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In the textbook view, NMDA receptors (NMDARs) act as coincidence detectors in Hebbian plasticity by fluxing Ca 2+ when simultaneously depolarized and glutamate bound. Hebbian coincidence detection requires that NMDARs be located postsynaptically, but enigmatic presynaptic NMDARs (preNMDARs) also exist. It is known that preNMDARs regulate neurotransmitter release, but precisely how remains poorly understood. Emerging evidence suggests that NMDARs can also signal non-ionotropically, without the need for Ca 2+ flux. At synapses between developing visual cortex layer-5 (L5) pyramidal cells (PCs), preNMDARs rely on Mg 2+ and Rab3-interacting molecule 1αβ (RIM1αβ) to regulate evoked release during periods of high-frequency firing, but they signal non-ionotropically via c-Jun N-terminal kinase 2 (JNK2) to regulate spontaneous release regardless of frequency. At the same synapses, timing-dependent long-term depression (tLTD) depends on preNMDARs but not on frequency. We, therefore, tested in juvenile mouse visual cortex if tLTD relies on non-ionotropic preNMDAR signaling. We found that tLTD at L5 PC→PC synapses was abolished by pre- but not postsynaptic NMDAR deletion, cementing the view that tLTD requires preNMDARs. In agreement with non-ionotropic NMDAR signaling, tLTD prevailed after channel pore blockade with MK-801, unlike tLTP. Homozygous RIM1αβ deletion did not affect tLTD, but wash-in of the JNK2 blocker SP600125 abolished tLTD. Consistent with a presynaptic need for JNK2, a peptide blocking the interaction between JNK2 and Syntaxin-1a (STX1a) abolished tLTD if loaded pre- but not postsynaptically, regardless of frequency. Finally, low-frequency tLTD was not blocked by the channel pore blocker MK-801, nor by 7-CK, a non-competitive NMDAR antagonist at the co-agonist site. We conclude that neocortical L5 PC→PC tLTD relies on non-ionotropic preNMDAR signaling via JNK2/STX1a. Our study brings closure to long-standing controversy surrounding preNMDARs and highlights how the textbook view of NMDARs as ionotropic coincidence detectors in plasticity needs to be reassessed.

In the textbook view, NMDA receptors (NMDARs) act as coincidence detectors in Hebbian plasticity by fluxing Ca 2+ when simultaneously depolarized and glutamate bound. Hebbian coincidence detection requires that NMDARs be located postsynaptically, but enigmatic presynaptic NMDARs (preNMDARs) also exist. It is known that preNMDARs regulate neurotransmitter release, but precisely how remains poorly understood. Emerging evidence suggests that NMDARs can also signal non-ionotropically, without the need for Ca 2+ flux. At synapses between developing visual cortex layer-5 (L5) pyramidal cells (PCs), preNMDARs rely on Mg 2+ and Rab3-interacting molecule 1αβ (RIM1αβ) to regulate evoked release during periods of high-frequency firing, but they signal non-ionotropically via c-Jun N-terminal kinase 2 (JNK2) to regulate spontaneous release regardless of frequency. At the same synapses, timing-dependent long-term depression (tLTD) depends on preNMDARs but not on frequency. We, therefore, tested in juvenile mouse visual cortex if tLTD relies on non-ionotropic preNMDAR signaling. We found that tLTD at L5 PC→PC synapses was abolished by pre- but not postsynaptic NMDAR deletion, cementing the view that tLTD requires preNMDARs. In agreement with non-ionotropic NMDAR signaling, tLTD prevailed after channel pore blockade with MK-801, unlike tLTP. Homozygous RIM1αβ deletion did not affect tLTD, but wash-in of the JNK2 blocker SP600125 abolished tLTD. Consistent with a presynaptic need for JNK2, a peptide blocking the interaction between JNK2 and Syntaxin-1a (STX1a) abolished tLTD if loaded pre- but not postsynaptically, regardless of frequency. Finally, low-frequency tLTD was not blocked by the channel pore blocker MK-801, nor by 7-CK, a non-competitive NMDAR antagonist at the co-agonist site. We conclude that neocortical L5 PC→PC tLTD relies on non-ionotropic preNMDAR signaling via JNK2/STX1a. Our study brings closure to long-standing controversy surrounding preNMDARs and highlights how the textbook view of NMDARs as ionotropic coincidence detectors in plasticity needs to be reassessed.

