Authors: Pearson CS, Mencio CP, Barber AC, Martin KR, Geller HM
Journal: Elife. 2018 May 15;7. pii: e37139. doi: 10.7554/eLife.37139. [Epub ahead of print]
The failure of mammalian CNS neurons to regenerate their axons derives from a combination of intrinsic deficits and extrinsic factors. Following injury, chondroitin sulfate proteoglycans (CSPGs) within the glial scar inhibit axonal regeneration, an action mediated by the sulfated glycosaminoglycan (GAG) chains of CSPGs, especially those with 4-sulfated (4S) sugars. Arylsulfatase B (ARSB) selectively cleaves 4S groups from the non-reducing ends of GAG chains without disrupting other, growth-permissive motifs. We demonstrate that ARSB is effective in reducing the inhibitory actions of CSPGs both in in vitro models of the glial scar and after optic nerve crush (ONC) in adult mice. ARSB is clinically approved for replacement therapy in patients with mucopolysaccharidosis VI and therefore represents an attractive candidate for translation to the human CNS.
Authors: Martin-Martin I, Chagas AC, Guimaraes-Costa AB, Amo L, Oliveira F, Moore IN, DeSouza-Vieira TS, Sanchez EE, Suntravat M, Valenzuela JG, Ribeiro JMC, Calvo E
Journal: PLoS Pathog. 2018 May 3;14(5):e1007006. doi: 10.1371/journal.ppat.1007006. [Epub ahead of print]
Salivary components from disease vectors help arthropods to acquire blood and have been shown to enhance pathogen transmission in different model systems. Here we show that two salivary enzymes from Lutzomyia longipalpis have a synergist effect that facilitates a more efficient blood meal intake and diffusion of other sialome components. We have previously shown that Lundep, a highly active endonuclease, enhances parasite infection and prevent blood clotting by inhibiting the intrinsic pathway of coagulation. To investigate the physiological role of a salivary hyaluronidase in blood feeding we cloned and expressed a recombinant hyaluronidase from Lu. longipalpis. Recombinant hyaluronidase (LuloHya) was expressed in mammalian cells and biochemically characterized in vitro. Our study showed that expression of neutrophil CXC chemokines and colony stimulating factors were upregulated in HMVEC cells after incubation with LuloHya and Lundep. These results were confirmed by the acute hemorrhage, edema and inflammation in a dermal necrosis (dermonecrotic) assay involving a massive infiltration of leukocytes, especially neutrophils, in mice co-injected with hemorrhagic factor and these two salivary proteins. Moreover, flow cytometry results showed that LuloHya and Lundep promote neutrophil recruitment to the bite site that may serve as a vehicle for establishment of Leishmania infection. A vaccination experiment demonstrated that LuloHya and Lundep confer protective immunity against cutaneous leishmaniasis using the Lu. longipalpis-Leishmania major combination as a model. Animals (C57BL/6) immunized with LuloHya or Lundep showed minimal skin damage while lesions in control animals remained ulcerated. This protective immunity was abrogated when B-cell-deficient mice were used indicating that antibodies against both proteins play a significant role for disease protection. Rabbit-raised anti-LuloHya antibodies completely abrogated hyaluronidase activity in vitro. Moreover, in vivo experiments demonstrated that blocking LuloHya with specific antibodies interferes with sand fly blood feeding. This work highlights the relevance of vector salivary components in blood feeding and parasite transmission and further suggests the inclusion of these salivary proteins as components for an anti-Leishmania vaccine.
Authors: Katki HA, Kovalchik SA, Petito LC, Cheung LC, Jacobs E, Jemal A, Berg C, Chaturvedi AK
Journal: Ann Intern Med. 2018 May 15. doi: 10.7326/M17-2701. [Epub ahead of print]
Background: Lung cancer screening guidelines recommend using individualized risk models to refer ever-smokers for screening. However, different models select different screening populations. The performance of each model in selecting ever-smokers for screening is unknown.
Objective: To compare the U.S. screening populations selected by 9 lung cancer risk models (the Bach model; the Spitz model; the Liverpool Lung Project [LLP] model; the LLP Incidence Risk Model [LLPi]; the Hoggart model; the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Model 2012 [PLCOM2012]; the Pittsburgh Predictor; the Lung Cancer Risk Assessment Tool [LCRAT]; and the Lung Cancer Death Risk Assessment Tool [LCDRAT]) and to examine their predictive performance in 2 cohorts.
