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Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment ...of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo3.1.0hexane glutamic acid analogs as orthosteric (glutamate site) mGlu2/3 receptor antagonists. This work led to the discovery of a highly potent and efficacious tool compound 18 (hmGlu2 IC50 46±14.2nM, hmGlu3 IC50=46.1±36.2nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10mg/kg ip without any significant effects on locomotor activity. Compound 18 thus represents a novel tool molecule for studying the impact of blocking mGlu2/3 receptors both in vitro and in vivo.
Despite the growing popularity of online game playing, there have been no surveys comparing adolescent and adult players. Therefore, an online questionnaire survey was used to examine various factors ...of online computer game players (
n=540) who played the most popular online game
Everquest. The survey examined basic demographic information, playing frequency (i.e. amount of time spent playing the game a week), playing history (i.e. how long they had been playing the game, who they played the game with, whether they had ever gender swapped their game character, the favourite and least favourite aspects of playing the game, and what they sacrifice (if anything) to play the game. Results showed that adolescent gamers were significantly more likely to be male, significantly less likely to gender swap their characters, and significantly more likely to sacrifice their education or work. In relation to favourite aspects of game play, the biggest difference between the groups was that significantly more adolescents than adults claimed their favourite aspect of playing was violence. Results also showed that in general, the younger the player, the longer they spent each week playing.
Perivascular spaces (PVS) and cerebrospinal fluid (CSF) are essential components of the glymphatic system, regulating brain homeostasis and clearing neural waste throughout the lifespan. Enlarged PVS ...have been implicated in neurological disorders and sleep problems in adults, and excessive CSF volume has been reported in infants who develop autism. Enlarged PVS have not been sufficiently studied longitudinally in infancy or in relation to autism outcomes or CSF volume.
To examine whether enlarged PVS are more prevalent in infants who develop autism compared with controls and whether they are associated with trajectories of extra-axial CSF volume (EA-CSF) and sleep problems in later childhood.
This prospective, longitudinal cohort study used data from the Infant Brain Imaging Study. Magnetic resonance images were acquired at ages 6, 12, and 24 months (2007-2017), with sleep questionnaires performed between ages 7 and 12 years (starting in 2018). Data were collected at 4 sites in North Carolina, Missouri, Pennsylvania, and Washington. Data were analyzed from March 2021 through August 2022.
PVS (ie, fluid-filled channels that surround blood vessels in the brain) that are enlarged (ie, visible on magnetic resonance imaging).
Outcomes of interest were enlarged PVS and EA-CSF volume from 6 to 24 months, autism diagnosis at 24 months, sleep problems between ages 7 and 12 years.
A total of 311 infants (197 63.3% male) were included: 47 infants at high familial likelihood for autism (ie, having an older sibling with autism) who were diagnosed with autism at age 24 months, 180 high likelihood infants not diagnosed with autism, and 84 low likelihood control infants not diagnosed with autism. Sleep measures at school-age were available for 109 participants. Of infants who developed autism, 21 (44.7%) had enlarged PVS at 24 months compared with 48 infants (26.7%) in the high likelihood but no autism diagnosis group (P = .02) and 22 infants in the control group (26.2%) (P = .03). Across all groups, enlarged PVS at 24 months was associated with greater EA-CSF volume from ages 6 to 24 months (β = 4.64; 95% CI, 0.58-8.72; P = .002) and more frequent night wakings at school-age (F = 7.76; η2 = 0.08; P = .006).
These findings suggest that enlarged PVS emerged between ages 12 and 24 months in infants who developed autism. These results add to a growing body of evidence that, along with excessive CSF volume and sleep dysfunction, the glymphatic system could be dysregulated in infants who develop autism.
Younger siblings of children with autism spectrum disorder (ASD) are themselves at increased risk for ASD and other developmental concerns. It is unclear if infants who display developmental ...concerns, but are unaffected by ASD, share similar or dissimilar behavioral and brain phenotypes to infants with ASD. Most individuals with ASD exhibit heterogeneous difficulties with language, and their receptive-expressive language profiles are often atypical. Yet, little is known about the neurobiology that contributes to these language difficulties.
In this study, we used behavioral assessments and structural magnetic resonance imaging to investigate early brain structures and associations with later language skills. High-risk infants who were later diagnosed with ASD (n = 86) were compared with high-risk infants who showed signs of early language delay (n = 41) as well as with high- and low-risk infants who did not have ASD or language delay (n = 255 and 143, respectively).
