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Found 35755 matches. Displaying 131-140
Guarecuco R, Williams RT, Baudrier L, La K, Passarelli MC, Ekizoglu N, Mestanoglu M, Alwaseem H, Rostandy B, Fidelin J, Garcia-Bermudez J, Molina H, Birsoy K
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Dietary thiamine influences L-asparaginase sensitivity in a subset of leukemia cells

SCIENCE ADVANCES 2020 OCT; 6(41):? Article eabc7120
Tumor environment influences anticancer therapy response but which extracellular nutrients affect drug sensitivity is largely unknown. Using functional genomics, we determine modifiers of l-asparaginase (ASNase) response and identify thiamine pyrophosphate kinase 1 as a metabolic dependency under ASNase treatment. While thiamine is generally not limiting for cell proliferation, a DNA-barcode competition assay identifies leukemia cell lines that grow suboptimally under low thiamine and are characterized by low expression of solute carrier family 19 member 2 (SLC19A2), a thiamine transporter. SLC19A2 is necessary for optimal growth and ASNase resistance, when standard medium thiamine is lowered similar to 100-fold to human plasma concentrations. In addition, humanizing blood thiamine content of mice through diet sensitizes SLC19A2-low leukemia cells to ASNase in vivo. Together, our work reveals that thiamine utilization is a determinant of ASNase response for some cancer cells and that oversupplying vitamins may affect therapeutic response in leukemia.
Wang ZJ, Zhong P, Ma KJ, Seo JS, Yang FW, Hu ZH, Zhang F, Lin L, Wang J, Liu T, Matas E, Greengard P, Yan Z
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Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice (vol 25, pg 2517, 2020)

MOLECULAR PSYCHIATRY 2020 OCT; 25(10):2641-2641
A correction to this paper has been published and can be accessed via a link at the top of the paper.
Bewersdorf JP, Giri S, Wang R, Podoltsev N, Williams RT, Rampal RK, Tallman MS, Zeidan AM, Stahl M
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Interferon Therapy in Myelofibrosis: Systematic Review and Meta-analysis

Interferon (IFN)-alpha has been used for several decades for the treatment of myelofibrosis, with conflicting results. In this systematic review and meta-analysis of 10 studies with 141 patients, we found that IFN led to hematologic improvements in 49% of patients. Background: Myelofibrosis (MF) is a Philadelphia chromosome-negative myeloproliferative neoplasm characterized by progressive bone marrow failure, increased risk of progression to acute myeloid leukemia, and constitutional symptoms. For over 3 decades, various formulations of interferon (IFN) have been used for the treatment of MF, with variable results, and the role of IFN in the treatment of MF is evolving. Patients and Methods: For this systematic review and meta-analysis, Medline and Embase via Ovid, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science were searched from inception through March 2019 for studies of pegylated IFN (pegIFN) and nonepeg-IFN in MF patients. The primary outcome of overall response rate was defined as a composite of complete response, partial response, complete hematologic response, and partial hematologic response. Randomeffects models were used to pool overall response rate, and metaregression analyses were performed to compare peg-IFN and non-epeg-IFN formulations. Results: Among the 10 studies with 141 MF patients included, the overall response rate was 49.9% (95% confidence interval [CI], 30.4-69.3), and there was no statistically significant difference (P=.99) between peg-IFN (50.0%; 95% CI, 26.2-73.9; I-2 = 76.9%) and non-peg-IFN (49.6%; 95% CI, 20.5-79.0; I-2 = 56.7%). Treatment discontinuation resulting from adverse events was common with non-peg-IFN at 35.8% (95% CI, 3.5-68.1) per year, and less in the one study on peg-IFN (0.5% per year). Conclusion: IFN can lead to hematologic improvements in a subset of MF patients, but study quality is limited and heterogenous. Biomarkers predicting response to IFN and formulations with improved tolerability are needed.
Shrestha P, Shan Z, Mamcarz M, Ruiz KS, Zerihoun AT, Juan CY, Herrero-Vidal PM, Pelletier J, Heintz N, Klann E
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Amygdala inhibitory neurons as loci for translation in emotional memories