Design: Population-based prospective studies.
Setting: United States.
Participants: Models selected U.S. screening populations by using data from the National Health Interview Survey from 2010 to 2012. Model performance was evaluated using data from 337 388 ever-smokers in the National Institutes of Health–AARP Diet and Health Study and 72 338 ever-smokers in the CPS-II (Cancer Prevention Study II) Nutrition Survey cohort.
Measurements: Model calibration (ratio of model-predicted to observed cases [expected–observed ratio]) and discrimination (area under the curve [AUC]).
Results: At a 5-year risk threshold of 2.0%, the models chose U.S. screening populations ranging from 7.6 million to 26 million ever-smokers. These disagreements occurred because, in both validation cohorts, 4 models (the Bach model, PLCOM2012, LCRAT, and LCDRAT) were well-calibrated (expected–observed ratio range, 0.92 to 1.12) and had higher AUCs (range, 0.75 to 0.79) than 5 models that generally overestimated risk (expected–observed ratio range, 0.83 to 3.69) and had lower AUCs (range, 0.62 to 0.75). The 4 best-performing models also had the highest sensitivity at a fixed specificity (and vice versa) and similar discrimination at a fixed risk threshold. These models showed better agreement on size of the screening population (7.6 million to 10.9 million) and achieved consensus on 73% of persons chosen.
Limitation: No consensus on risk thresholds for screening.
Conclusion: The 9 lung cancer risk models chose widely differing U.S. screening populations. However, 4 models (the Bach model, PLCOM2012, LCRAT, and LCDRAT) most accurately predicted risk and performed best in selecting ever-smokers for screening.
Authors: Feng LR, Fernández-Martínez JL, Zaal KJM, deAndrés-Galiana EJ, Wolff BS, Saligan LN
Journal: Transl Psychiatry. 2018 May 30;8(1):110. doi: 10.1038/s41398-018-0161-3.
Cancer-related fatigue (CRF) is a common burden in cancer patients and little is known about its underlying mechanism. The primary aim of this study was to identify gene signatures predictive of post-radiotherapy fatigue in prostate cancer patients. We employed Fisher Linear Discriminant Analysis (LDA) to identify predictive genes using whole genome microarray data from 36 men with prostate cancer. Ingenuity Pathway Analysis was used to determine functional networks of the predictive genes. Functional validation was performed using a T lymphocyte cell line, Jurkat E6.1. Cells were pretreated with metabotropic glutamate receptor 5 (mGluR5) agonist (DHPG), antagonist (MPEP), or control (PBS) for 20 min before irradiation at 8 Gy in a Mark-1 γ-irradiator. NF-κB activation was assessed using a NF-κB/Jurkat/GFP Transcriptional Reporter Cell Line. LDA achieved 83.3% accuracy in predicting post-radiotherapy fatigue. "Glutamate receptor signaling" was the most significant (p = 0.0002) pathway among the predictive genes. Functional validation using Jurkat cells revealed clustering of mGluR5 receptors as well as increased regulated on activation, normal T cell expressed and secreted (RANTES) production post irradiation in cells pretreated with DHPG, whereas inhibition of mGluR5 activity with MPEP decreased RANTES concentration after irradiation. DHPG pretreatment amplified irradiation-induced NF-κB activation suggesting a role of mGluR5 in modulating T cell activation after irradiation. These results suggest that mGluR5 signaling in T cells may play a key role in the development of chronic inflammation resulting in fatigue and contribute to individual differences in immune responses to radiation. Moreover, modulating mGluR5 provides a novel therapeutic option to treat CRF.
