Daily activities and sleep quality in college students

There is growing evidence that social rhythms (e.g., daily activities such as getting into or out of bed, eating, and adhering to a work schedule) have important implications for sleep. The present study used a prospective measure of daily activities to assess the relation between sleep and social rhythms. College students (n=243) 18 to 39 yrs of age, completed the Social Rhythm Metric (SRM) each day for 14 d and then completed the Pittsburgh Sleep Quality Index (PSQI). The sample was divided into groups of good or poor sleepers, according to a PSQI cut‐off score of 5 points and was compared on the regularity, frequency, timing, and extent of social engagement during activities. There was a lower frequency and less regularity of social rhythms in poor sleepers relative to good sleepers. Good sleepers engaged more regularly in activities with active social engagement. Earlier rise time, first consumption of a beverage, going outdoors for the first time, and bedtime were associated with better sleep. Greater variability in rise time, consuming a morning beverage, returning home for the last time, and bedtime were associated with more disturbed sleep. The results are consistent with previous findings of reduced regularity in bedtime and rise time schedules in undergraduates, other age groups, and in clinical populations. Results augment the current thought that regulating behavioral zeitgebers may be important in influencing bed and rise times, and suggest that engaging in activities with other people may increase regularity.     

N-Acyl-N′-arylpiperazines as negative allosteric modulators of mGlu1: Identification of VU0469650, a potent and selective tool compound with CNS exposure in rats

Development of SAR in an N-acyl-N′-arylpiperazine series of negative allosteric modulators of mGlu₁ using a functional cell-based assay is described in this Letter. Characterization of selected compounds in protein binding assays was used to aid in selecting VU0469650 for further profiling in ancillary pharmacology assays and pharmacokinetic studies. VU0469650 demonstrated an excellent selectivity profile and good exposure in both plasma and brain samples following intraperitoneal dosing in rats.     

Discovery of ML326: The first sub-micromolar,selective M5 PAM

This Letter describes the further chemical optimization of the M₅ PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M₅ PAMs (M₅ EC₅₀ >10 μM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M₅ PAM, ML326 (VU0467903), (human and rat M₅ EC₅₀s of 409 nM and 500 nM, respectively) with excellent mAChR selectivity (M₁–M₄ EC₅₀s >30 μM) and a robust 20-fold leftward shift of the ACh CRC.     

DNA adduct levels in fish from pristine areas are not detectable or low when analysed using the nuclease P1 version of the 32P-postlabelling technique

In order to understand and apply DNA adduct formation in fish liver as a biomarker for aquatic pollution, information concerning the natural background levels in non-contaminated organisms, caused by endogenous compounds, is of fundamental importance. In this study, DNA adducts were analysed in liver of 11 fish species from arctic and sub-arctic areas in the northern Atlantic using the nuclease P1 version of the ³²P-postlabelling technique. The collected fish were assumed not to have been influenced by anthropogenic pollution apart from possible long-range transported pollutants. As polycyclic aromatic hydrocarbons (PAHs) are thought to be fundamental in forming the type of DNA adducts detected by the method used, biliary PAH metabolite levels were measured in a selection of the investigated species. In all investigated individuals, the levels of PAH metabolites were undetectable. Controlled on-site exposure experiments with benzo[a]pyrene (polar cod) and laboratory experiments with crude oil (polar cod and Atlantic cod) were conducted. DNA adducts were formed in both these species. The field-sampled fish showed undetectable levels of DNA adducts or levels just above the detection limit. The present study supports the assumption that when DNA adducts are detected by the nuclease P1 version of the ³²P-postlabelling method in fish liver, it can be interpreted as DNA damage caused by pollutants.     

Anthropogenic noise decreases urban songbird diversity and may contribute to homogenization

