Search

Abstract SAR202 bacteria in the Chloroflexota phylum are abundant and widely distributed in the ocean. Their genome coding capacities indicate their potential roles in degrading complex and recalcitrant organic compounds in the ocean. However, our understanding of their genomic diversity, vertical distribution, and depth-related metabolisms is still limited by the number of assembled SAR202 genomes. In this study, we apply deep metagenomic sequencing (180 Gb per sample) to investigate microbial communities collected from six representative depths at the Bermuda Atlantic Time Series (BATS) station. We obtain 173 SAR202 metagenome-assembled genomes (MAGs). Intriguingly, 154 new species and 104 new genera are found based on these 173 SAR202 genomes. We add 12 new subgroups to the current SAR202 lineages. The vertical distribution of 20 SAR202 subgroups shows their niche partitioning in the euphotic, mesopelagic, and bathypelagic oceans, respectively. Deep-ocean SAR202 bacteria contain more genes and exhibit more metabolic potential for degrading complex organic substrates than those from the euphotic zone. With deep metagenomic sequencing, we uncover many new lineages of SAR202 bacteria and their potential functions which greatly deepen our understanding of their diversity, vertical profile, and contribution to the ocean’s carbon cycling, especially in the deep ocean.

ABSTRACTPhytoplankton are important drivers of aquatic ecosystem function and environmental health. Their community compositions and distributions are directly impacted by environmental processes and human activities, including in the largest estuary in North America, the Chesapeake Bay. It is crucial to uncover how planktonic eukaryotes play fundamental roles as primary producers and trophic links and sustain estuarine ecosystems. In this study, we investigated the detailed community structure and spatiotemporal variations of planktonic eukaryotes in the Chesapeake Bay across space and time for three consecutive years. A clear seasonal and spatial shift of total, abundant, and rare planktonic eukaryotes was evident, and the pattern recurred interannually. Multiple harmful algal species have been identified in the Bay with varied distribution patterns, such as Karlodinium, Heterosigma akashiwo, Protoperidinium sp., etc. Compared to abundant taxa, rare subcommunities were more sensitive to environmental disturbance in terms of richness, diversity, and distribution. The combined effects of temporal variation (13.3%), nutrient availability (10.0%), and spatial gradients (8.8%) structured the distribution of eukaryotic microbial communities in the Bay. Similar spatiotemporal patterns between planktonic prokaryotes and eukaryotes suggest common mechanisms of adjustment, replacement, and species interaction for planktonic microbiomes under strong estuarine gradients. To our best knowledge, this work represents the first systematic study on planktonic eukaryotes in the Bay. A comprehensive view of the distribution of planktonic microbiomes and their interactions with environmental processes is critical in understanding the underlying microbial mechanisms involved in maintaining the stability, function, and environmental health of estuarine ecosystems.IMPORTANCEDeep sequencing analysis of planktonic eukaryotes in the Chesapeake Bay reveals high community diversity with many newly recognized phytoplankton taxa. The Chesapeake Bay planktonic eukaryotes show distinct seasonal and spatial variability, with recurring annual patterns of total, abundant, and rare groups. Rare taxa mainly contribute to eukaryotic diversity compared to abundant groups, and they are more sensitive to spatiotemporal variations and environmental filtering. Temporal variations, nutrient availability, and spatial gradients significantly affect the distribution of eukaryotic microbial communities. Similar spatiotemporal patterns in prokaryotes and eukaryotes suggest common mechanisms of adjustment, substitution, and species interactions in planktonic microbiomes under strong estuarine gradients. Interannually recurring patterns demonstrate that diverse eukaryotic taxa have well adapted to the estuarine environment with a long residence time. Further investigations of how human activities impact estuarine planktonic eukaryotes are critical in understanding their essential ecosystem roles and in maintaining environmental safety and public health.