Authors: Amita H, Kim HF, Smith M, Gopal A, Hikosaka O
Journal: Eur J Neurosci. 2018 May 8. doi: 10.1111/ejn.13936. [Epub ahead of print]
Direct and indirect pathways in the basal ganglia work together for controlling behavior. However, it is still a controversial topic whether these pathways are segregated or merged with each other. To address this issue, we studied the connections of these two pathways in the caudal parts of the basal ganglia of rhesus monkeys using anatomical tracers. Our previous studies showed that the caudal basal ganglia control saccades by conveying long-term values (stable values) of many visual objects toward the superior colliculus. In experiment 1, we injected a tracer in the caudate tail (CDt), and found local dense plexuses of axon terminals in the caudal-dorsal-lateral part of substantia nigra pars reticulata (cdlSNr) and the caudal-ventral part of globus pallidus externus (cvGPe). These anterograde projections may correspond to the direct and indirect pathways, respectively. To verify this in experiment 2, we injected different tracers into cdlSNr and cvGPe, and found many retrogradely labeled neurons in CDt and, in addition, the caudal-ventral part of the putamen (cvPut). These cdlSNr-projecting and cvGPe-projecting neurons were found intermingled in both CDt and cvPut (which we call 'striatum tail'). A small but significant proportion of neurons (< 15%) were double-labeled, indicating that they projected to both cdlSNr and cvGPe. These anatomical results suggest that stable value signals (good vs. bad) are sent from the striatum tail to cdlSNr and cvGPe in a biased (but not exclusive) manner. These connections may play an important role in biasing saccades toward higher-valued objects and away from lower-valued objects.
Authors: Begaye B, Piaggi P, Thearle MS, Haskie K, Walter M, Schlögl M, Bonfiglio S, Krakoff J, Vinales KL
Journal: J Clin Endocrinol Metab. 2018 May 16. doi: 10.1210/jc.2018-00387. [Epub ahead of print]
CONTEXT: In healthy adults with detectable cold-induced brown fat activation (CIBA), the relationships between sympathetic nervous system (SNS) or thyroid activity during energy balance (EBL) with CIBA and body composition change are undetermined.
OBJECTIVE: To investigate the relationships between CIBA and thermoneutral catecholamines and thyroid hormones measured during EBL and to determine if CIBA, catecholamines, or thyroid hormones predict body composition changes.
DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: Twelve healthy volunteers (7M/5F) with positive CIBA (>2 standardized uptake value (g/mL)) had 24-h energy expenditure (24hEE) assessed during EBL via whole-room indirect calorimetry while residing on a clinical research unit. Positron-emission tomography/computed tomography scans were performed after exposure to 16°C for 2h to quantify CIBA.
MAIN OUTCOME MEASURES: CIBA, 24hEE during EBL and thermoneutrality with concomitant measurement of urinary catecholamines and plasma free T3 (fT3) and free t4 (fT4). Body composition at baseline and six months by DXA.
RESULTS: Lower urinary norepinephrine and fT4 were associated with higher CIBA (r = ‒0.65, p = 0.03 and r = ‒0.75, p<0.01, respectively), but CIBA was not associated with 24hEE at thermoneutrality (p=0.77). Lower CIBA (β = ̶̶ 3.5 kg/SUV, p<0.01) predicted fat mass gain; whereas, higher urinary norepinephrine and fT4 predicted future fat mass gain at 6 months (β = 3.0 kg per two-fold difference in norepinephrine, p=0.03; β = 1.2 kg per 0.1 ng/dL difference in fT4, p=0.03, respectively).
CONCLUSION: Lower SNS and free thyroid measurements at baseline indicate a greater capacity for CIBA, which may be predictive against fat mass gain.
Authors: Nadal-Nicolas FM, Becerra SP
Journal: Adv Exp Med Biol. 2018;1074:457-464. doi: 10.1007/978-3-319-75402-4_56.
Oxidative stress has been implicated in neurodegenerative diseases, such as age-related macular degeneration. Hydrogen peroxide and sodium iodate can mediate oxidative injury. Sodium iodate induces a selective retinal degeneration targeting the RPE. We describe a method of chronic sodium iodate-mediated injury on RPE cells that may serve to evaluate protective factors against oxidative stress. Cytotoxicity and cell viability curves of ARPE-19 cells with sodium iodate were generated. The antioxidant pigment epithelium-derived factor decreased sodium iodate-mediated cytotoxicity without affecting ARPE-19 cell viability. A cell culture system to evaluate protection against oxidative stress injury with PEDF is discussed.