NATURE 2020 OCT 7; 586(7829):407-411
Protein synthesis is required in distinct populations of inhibitory neurons in the mouse amygdala to store memories of danger and safety. To survive in a dynamic environment, animals need to identify and appropriately respond to stimuli that signal danger(1). Survival also depends on suppressing the threat-response during a stimulus that predicts the absence of threat (safety)(2-5). An understanding of the biological substrates of emotional memories during a task in which animals learn to flexibly execute defensive responses to a threat-predictive cue and a safety cue is critical for developing treatments for memory disorders such as post-traumatic stress disorder(5). The centrolateral amygdala is an important node in the neuronal circuit that mediates defensive responses(6-9), and a key brain area for processing and storing threat memories. Here we applied intersectional chemogenetic strategies to inhibitory neurons in the centrolateral amygdala of mice to block cell-type-specific translation programs that are sensitive to depletion of eukaryotic initiation factor 4E (eIF4E) and phosphorylation of eukaryotic initiation factor 2 alpha (p-eIF2 alpha). We show that de novo translation in somatostatin-expressing inhibitory neurons in the centrolateral amygdala is necessary for the long-term storage of conditioned-threat responses, whereas de novo translation in protein kinase C delta-expressing inhibitory neurons in the centrolateral amygdala is necessary for the inhibition of a conditioned response to a safety cue. Our results provide insight into the role of de novo protein synthesis in distinct inhibitory neuron populations in the centrolateral amygdala during the consolidation of long-term memories.
Hsiao KF, Noble C, Pitman W, Yadav N, Kumar S, Keele GR, Terceros A, Kanke M, Conniff T, Cheleuitte-Nieves C, Tolwani R, Sethupathy P, Rajasethupathy P
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A Thalamic Orphan Receptor Drives Variability in Short-Term Memory

CELL 2020 OCT 15; 183(2):522-536.e19
Working memory is a form of short-term memory that involves maintaining and updating task-relevant information toward goal-directed pursuits. Classical models posit persistent activity in prefrontal cortex (PFC) as a primary neural correlate, but emerging views suggest additional mechanisms may exist. We screened similar to 200 genetically diverse mice on a working memory task and identified a genetic locus on chromosome 5 that contributes to a substantial proportion (17%) of the phenotypic variance. Within the locus, we identified a gene encoding an orphan G-protein-coupled receptor. Gpr12, which is sufficient to drive substantial and bidirectional changes in working memory. Molecular, cellular, and imaging studies revealed that Gpr12 enables high thalamus-PFC synchrony to support memory maintenance and choice accuracy. These findings identify an orphan receptor as a potent modifier of short-term memory and supplement classical PFC-based models with an emerging thalamus-centric framework for the mechanistic understanding of working memory.
Najarro EH, Huang J, Jacobo A, Quiruz LA, Grillet N, Cheng AG
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Dual regulation of planar polarization by secreted Wnts and Vangl2 in the developing mouse cochlea

DEVELOPMENT 2020 OCT; 147(19):? Article dev191981
Planar cell polarity (PCP) proteins localize asymmetrically to instruct cell polarity within the tissue plane, with defects leading to deformities of the limbs, neural tube and inner ear. Wnt proteins are evolutionarily conserved polarity cues, yet Wnt mutants display variable PCP defects; thus, how Wnts regulate PCP remains unresolved. Here, we have used the developing cochlea as a model system to show that secreted Wnts regulate PCP through polarizing a specific subset of PCP proteins. Conditional deletion of Wntless or porcupine, both of which are essential for secretion of Wnts, caused misrotated sensory cells and shortened cochlea - both hallmarks of PCP defects. Wntless-deficient cochleae lacked the polarized PCP components dishevelled 1/2 and frizzled 3/6, while other PCP proteins (Vangl1/2, Celsr1 and dishevelled 3) remained localized. We identified seven Wnt paralogues, including the major PCP regulator Wnt5a, which was, surprisingly, dispensable for planar polarization in the cochlea. Finally, Vangl2 haploinsufficiency markedly accentuated sensory cell polarization defects in Wntless-deficient cochlea. Together, our study indicates that secreted Wnts and Vangl2 coordinate to ensure proper tissue polarization during development.
Audet JN
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Neurobiological and Ecological Correlates of Avian Innovation

In the wild, particularly in rapidly changing conditions, being capable of solving new problems can increase an animal's chances of survival and reproduction. In the current context of widespread habitat destruction and increasing urbanization, innovativeness might be a crucial trait. In the past few decades, birds have proven to be a model taxon for the study of innovation, thanks to the abundant literature on avian innovation reports. Innovation databases in birds have been successfully employed to assess associations between innovativeness and other traits such as invasion success, life history, generalism, and brain encephalization. In order to more directly assess the causes of variation in innovation, a complementary approach consists in measuring innovativeness in wild-caught animals using problem-solving tasks that mimic innovations in the field. This method can allow for finer scale evaluation of ecological and neural correlates of innovation. Here, I review some of the most important findings on the correlates of innovation, with a particular focus on neural ones. I conclude by discussing avenues for future research, which I suggest should focus on neurobiology.
Yamazaki T, Liu LZ, Conlon EG, Manley JL
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Burkitt lymphoma-relatedTCF3mutations alter TCF3 alternative splicing by disrupting hnRNPH1 binding