ABSTRACT The Mariana Trench, a stable marine ecosystem minimally impacted by human activities, has the greatest vertical depth in the ocean. Depth gradients profoundly influence the physical, chemical, and biotic conditions in the deep oceans. Therefore, elucidating the depth-related effects on microbiome assembly and interaction is integral to understanding marine hadal ecosystems. In this study, eight samples were collected along vertical gradients to compare the assembly and associations of bacteria, archaea, and microeukaryotes, in the Marina Trench using high-throughput sequencing. There is no significant difference in the niche breadth occupied by bacteria, archaea, and microeukaryotes, indicating that microorganisms from the surface to the hadal water of the trench are well adapted to this environment. Stochastic processes significantly influenced the distribution of bacteria and microeukaryotes as well as archaea when the phylogenetic distance was considered. Although diversities of all three microbial domains were consistent across depth, distinct bacterial and archaeal community structures occurred between hadal waters (3,699–8,727 m) and upper bathypelagic waters (≤1,000 m). Bacteria and archaea in upper bathypelagic zones were more affected by a random process and exhibited higher phylogenetic distance than those in hadal waters. In contrast, stochasticity in assembly and phylogenetic distance of microeukaryotes remained unchanged. Bacteria made vital contributions to the stability of trench microbiomes, while consistent community stability was observed between the upper bathypelagic and hadal zones. Our results reveal the complexity of community assembly and associations of multi-domain microbiomes in hadal ecosystems and also highlight the differential adaptations and contributions of prokaryotes vs. microeukaryotes to microbiome community stability and robustness. IMPORTANCE Exploring microbial interactions and their stability/resilience from the surface to the hadal ocean is critical for further understanding of the microbiome structure and ecosystem function in the Mariana Trench. Vertical gradients did not destabilize microbial communities after long-term evolution and adaption. The uniform niche breadth, diversity, community complexity, and stability of microbiomes in both upper bathypelagic and hadal waters suggest the consistent roles of microbiomes in elemental cycling and adaptive strategies to overcome extreme environmental conditions. Compared with microeukaryotes, bacteria and archaea play a pivotal role in shaping the stability of the hadal microbiome. The consistent co-occurrence stability of microbiomes across vertical gradients was observed in the Mariana Trench. These results illuminate a key principle of microbiomes inhabiting the deepest trench: although distinct microbial communities occupy specific habitats, the interactions within microbial communities remain consistently stable from the upper bathypelagic to the hadal waters.

Abstract Certain microalgal species can grow under high CO2 concentrations providing potential for mitigating CO2 pollution in flue gas produced by power plants. Microalga Scenedesmus obliquus strain HTB1 was isolated from the Chesapeake Bay and grow rapidly in a high level of CO2. However, little is known about the molecular responses of HTB1 to high CO2 levels. Here, we investigated how HTB1 responds to 10% CO2 using the time‐resolved transcriptome analysis. Gene expression profiles indicated that HTB1 responds quickly (in 2 h) and becomes adaptive within 12 h when exposed to 10% CO2. Interestingly, certain genes of light‐harvesting, chlorophyll synthesis and carbon fixation (i.e. rbcS) were up‐regulated at 10% CO2, and these functional responses are consistent with the increased photosynthesis efficiency and algal biomass under 10% CO2. Nitrate assimilation was strongly enhanced, with amino acid biosynthesis and aminoacyl tRNA biosynthesis genes being markedly up‐regulated, indicating that HTB1 actively takes up nitrogen and accelerates protein synthesis at 10% CO2. Carbon metabolism including fatty acid biosynthesis and TCA cycle was enhanced at 10% CO2, supporting the earlier observation of increased lipid content of Scenedesmus sp. under high CO2 levels. Interestingly, key genes like RuBisCO (rbcL) and carbonic anhydrase in carboxysomes did not respond actively to 10% CO2, implying that exposure to 10% CO2 has little impact on the carbon concentrating mechanisms and CO2 fixation of the Calvin cycle. It appears that HTB1 can grow rapidly at 10% CO2 without significant metabolic changes in carbon fixation and ATP synthesis.