NMDA receptors (NMDARs) play a critical role in neuronal communication and are essential mediators of synaptic plasticity mechanisms within the central nervous system. In the traditional view, NMDARs act as coincidence detectors in Hebbian plasticity, fluxing calcium when simultaneously glutamate bound and depolarized to initiate signalling cascades which ultimately result in synaptic modification. Coincidence detection relies on NMDARs situated postsynaptically, yet NMDARs also exist presynaptically (preNMDARs) at select synapse-types, which suggests their contributions to synaptic plasticity and information processing may be distinct. Indeed, preNMDARs regulate the probability of neurotransmitter release, however the underlying molecular mechanisms remain largely unknown. Our lab has recently shown that in L5 pyramidal cells of mouse primary visual cortex, preNMDARs differentially regulate evoked and spontaneous neurotransmitter release through two presynaptic proteins: RIM1αβ and JNK2, respectively. Here I further explore this dichotomy. As preNMDAR-mediated induction of timing-dependent long-term depression (tLTD) has been shown to be independent of presynaptic firing frequency, I hypothesized that preNMDARs may further rely on JNK2 signalling to regulate tLTD in a similar manner as spontaneous release. Indeed, in patch recordings of L5 pyramidal cell pairs, tLTD was abolished upon JNK2 inhibition; however, tLTD in RIM1αβ knock out was indistinguishable from control. In sum, tLTD requires preNMDAR-mediated JNK2 signalling in a manner independent of RIM1αβ. This finding elucidates the criteria by which preNMDARs may select competing signalling pathways; preNMDARs appear to form a dual-pass filter, capable of regulating neurotransmitter release through independent mechanisms depending on presynaptic frequency requirements. As preNMDARs operate in a non-ionotropic manner during JNK-mediated regulation of spontaneous release, tLTD may similarly require this mode of unconventional NMDAR signalling

Throughout the nation and in the state of Texas, English language learners' academic achievements fall below their non-English language learner peers (U.S. Department of Education, Institute of Education Sciences, National Center for Education Statistics, & National Assessment of Educational Programs, 2013; Texas Education Agency [TEA], 2014d). Literacy coaches are often used to increase teacher capacity through a collaborative process. This dissertation explores the perceptions of literacy coaches on what knowledge base they need to effectively support teachers of English language learners, as well as the patterns that emerge from their perceptions. Data collected through 10 individual interviews and a focus group session was used to examine the perceptions of the coaches and determine future steps for improving coaching methods in serving teachers of culturally and linguistically diverse students. KEY WORDS: Literacy coach, Instructional coaching, English language learners, ELLs, Sam Houston State University, Graduate school, Texas