More humans reside in urban areas than at any other time in history. Protected urban green spaces and transportation greenbelts support many species, but diversity in these areas is generally lower than in undeveloped landscapes. Habitat degradation and fragmentation contribute to lowered diversity and urban homogenization, but less is known about the role of anthropogenic noise. Songbirds are especially vulnerable to anthropogenic noise because they rely on acoustic signals for communication. Recent studies suggest that anthropogenic noise reduces the density and reproductive success of some bird species, but that species which vocalize at frequencies above those of anthropogenic noise are more likely to inhabit noisy areas. We hypothesize that anthropogenic noise is contributing to declines in urban diversity by reducing the abundance of select species in noisy areas, and that species with low‐frequency songs are those most likely to be affected. To examine this relationship, we calculated the noise‐associated change in overall species richness and in abundance for seven common songbird species. After accounting for variance due to vegetative differences, species richness and the abundance of three of seven species were reduced in noisier locations. Acoustic analysis revealed that minimum song frequency was highly predictive of a species' response to noise, with lower minimum song frequencies incurring greater noise‐associated reduction in abundance. These results suggest that anthropogenic noise affects some species independently of vegetative conditions, exacerbating the exclusion of some songbird species in otherwise suitable habitat. Minimum song frequency may provide a useful metric to predict how particular species will be affected by noise. In sum, mitigation of noise may enhance habitat suitability for many songbird species, especially for species with songs that include low‐frequency elements.     

Cis‐Golgi Cisternal Assembly and Biosynthetic Activation Occur Sequentially in Plants and Algae

The cisternal progression/maturation model of Golgi trafficking predicts that cis‐Golgi cisternae are formed de novo on the cis‐side of the Golgi. Here we describe structural and functional intermediates of the cis cisterna assembly process in high‐pressure frozen algae (Scherffelia dubia, Chlamydomonas reinhardtii) and plants (Arabidopsis thaliana, Dionaea muscipula; Venus flytrap) as determined by electron microscopy, electron tomography and immuno‐electron microscopy techniques. Our findings are as follows: (i) The cis‐most (C1) Golgi cisternae are generated de novo from cisterna initiators produced by the fusion of 3–5 COPII vesicles in contact with a C2 cis cisterna. (ii) COPII vesicles fuel the growth of the initiators, which then merge into a coherent C1 cisterna. (iii) When a C1 cisterna nucleates its first cisterna initiator it becomes a C2 cisterna. (iv) C2‐Cn cis cisternae grow through COPII vesicle fusion. (v) ER‐resident proteins are recycled from cis cisternae to the ER via COPIa‐type vesicles. (vi) In S. dubia the C2 cisternae are capable of mediating the self‐assembly of scale protein complexes. (vii) In plants, ～90% of native α‐mannosidase I localizes to medial Golgi cisternae. (viii) Biochemical activation of cis cisternae appears to coincide with their conversion to medial cisternae via recycling of medial cisterna enzymes. We propose how the different cis cisterna assembly intermediates of plants and algae may actually be related to those present in the ERGIC and in the pre‐cis Golgi cisterna layer in mammalian cells.     

A variant in MCF2L is associated with osteoarthritis

Osteoarthritis (OA) is a prevalent, heritable degenerative joint disease with a substantial public health impact. We used a 1000-Genomes-Project-based imputation in a genome-wide association scan for osteoarthritis (3177 OA cases and 4894 controls) to detect a previously unidentified risk locus. We discovered a small disease-associated set of variants on chromosome 13. Through large-scale replication, we establish a robust association with SNPs in MCF2L (rs11842874, combined odds ratio [95% confidence interval] 1.17 [1.11–1.23], p = 2.1 × 10⁻⁸) across a total of 19,041 OA cases and 24,504 controls of European descent. This risk locus represents the third established signal for OA overall. MCF2L regulates a nerve growth factor (NGF), and treatment with a humanized monoclonal antibody against NGF is associated with reduction in pain and improvement in function for knee OA patients.     

Characterization of new medium-chain alcohol dehydrogenases adds resolution to duplications of the class I/III and the sub-class I genes

Four additional variants of alcohol and aldehyde dehydrogenases have been purified and functionally characterized, and their primary structures have been determined. The results allow conclusions about the structural and evolutionary relationships within the large family of MDR alcohol dehydrogenases from characterizations of the pigeon (Columba livia) and dogfish (Scyliorhinus canicula) major liver alcohol dehydrogenases. The pigeon enzyme turns out to be of class I type and the dogfish enzyme of class III type. This result gives a third type of evidence, based on purifications and enzyme characterization in lower vertebrates, that the classical liver alcohol dehydrogenase originated by a gene duplication early in the evolution of vertebrates. It is discernable as the major liver form at about the level in-between cartilaginous and osseous fish. The results also show early divergence within the avian orders. Structures were determined by Edman degradations, making it appropriate to acknowledge the methodological contributions of Pehr Edman during the 65 years since his thesis at Karolinska Institutet, where also the present analyses were performed.