Authors: Picchioni D, Schmidt KC, McWhirter KK, Loutaev I, Pavletic AJ, Speer AM, Zametkin AJ, Miao N, Bishu S, Turetsky KM, Morrow AS, Nadel JL, Evans BC, Vesselinovitch DM, Sheeler CA, Balkin TJ, Smith CB
Journal: Sleep. 2018 May 15. doi: 10.1093/sleep/zsy088. [Epub ahead of print]
If protein synthesis during sleep is required for sleep-dependent memory consolidation, we might expect rates of cerebral protein synthesis (rCPS) to increase during sleep in the local brain circuits that support performance on a particular task following training on that task. To measure circuit-specific brain protein synthesis during a daytime nap opportunity, we used the L-[1-(11)C]leucine positron emission tomography (PET) method with simultaneous polysomnography. We trained subjects on the visual texture discrimination task (TDT). This was followed by a nap opportunity during the PET scan, and we retested them later in the day after the scan. The TDT is considered retinotopically specific, so we hypothesized that higher rCPS in primary visual cortex would be observed in the trained hemisphere compared to the untrained hemisphere in subjects who were randomized to a sleep condition. Our results indicate that the changes in rCPS in primary visual cortex depended on whether subjects were in the wakefulness or sleep condition but were independent of the side of the visual field trained. That is, only in the subjects randomized to sleep, rCPS in the right primary visual cortex was higher than the left regardless of side trained. Other brain regions examined were not so affected. In the subjects who slept, performance on the TDT improved similarly regardless of the side trained. Results indicate a regionally selective and sleep-dependent effect that occurs with improved performance on the TDT.
Authors: Huang Y, Hill J, Yatteau A, Wong L, Jiang T, Petrovic J, Gan L, Dong L, Wu DK
Journal: J Neurosci. 2018 May 16. pii: 2484-17. doi: 10.1523/JNEUROSCI.2484-17.2018. [Epub ahead of print]
LIM-domain containing transcription factors (LIM-TFs) are conserved factors important for embryogenesis. The specificity of these factors in transcriptional regulation is conferred by the complexes they form with other proteins such as LIM-domain-binding (Ldb) proteins and LIM-domain only (LMO) proteins. Unlike LIM-TF, these proteins do not bind DNA directly. LMO are negative regulators of LIM-TF and they function by competing with LIM-TFs for binding to Ldbs. Although the LIM-TF Lmx1a is expressed in the developing mouse hindbrain, which provides many of the extrinsic signals for inner ear formation, conditional knockout embryos of both sexes show that the inner ear source of Lmx1a is the major contributor of ear patterning. Additionally, we have identified that the reciprocal interaction between Lmx1a and Lmo4 (a LMO protein within the inner ear) mediates formation of both vestibular and auditory structures. Lmo4 negatively regulates Lmx1a to form the three sensory cristae, the anterior semicircular canal and the shape of the utricle in the vestibule. Furthermore, this negative regulation blocks ectopic sensory formation in the cochlea. By contrast, Lmx1a negatively regulates Lmo4 in mediating epithelial resorption of the canal pouch, which gives rise to the anterior and posterior semicircular canals. We also found that Lmx1a is independently required for the formation of the endolymphatic duct and hair cells in the basal cochlear region.
Significance Statement: The mammalian inner ear is a structurally complex organ responsible for detecting sound and maintaining balance. Failure to form the intricate three-dimensional structure of this organ properly during development most likely will result in sensory deficits on some level. Here we provide genetic evidence that a transcription factor, Lmx1a, interacts with its negative regulator, Lmo4, to pattern various vestibular and auditory components of the mammalian inner ear. Identifying these key molecules that mediate formation of this important sensory organ will be helpful for designing strategies and therapeutics to alleviate hearing loss and balance disorders.
Authors: Meng C, Zhou J, Papaneri A, Peddada T, Xu K, Cui G
Journal: Neuron. 2018 May 16;98(4):707-717.e4. doi: 10.1016/j.neuron.2018.04.012. Epub 2018 May 3.
To achieve simultaneous measurement of multiple cellular events in molecularly defined groups of neurons in vivo, we designed a spectrometer-based fiber photometry system that allows for spectral unmixing of multiple fluorescence signals recorded from deep brain structures in behaving animals. Using green and red Ca2+ indicators differentially expressed in striatal direct- and indirect-pathway neurons, we were able to simultaneously monitor the neural activity in these two pathways in freely moving animals. We found that the activities were highly synchronized between the direct and indirect pathways within one hemisphere and were desynchronized between the two hemispheres. We further analyzed the relationship between the movement patterns and the magnitude of activation in direct- and indirect-pathway neurons and found that the striatal direct and indirect pathways coordinately control the dynamics and fate of movement.