Abstract Parkinson’s disease (PD) is the most common neurodegenerative motor disorder, and its pathologic hallmarks include extensive dopaminergic neuronal degeneration in the Substantia nigra associated with Lewy bodies, predominantly consisting of phosphorylated and truncated α-Synuclein (α-Syn). Asparagine endopeptidase (AEP) cleaves human α-Syn at N103 residue and promotes its aggregation, contributing to PD pathogenesis. However, how AEP mediates Lewy body pathologies during aging and elicits PD onset remains incompletely understood. Knockout of AEP or C/EBPβ from α-SNCA mice, and their chronic rotenone exposure models were used, and the mechanism of α-Syn from the gut that spread to the brain was observed. Here we report that C/EBPβ/AEP pathway, aggravated by oxidative stress, is age-dependently activated and cleaves α-Syn N103 and regulates Lewy body-like pathologies spreading from the gut into the brain in human α-SNCA transgenic mice. Deletion of C/EBPβ or AEP substantially diminished the oxidative stress, neuro-inflammation, and PD pathologies, attenuating motor dysfunctions in aged α-SNCA mice. Noticeably, PD pathologies initiate in the gut and progressively spread into the brain. Chronic gastric exposure to a low dose of rotenone initiates Lewy body-like pathologies in the gut that propagate into the brain in a C/EBPβ/AEP-dependent manner. Hence, our studies demonstrate that C/EBPβ/AEP pathway is critical for mediating Lewy body pathology progression in PD.

ABSTRACT The world’s largest macroalgal green tide, caused by Ulva prolifera, has resulted in serious consequences for coastal waters of the Yellow Sea, China. Although viruses are considered to be one of the key factors in controlling microalgal bloom demise, understanding of the relationship between viral communities and the macroalgal green tide is still poor. Here, a Qingdao coastal virome (QDCV) time-series data set was constructed based on the metagenomic analysis of 17 DNA viromes along three coastal stations of the Yellow Sea, covering different stages of the green tide from Julian days 165 to 271. A total of 40,076 viral contigs were detected and clustered into 28,058 viral operational taxonomic units (vOTUs). About 84% of the vOTUs could not be classified, and 62% separated from vOTUs in other ecosystems. Green tides significantly influenced the spatiotemporal dynamics of the viral community structure, diversity, and potential functions. For the classified vOTUs, the relative abundance of Pelagibacter phages declined with the arrival of the bloom and rebounded after the bloom, while Synechococcus and Roseobacter phages increased, although with a time lag from the peak of their hosts. More than 80% of the vOTUs reached peaks in abundance at different specific stages, and the viral peaks were correlated with specific hosts at different stages of the green tide. Most of the viral auxiliary metabolic genes (AMGs) were associated with carbon and sulfur metabolism and showed spatiotemporal dynamics relating to the degradation of the large amount of organic matter released by the green tide. IMPORTANCE To the best of our knowledge, this study is the first to investigate the responses of viruses to the world’s largest macroalgal green tide. It revealed the spatiotemporal dynamics of the unique viral assemblages and auxiliary metabolic genes (AMGs) following the variation and degradation of Ulva prolifera. These findings demonstrate a tight coupling between viral assemblages, and prokaryotic and eukaryotic abundances were influenced by the green tide.