In the textbook view, NMDA receptors (NMDARs) act as coincidence detectors in Hebbian plasticity by fluxing Ca2+ when simultaneously depolarized and glutamate bound. Hebbian coincidence detection requires that NMDARs be located postsynaptically, but enigmatic presynaptic NMDARs (preNMDARs) also exist. It is known that preNMDARs regulate neurotransmitter release, but precisely how remains poorly understood. Emerging evidence suggest that NMDARs can also signal non-ionotropically, without the need for Ca2+ flux. At synapses between developing visual cortex layer-5 (L5) pyramidal cells (PCs), preNMDARs rely on Mg2+ and Rab3-interacting molecule 1αβ (RIM1αβ) to regulate evoked release during periods of high-frequency firing, but they signal non-ionotropically via c-Jun N-terminal kinase 2 (JNK2) to regulate spontaneous release regardless of frequency. At the same synapses, timing-dependent long-term depression (tLTD) depends on preNMDARs but not on frequency. We therefore tested if tLTD relies on non-ionotropic preNMDAR signaling. We found that tLTD at L5 PC→PC synapses was abolished by pre- but not postsynaptic NMDAR deletion, cementing the view that tLTD requires preNMDARs. In agreement with non-ionotropic NMDAR signaling, tLTD prevailed after channel pore blockade with MK-801, unlike tLTP. Homozygous RIM1αβ deletion did not affect tLTD, but wash-in of the JNK2 blocker SP600125 abolished tLTD. Consistent with a presynaptic need for JNK2, a peptide blocking the interaction between JNK2 and Syntaxin-1a (STX1a) abolished tLTD if loaded pre- but not postsynaptically, regardless of frequency. Finally, low-frequency tLTD was not blocked by the channel pore blocker MK-801, nor by 7-CK, a non-competitive NMDAR antagonist at the co-agonist site. We conclude that neocortical L5 PC→PC tLTD relies on non-ionotropic preNMDAR signaling via JNK2/STX1a. Our study brings closure to long-standing controversy surrounding preNMDARs and highlights how the textbook view of NMDARs as ionotropic coincidence detectors in plasticity needs to be reassessed.Competing Interest StatementThe authors have declared no competing interest.

Current methods for bioprinting functional tissue lack appropriate biofabrication techniques to build complex 3D microarchitectures essential for guiding cell growth and promoting tissue maturation 1 . 3D printing of central nervous system (CNS) structures has not been accomplished, possibly owing to the complexity of CNS architecture. Here, we report the use of a microscale continuous projection printing method (μCPP) to create a complex CNS structure for regenerative medicine applications in the spinal cord. μCPP can print 3D biomimetic hydrogel scaffolds tailored to the dimensions of the rodent spinal cord in 1.6 s and is scalable to human spinal cord sizes and lesion geometries. We tested the ability of µCPP 3D-printed scaffolds loaded with neural progenitor cells (NPCs) to support axon regeneration and form new ‘neural relays’ across sites of complete spinal cord injury in vivo in rodents 1 , 2 . We find that injured host axons regenerate into 3D biomimetic scaffolds and synapse onto NPCs implanted into the device and that implanted NPCs in turn extend axons out of the scaffold and into the host spinal cord below the injury to restore synaptic transmission and significantly improve functional outcomes. Thus, 3D biomimetic scaffolds offer a means of enhancing CNS regeneration through precision medicine. Fast scalable 3D bioprinting generates biocompatible and biomimetic scaffolds to precisely fit the geometries of spinal cord lesions, promote axonal regeneration, and support stem cell grafts to promote recovery from spinal cord injury in rodents.

Background The gut microbiome has an important role in infant health and immune development and may be affected by early-life exposures. Maternal diet may influence the infant gut microbiome through vertical transfer of maternal microbes to infants during vaginal delivery and breastfeeding. We aimed to examine the association of maternal diet during pregnancy with the infant gut microbiome 6 weeks post-delivery in mother-infant dyads enrolled in the New Hampshire Birth Cohort Study. Infant stool samples were collected from 145 infants, and maternal prenatal diet was assessed using a food frequency questionnaire. We used targeted sequencing of the 16S rRNA V4-V5 hypervariable region to characterize infant gut microbiota. To account for differences in baseline and trajectories of infant gut microbial profiles, we stratified analyses by delivery mode. Results We identified three infant gut microbiome clusters, characterized by increased abundance of Bifidobacterium , Streptococcus and Clostridium , and Bacteroides , respectively, overall and in the vaginally delivered infant stratum. In the analyses stratified to infants born vaginally and adjusted for other potential confounders, maternal fruit intake was associated with infant gut microbial community structure (PERMANOVA, p  < 0.05). In multinomial logistic regression analyses, increased fruit intake was associated with an increased odds of belonging to the high Streptococcus / Clostridium group among infants born vaginally (OR (95% CI) = 2.73 (1.36, 5.46)). In infants delivered by Cesarean section, we identified three clusters that differed slightly from vaginally delivered infants, which were characterized by a high abundance of Bifidobacterium , high Clostridium and low Streptococcus and Ruminococcus genera, and high abundance of the family Enterobacteriaceae . Maternal dairy intake was associated with an increased odds of infants belonging to the high Clostridium cluster in infants born by Cesarean section (OR (95% CI) = 2.36 (1.05, 5.30)). Linear models suggested additional associations between maternal diet and infant intestinal microbes in both delivery mode strata. Conclusions Our data indicate that maternal diet influences the infant gut microbiome and that these effects differ by delivery mode.