RNA BIOLOGY 2020 OCT; 17(10):1383-1390
Burkitt lymphoma (BL) is an aggressive B-cell lymphoma characterized by translocation and deregulation of the proto-oncogene c-MYC. Transcription factor 3 (TCF3) has also been shown to be involved in BL pathogenesis. In BL, TCF3 is constitutively active, and/or expression of its transcriptional targets are altered as a result of BL-associated mutations. Here, we found that BL-relatedTCF3mutations affect TCF3 alternative splicing, in part by reducing binding of the splicing regulator hnRNPH1 to exon 18b. This leads to greater exon 18b inclusion, thereby generating more of the mutated E47 isoform of TCF3. Interestingly, upregulation of E47 dysregulates the expression of TCF3 targetsPTPN6, and perhapsCCND3, which are known to be involved in BL pathogenesis. Our findings thus reveal a mechanism by whichTCF3somatic mutations affect multilayered gene regulation underlying BL pathogenesis.
Zhang Y, Kreek MJ
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Nalfurafine modulates the reinforcing effects of oxycodone in male and female adolescent C57BL/6J mice

NEUROPHARMACOLOGY 2020 OCT 1; 176(?):? Article 108244
Addiction to prescription opioid, such as oxycodone, has affected millions of adolescents and young adults. Kappa opioid receptor (KOP-r) agonist can counterbalance the euphoria effects of mu opioid agonists like oxycodone. Nalfurafine is a KOP-r agonist. The current study examined how nalfurafine affected the reinforcing-effect of oxycodone in adolescent male and female mice using intravenous self-administration (SA) and conditioned place preference (CPP) paradigms. Adolescent mice (5 week-old) first received surgery for catheter implantation. After recovery, mice were then placed into the SA chambers and allowed to self-administer oxycodone, 2 h per day for 14 days. Following 14 day oxycodone SA, mice were injected with saline and a single dose of nalfurafine (10, 20, 30, 40 mu g/kg, s.c.) 10 min before each oxycodone SA session for 5 consecutive days. The mice were then injected with Nor-BNI (10 mg/kg, i.p.) 24 h before oxycodone SA following injection of nalfurafine (40 mu g/kg, s.c.). Separate groups of male and female adolescent mice underwent oxycodone CPP or hot plate test with or without nalfurafine preinjection. Nalfurafine decreased oxycodone SA in a dose dependent manner. Nor-BNI blocked the effect of nalfurafine on oxycodone SA. Nalfurafine significantly attenuated the oxycodone-induced hyperlocomotor activities and CPP, but enhanced oxycodone-induced analgesia. In conclusion, nalfurafine reduced the reinforcing effects of oxycodone in male and female adolescent mice. Nalfurafine also increased oxycodone-induced antinociception.
Edlow BL, Barra ME, Zhou DW, Foulkes AS, Snider SB, Threlkeld ZD, Chakravarty S, Kirsch JE, Chan ST, Meisler SL, Bleck TP, Fins JJ, Giacino JT, Hochberg LR, Solt K, Brown EN, Bodien YG
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Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit

NEUROCRITICAL CARE 2020 OCT; 33(2):364-375
There are currently no therapies proven to promote early recovery of consciousness in patients with severe brain injuries in the intensive care unit (ICU). For patients whose families face time-sensitive, life-or-death decisions, treatments that promote recovery of consciousness are needed to reduce the likelihood of premature withdrawal of life-sustaining therapy, facilitate autonomous self-expression, and increase access to rehabilitative care. Here, we present the Connectome-based Clinical Trial Platform (CCTP), a new paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU. We report the protocol for STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTIvation of Consciousness), a CCTP-based trial in which intravenous methylphenidate will be used for targeted stimulation of dopaminergic circuits within the subcortical ascending arousal network ( NCT03814356). The scientific premise of the CCTP and the STIMPACT trial is that personalized brain network mapping in the ICU can identify patients whose connectomes are amenable to neuromodulation. Phase 1 of the STIMPACT trial is an open-label, safety and dose-finding study in 22 patients with disorders of consciousness caused by acute severe traumatic brain injury. Patients in Phase 1 will receive escalating daily doses (0.5-2.0 mg/kg) of intravenous methylphenidate over a 4-day period and will undergo resting-state functional magnetic resonance imaging and electroencephalography to evaluate the drug's pharmacodynamic properties. The primary outcome measure for Phase 1 relates to safety: the number of drug-related adverse events at each dose. Secondary outcome measures pertain to pharmacokinetics and pharmacodynamics: (1) time to maximal serum concentration; (2) serum half-life; (3) effect of the highest tolerated dose on resting-state functional MRI biomarkers of connectivity; and (4) effect of each dose on EEG biomarkers of cerebral cortical function. Predetermined safety and pharmacodynamic criteria must be fulfilled in Phase 1 to proceed to Phase 2A. Pharmacokinetic data from Phase 1 will also inform the study design of Phase 2A, where we will test the hypothesis that personalized connectome maps predict therapeutic responses to intravenous methylphenidate. Likewise, findings from Phase 2A will inform the design of Phase 2B, where we plan to enroll patients based on their personalized connectome maps. By selecting patients for clinical trials based on a principled, mechanistic assessment of their neuroanatomic potential for a therapeutic response, the CCTP paradigm and the STIMPACT trial have the potential to transform the therapeutic landscape in the ICU and improve outcomes for patients with severe brain injuries.