Abstract Background Annually reoccurring microbial populations with strong spatial and temporal variations have been identified in estuarine environments, especially in those with long residence time such as the Chesapeake Bay (CB). However, it is unclear how microbial taxa cooccurr and how the inter-taxa networks respond to the strong environmental gradients in the estuaries. Results Here, we constructed co-occurrence networks on prokaryotic microbial communities in the CB, which included seasonal samples from seven spatial stations along the salinity gradients for three consecutive years. Our results showed that spatiotemporal variations of planktonic microbiomes promoted differentiations of the characteristics and stability of prokaryotic microbial networks in the CB estuary. Prokaryotic microbial networks exhibited a clear seasonal pattern where microbes were more closely connected during warm season compared to the associations during cold season. In addition, microbial networks were more stable in the lower Bay (ocean side) than those in the upper Bay (freshwater side). Multivariate regression tree (MRT) analysis and piecewise structural equation modeling (SEM) indicated that temperature, salinity and total suspended substances along with nutrient availability, particulate carbon and Chl a, affected the distribution and co-occurrence of microbial groups, such as Actinobacteria, Bacteroidetes, Cyanobacteria, Planctomycetes, Proteobacteria, and Verrucomicrobia. Interestingly, compared to the abundant groups (such as SAR11, Saprospiraceae and Actinomarinaceae), the rare taxa including OM60 (NOR5) clade (Gammaproteobacteria), Micrococcales (Actinobacteria), and NS11-12 marine group (Bacteroidetes) contributed greatly to the stability of microbial co-occurrence in the Bay. Modularity and cluster structures of microbial networks varied spatiotemporally, which provided valuable insights into the ‘small world’ (a group of more interconnected species), network stability, and habitat partitioning/preferences. Conclusion Our results shed light on how estuarine gradients alter the spatiotemporal variations of prokaryotic microbial networks in the estuarine ecosystem, as well as their adaptability to environmental disturbances and co-occurrence network complexity and stability.

Coastal eutrophication may be a vital inducement of green tide. Denitrification is an important nitrogen removal pathway that involves a series of enzymatic reactions. The rate-limiting step in the conversion of nitrite to nitric oxide is encoded by two functionally equivalent but structurally distinct genes, copper-containing nitrite reductase gene (nirK) and cytochrome cd1-containing nitrite reductase gene (nirS). Here, we used Illumina Miseq sequencing approach to examine the variations in denitrifying bacterial community characteristics and interactions during an Ulva prolifera green tide in coastal Qingdao areas. Our findings suggested that the variations in the denitrifying bacterial community structure during the green tide were closely related to the changes of chlorophyll a content, salinity and dissolved oxygen content. The nirK-type denitrifying bacteria were more sensitive to green tide than the nirS-type denitrifying bacteria. Additionally, the nirK-type denitrifying bacterial interactions were more stable and complex during the outbreak phase, while the nirS-type denitrifying bacterial interactions were more stable and complex during the decline phase. All of these characters demonstrated that the nirK-type and nirS-type denitrifying bacteria respond differently to the green tide, implying that they may occupy different niches during the green tide in coastal Qingdao areas.

Abstract Background Marine bacteriophages play key roles in the community structure of microorganisms, biogeochemical cycles, and the mediation of genetic diversity through horizontal gene transfer. Recently, traditional isolation methods, complemented by high-throughput sequencing metagenomics technology, have greatly increased our understanding of the diversity of bacteriophages. Oceanospirillum, within the order Oceanospirillales, are important symbiotic marine bacteria associated with hydrocarbon degradation and algal blooms, especially in polar regions. However, until now there has been no isolate of an Oceanospirillum bacteriophage, and so details of their metagenome has remained unknown. Results Here, we reported the first Oceanospirillum phage, vB_OliS_GJ44, which was assembled into a 33,786 bp linear dsDNA genome, which includes abundant tail-related and recombinant proteins. The recombinant module was highly adapted to the host, according to the tetranucleotides correlations. Genomic and morphological analyses identified vB_OliS_GJ44 as a siphovirus, however, due to the distant evolutionary relationship with any other known siphovirus, it is proposed that this virus could be classified as the type phage of a new Oceanospirivirus genus within the Siphoviridae family. vB_OliS_GJ44 showed synteny with six uncultured phages, which supports its representation in uncultured environmental viral contigs from metagenomics. Homologs of several vB_OliS_GJ44 genes have mostly been found in marine metagenomes, suggesting the prevalence of this phage genus in the oceans. Conclusions These results describe the first Oceanospirillum phage, vB_OliS_GJ44, that represents a novel viral cluster and exhibits interesting genetic features related to phage–host interactions and evolution. Thus, we propose a new viral genus Oceanospirivirus within the Siphoviridae family to reconcile this cluster, with vB_OliS_GJ44 as a representative member.