The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. Here we develop and validate a method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and use solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise a mixture of single protofilament and two protofilament fibrils with very low twist. The protofilament fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural characterization of LBD Asyn fibrils and approaches for studying disease mechanisms, imaging agents and therapeutics targeting Asyn. The accumulation of alpha-synuclein fibrils within neurons is the defining feature of Lewy body dementia (LBD). Here the authors report a method to produce large quantities of alpha-synuclein fibrils that reproduce the complex structure of the fibrils that accumulate in LBD brain tissue.

Recently, organoid technology has been used to generate a large repository of breast cancer organoids. Here we present an extensive evaluation of the ability of organoid culture technology to preserve complex stem/progenitor and differentiated cell types via long-term propagation of normal human mammary tissues. Basal/stem and luminal progenitor cells can differentiate in culture to generate mature basal and luminal cell types, including ER+ cells that have been challenging to maintain in culture. Cells associated with increased cancer risk can also be propagated. Single-cell analyses of matched organoid cultures and native tissues by mass cytometry for 38 markers provide a higher resolution representation of the multiple mammary epithelial cell types in the organoids, and demonstrate that protein expression patterns of the tissue of origin can be preserved in culture. These studies indicate that organoid cultures provide a valuable platform for studies of mammary differentiation, transformation, and breast cancer risk. Organoid technology has enabled the generation of several breast cancer organoids. Here, the authors combine propagation of normal human mammary tissues with mass cytometry to evaluate the ability of organoid culture technologies to preserve stem cells and differentiated cell types.

Study Objectives: Sleep disturbances are common in United States military personnel. Despite their exposure to combat and trauma, little is known about nightmares in this population. The purpose of this study was to describe the prevalence and associated clinical and polysomnographic characteristics of nightmares in United States military personnel with sleep disturbances. Methods: Retrospective review of 500 active duty United States military personnel who underwent a sleep medicine evaluation and polysomnography at our sleep center. The Pittsburgh Sleep Quality Index and the Pittsburgh Sleep Quality Index-Addendum were used to characterize clinically significant nightmares. Subjective and objective sleep attributes were compared between groups. Results: At least weekly nightmares were present in 31.2%; yet, only 3.9% reported nightmares as a reason for evaluation. Trauma-related nightmares occurred in 60% of those patients with nightmares. Patients with nightmares had increased sleep onset latency (SOL) and rapid eye movement (REM) sleep latency (mean SOL/REM sleep latency 16.6/145 minutes, P = .02 and P = .01 respectively) compared to those without (mean SOL/REM sleep latency 12.5/126 minutes). The comorbid disorders of depression ( P ≤ .01, relative risk [RR] 3.55 [95% CI, 2.52–4.98]), anxiety ( P ≤ .01, RR 2.57 [95% CI, 1.93–3.44]), posttraumatic stress disorder ( P ≤ .01, RR 5.11 [95% CI, 3.43–7.62]), and insomnia ( P ≤ .01, RR 1.59 [95% CI, 1.42–1.79]) were all associated with nightmares. Conclusions: Clinically significant nightmares are highly prevalent in United States military personnel with sleep disturbances. Nightmares are associated with both subjective and objective sleep disturbances and are frequently comorbid with other sleep and mental health disorders. Commentary: A commentary on this article appears in this issue on page 303. Citation: Creamer JL, Brock MS, Matsangas P, Motamedi V, Mysliwiec V. Nightmares in United States military personnel with sleep disturbances. J Clin Sleep Med. 2018;14(3):419–426.