed viral control in the serum, and persistence in the brain. These data demonstrate that BST-2 is important in shaping the anatomical distribution and adaptive immune response against a persistent viral infection in vivo.
Authors: Banerjee A, Kikuchi Y, Mishkin M, Rauschecker JP, Horwitz B
Journal: eNeuro. 2018 Jul 3;5(3). pii: ENEURO.0420-17.2018. doi: 10.1523/ENEURO.0420-17.2018. eCollection 2018 May-Jun.
Animals and humans rapidly detect specific features of sounds, but the time courses of the underlying neural response for different stimulus categories is largely unknown. Furthermore, the intricate functional organization of auditory information processing pathways is poorly understood. Here, we computed neuronal response latencies from simultaneously recorded spike trains and local field potentials (LFPs) along the first two stages of cortical sound processing, primary auditory cortex (A1) and lateral belt (LB), of awake, behaving macaques. Two types of response latencies were measured for spike trains as well as LFPs: (1) onset latency, time-locked to onset of external auditory stimuli; and (2) selection latency, time taken from stimulus onset to a selective response to a specific stimulus category. Trial-by-trial LFP onset latencies predominantly reflecting synaptic input arrival typically preceded spike onset latencies, assumed to be representative of neuronal output indicating that both areas may receive input environmental signals and relay the information to the next stage. In A1, simple sounds, such as pure tones (PTs), yielded shorter spike onset latencies compared to complex sounds, such as monkey vocalizations ("Coos"). This trend was reversed in LB, indicating a hierarchical functional organization of auditory cortex in the macaque. LFP selection latencies in A1 were always shorter than those in LB for both PT and Coo reflecting the serial arrival of stimulus-specific information in these areas. Thus, chronometry on spike-LFP signals revealed some of the effective neural circuitry underlying complex sound discrimination.
Authors: Gu F, Chen TH, Pfeiffer RM, Fargnoli MC, Calista D, Ghiorzo P, Peris K, Puig S, Menin C, De Nicolo A, Rodolfo M, Pellegrini C, Pastorino L, Evangelou E, Zhang T, Hua X, DellaValle CT, Timothy Bishop D, MacGregor S, Iles MI, Law MH, Cust A, Brown KM, Stratigos AJ, Nagore E, Chanock S, Shi J; Melanoma Meta-Analysis Consortium; MelaNostrum Consortium, Landi MT
Journal: Hum Mol Genet. 2018 Jul 30. doi: 10.1093/hmg/ddy282. [Epub ahead of print]
Melanoma heritability is among the highest for cancer and single nucleotide polymorphisms (SNPs) contribute to it. To date, only SNPs that reached statistical significance in genome-wide association studies or few candidate SNPs have been included in melanoma risk prediction models. We compared four approaches for building polygenic risk scores (PRS) using 12,874 melanoma cases and 23,203 controls from Melanoma Meta-Analysis Consortium as a training set, and newly genotyped 3,102 cases and 2,301 controls from the MelaNostrum consortium for validation. We estimated adjusted odds ratios (ORs) for melanoma risk using traditional melanoma risk factors and the PRS with the largest area under the Receiver Operator Characteristics curve (AUC). We estimated absolute risks combining the PRS and other risk factors, with age- and sex-specific melanoma incidence and competing mortality rates from Italy as an example. The best PRS, including 204 SNPs (AUC= 64.4%; 95% CI=63-65.8%), developed using winner's curse estimate corrections, had a per-quintile OR=1.35 (95% CI=1.30-1.41), corresponding to a 3.33-fold increase comparing the 5th to the 1st PRS quintile. The AUC improvement by adding the PRS was up to 7%, depending on adjusted factors and country. The 20-year absolute risk estimates based on the PRS, nevus count and pigmentation characteristics for a 60-year old Italian man ranged from 0.5% to 11.8% (RR=26.34), indicating good separation.
Authors: Wen H, Morales Martinez A, Miao H, Larsen TC, Nguyen CP, Bennett EE, Moorse KP, Yu ZX, Remaley AT, Boehm M, Gharib AM
Journal: Sci Rep. 2018 Jul 20;8(1):10978. doi: 10.1038/s41598-018-29379-6.
Histopathology protocols often require sectioning and processing of numerous microscopy slides to survey a sample. Trade-offs between workload and sampling density means that small features can be missed. Aiming to reduce the workload of routine histology protocols and the concern over missed pathology in skipped sections, we developed a prototype x-ray tomographic scanner dedicated to rapid scouting and identification of regions of interest in pathology specimens, thereby allowing targeted histopathology analysis to replace blanket searches. In coronary artery samples of a deceased HIV patient, the scanner, called Tomopath, obtained depth-resolved cross-sectional images at 15 µm resolution in a 15-minute scan, which guided the subsequent histological sectioning and microscopy. When compared to a commercial tabletop micro-CT scanner, the prototype provided several-fold contrast-to-noise ratio in 1/11th the scan time. Correlated tomographic and histological images revealed two types of micro calcifications: scattered loose calcifications typically found in atherosclerotic lesions; isolated focal calcifications in one or several cells in the internal elastic lamina and occasionally in the tunica media, which we speculate were the initiation of medial calcification linked to kidney disease, but rarely detected at this early stage due to their similarity to particle contaminants introduced during histological processing, if not for the evidence from the tomography scan prior to sectioning. Thus, in addition to its utility as a scouting tool, in this study it provided complementary information to histological microscopy. Overall, the prototype scanner represents a step toward a dedicated scouting and complementary imaging tool for routine use in pathology labs.