Results indicated that diminished language skills were evident at 12 months in infants with ASD and infants with early language delay. At 24 months of age, only the infants with ASD displayed atypical receptive-expressive language profiles. Associations between 12-month subcortical volumes and 24-month language skills were moderated by group status, indicating disordinal brain-behavior associations among infants with ASD and infants with language delay.
These results suggest that there are different brain mechanisms influencing language development in infants with ASD and infants with language delay, and that the two groups likely experience unique sets of genetic and environmental risk factors.
Starvation induces gut mucosal atrophy, but the effects of progressive dietary restriction are not defined. The study's purpose was to determine the effects of incremental starvation on gut ...epithelial cell turnover. After food intake of mice was determined, they were divided into five groups: control (ad libitum fed), 75% normal intake, 50% intake, 25% intake, and fasted. Mice were killed after 48 hours, and the proximal small bowel were assessed for weight and protein content. Histologic specimens were examined for villus morphology, apoptosis, and proliferation. After 48 hr of diet restriction, bowel weight decreased in the 50% intake, 25% intake, and fasted groups. Villus density also decreased in the fasted group. Proliferation progressively decreased in the diet-restricted groups. Apoptosis increased in the fasted group, primarily in the villus tip. In conclusion, incremental starvation produces progressive small bowel atrophy. The mechanism involves both decreased gut epithelial cell proliferation and increased apoptosis.
A processable total synthesis of a potent antitumor agent, desoxyepothilone F (dEpoF, 21-hydroxy-12,13-desoxyepothilone B, 21-hydroxyepothilone D), has been accomplished. The route is highly ...convergent. The new technology has also been applied to a total synthesis of 12,13-desoxyepothilone (dEpoB). The crucial point of departure from previous syntheses of dEpoB and dEpoF involves presentation of the C1−C11 sector for Suzuki coupling with C3 in reduced form. Hitherto, the required S stereochemistry at C3 had been implemented via reduction of a keto function after Suzuki coupling. Whereas that chemistry worked quite well in a synthesis of dEpoB, it was not transferable to a high-yielding synthesis of dEpoF. The reduction of the keto group at C3 via a Noyori protocol after Suzuki coupling had proved to be very difficult. In our current approach, two consecutive aldol reactions are used to fashion the acyl sector. In the first aldol condensation, C6 becomes attached to C7. Following protection at C7, a two-carbon acetate equivalent is used to join C2 and C3 with very high asymmetric induction at C3. Only after this center has been implemented is the Suzuki reaction conducted. This major advance allowed us to synthesize dEpoF in a straightforward fashion. These findings found ready application in the total synthesis of dEpoB. Another part of the study involved analysis of the factors associated with aldol condensations joining C6 to C7. In the work described herein, the consequences of the status of C3 in promoting the C6−C7 aldol coupling are probed in detail. Dramatic stereochemical long-range effects uncovered during the study are described, and a working model to explain these effects has emerged.
The synthesis of a six-carbon truncated sialic acid is described. A key step in the synthesis was an indium-mediated allyl addition to a serine-derived aldehyde. Careful choice of protecting groups ...was found to be necessary in order to prevent unwanted side reactions throughout the sequence. The truncated sialic acid was obtained in a form suitable for activation as a glycosyl donor.
To probe the conformational requirements of O-linked glycoproteins for binding to various enzymes and receptors, two conformationally constrained glycosylated amino acids, 2 and 3, were designed. The ...analogues were found to represent two potential low energy conformations of the parent conjugate, 1, by molecular modeling. A convergent synthesis of both 2 and 3 from d-galactose and l-methionine is presented.
As sensor networks operate over long periods of deployment in difficult to reach places, their requirements may change or new code may need to be uploaded to them. The current state-of-the-art ...protocols (Deluge and MNP) for network reprogramming perform the code dissemination in a multihop manner using a three-way handshake where metadata is exchanged prior to code exchange to suppress redundant transmissions. The code image is also pipelined through the network at the granularity of pages. In this article we propose a protocol called Freshet for optimizing the energy for code upload and speeding up the dissemination if multiple sources of code are available. The energy optimization is achieved by equipping each node with limited nonlocal topology information which it uses to determine the time when it can go to sleep since code is not being distributed in its vicinity. The protocol to handle multiple sources provides a loose coupling of nodes to a source and disseminates code in waves each originating at a source with a mechanism to handle collisions when the waves meet. The protocol's performance with respect to reliability, delay, and energy consumed is demonstrated through analysis, simulation, and implementation on the Berkeley mote platform.
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