Authors: Lehmann ML, Weigel TK, Cooper HA, Elkahloun AG, Kigar SL, Herkenham M
Journal: Sci Rep. 2018 Jul 26;8(1):11240. doi: 10.1038/s41598-018-28737-8.
An animal's ability to cope with or succumb to deleterious effects of chronic psychological stress may be rooted in the brain's immune responses manifested in microglial activity. Mice subjected to chronic social defeat (CSD) were categorized as susceptible (CSD-S) or resilient (CSD-R) based on behavioral phenotyping, and their microglia were isolated and analyzed by microarray. Microglia transcriptomes from CSD-S mice were enriched for pathways associated with inflammation, phagocytosis, oxidative stress, and extracellular matrix remodeling. Histochemical experiments confirmed the array predictions: CSD-S microglia showed elevated phagocytosis and oxidative stress, and the brains of CSD-S but not CSD-R or non-stressed control mice showed vascular leakage of intravenously injected fluorescent tracers. The results suggest that the inflammatory profile of CSD-S microglia may be precipitated by extracellular matrix degradation, oxidative stress, microbleeds, and entry and phagocytosis of blood-borne substances into brain parenchyma. We hypothesize that these CNS-centric responses contribute to the stress-susceptible behavioral phenotype.
Authors: Lui JC, Jee YH, Garrison P, Iben JR, Yue S, Ad M, Nguyen Q, Kikani B, Wakabayashi Y, Baron J
Journal: PLoS Biol. 2018 Jul 23;16(7):e2005263. doi: 10.1371/journal.pbio.2005263. eCollection 2018 Jul.
Bones at different anatomical locations vary dramatically in size. For example, human femurs are 20-fold longer than the phalanges in the fingers and toes. The mechanisms responsible for these size differences are poorly understood. Bone elongation occurs at the growth plates and advances rapidly in early life but then progressively slows due to a developmental program termed "growth plate senescence." This developmental program includes declines in cell proliferation and hypertrophy, depletion of cells in all growth plate zones, and extensive underlying changes in the expression of growth-regulating genes. Here, we show evidence that these functional, structural, and molecular senescent changes occur earlier in the growth plates of smaller bones (metacarpals, phalanges) than in the growth plates of larger bones (femurs, tibias) and that this differential aging contributes to the disparities in bone length. We also show evidence that the molecular mechanisms that underlie the differential aging between different bones involve modulation of critical paracrine regulatory pathways, including insulin-like growth factor (Igf), bone morphogenetic protein (Bmp), and Wingless and Int-1 (Wnt) signaling. Taken together, the findings reveal that the striking disparities in the lengths of different bones, which characterize normal mammalian skeletal proportions, is achieved in part by modulating the progression of growth plate senescence.
Authors: Wlaschin JJ, Gluski JM, Nguyen E, Silberberg H, Thompson JH, Chesler AT, Le Pichon CE
Journal: eLife. 2018;7:e33910. doi: 10.7554/eLife.33910.
Neuropathic pain resulting from nerve injury can become persistent and difficult to treat but the molecular signaling responsible for its development remains poorly described. Here, we identify the neuronal stress sensor dual leucine zipper kinase (DLK; Map3k12) as a key molecule controlling the maladaptive pathways that lead to pain following injury. Genetic or pharmacological inhibition of DLK reduces mechanical hypersensitivity in a mouse model of neuropathic pain. Furthermore, DLK inhibition also prevents the spinal cord microgliosis that results from nerve injury and arises distant from the injury site. These striking phenotypes result from the control by DLK of a transcriptional program in somatosensory neurons regulating the expression of numerous genes implicated in pain pathogenesis, including the immune gene Csf1. Thus, activation of DLK is an early event, or even the master regulator, controlling a wide variety of pathways downstream of nerve injury that ultimately lead to chronic pain.
Authors: Tubbs A, Sridharan S, van Wietmarschen N, Maman Y, Callen E, Stanlie A, Wu W, Wu X, Day A, Wong N, Yin M, Canela A, Fu H, Redon C, Pruitt SC, Jaszczyszyn Y, Aladjem MI, Aplan PD, Hyrien O, Nussenzweig A
Journal: Cell. 2018 Jul 24. pii: S0092-8674(18)30905-X. doi: 10.1016/j.cell.2018.07.011. [Epub ahead of print]
Replication origins, fragile sites, and rDNA have been implicated as sources of chromosomal instability. However, the defining genomic features of replication origins and fragile sites are among the least understood elements of eukaryote genomes. Here, we map sites of replication initiation and breakage in primary cells at high resolution. We find that replication initiates between transcribed genes within nucleosome-depleted structures established by long asymmetrical poly(dA:dT) tracts flanking the initiation site. Paradoxically, long (>20 bp) (dA:dT) tracts are also preferential sites of polar replication fork stalling and collapse within early-replicating fragile sites (ERFSs) and late-replicating common fragile sites (CFSs) and at the rDNA replication fork barrier. Poly(dA:dT) sequences are fragile because long single-strand poly(dA) stretches at the replication fork are unprotected by the replication protein A (RPA). We propose that the evolutionary expansion of poly(dA:dT) tracts in eukaryotic genomes promotes replication initiation, but at the cost of chromosome fragility.