Summary: The highest plateau on Earth, Qinghai-Tibet Plateau, contains thousands of lakes with broad salinity and diverse and unique microbial communities. However, little is known about their co-occurring viruses. Herein, we identify 4,560 viral Operational Taxonomic Units (vOTUs) from six viromes of three saline lakes on Qinghai-Tibet Plateau, with less than 1% that could be classified. Most of the predicted vOTUs were associated with the dominant bacterial and archaeal phyla. Virus-encoded auxiliary metabolic genes suggest that viruses influence microbial metabolisms of carbon, nitrogen, sulfur, and lipid; the antibiotic resistance mediation; and their salinity adaption. The six viromes clustered together with the ice core viromes and bathypelagic ocean viromes and might represent a new viral habitat. This study has revealed the unique characteristics and potential ecological roles of DNA viromes in the lakes of the highest plateau and established a foundation for the recognition of the viral roles in plateau lake ecosystems.

ABSTRACT Alteromonas is a ubiquitous, abundant, copiotrophic and phytoplankton-associated marine member of the Gammaproteobacteria with a range extending from tropical waters to polar regions and including hadal zones. Here, we describe a novel Alteromonas phage, ZP6, that was isolated from surface coastal waters of Qingdao, China. ZP6 contains a linear, double-stranded, 38,080-bp DNA molecule with 50.1% G+C content and 47 putative open reading frames (ORFs). Three auxiliary metabolic genes were identified, encoding metal-dependent phosphohydrolase, diaminopurine synthetase, and nucleotide pyrophosphohydrolase. The first two ORFs facilitate the replacement of adenine (A) by diaminopurine (Z) in phage genomes and help phages to evade attack from host restriction enzymes. The nucleotide pyrophosphohydrolase enables the host cells to stop programmed cell death and improves the survival rate of the host in a nutrient-depleted environment. Phylogenetic analysis based on the amino acid sequences of whole genomes and comparative genomic analysis revealed that ZP6 is most closely related to Enhodamvirus but with low similarity (shared genes,

Marinobacter is the abundant and important algal-associated and hydrocarbon biodegradation bacteria in the ocean. However, little knowledge about their phages has been reported. Here, a novel siphovirus, vB_MalS-PS3, infecting Marinobacter algicola DG893(T), was isolated from the surface waters of the western Pacific Ocean. Transmission electron microscopy (TEM) indicated that vB_MalS-PS3 has the morphology of siphoviruses. VB_MalS-PS3 was stable from −20 to 55°C, and with the latent and rise periods of about 80 and 10 min, respectively. The genome sequence of VB_MalS-PS3 contains a linear, double-strand 42,168-bp DNA molecule with a G + C content of 56.23% and 54 putative open reading frames (ORFs). Nineteen conserved domains were predicted by BLASTp in NCBI. We found that vB_MalS-PS3 represent an understudied viral group with only one known isolate. The phylogenetic tree based on the amino acid sequences of whole genomes revealed that vB_MalS-PS3 has a distant evolutionary relationship with other siphoviruses, and can be grouped into a novel viral genus cluster with six uncultured assembled viral genomes from metagenomics, named here as Marinovirus. This study of the Marinobacter phage vB_MalS-PS3 genome enriched the genetic database of marine bacteriophages, in addition, will provide useful information for further research on the interaction between Marinobacter phages and their hosts, and their relationship with algal blooms and hydrocarbon biodegradation in the ocean.

Green tides caused by Ulva prolifera occur annually in the Yellow Sea, potentially influencing the marine microorganisms. Here, we focused on the variations in marine bacterial and archaeal communities during an U. prolifera green tide in coastal Qingdao areas with Illumina high-throughput sequencing analysis. Our results revealed that the diversity and structure of bacterial and archaeal communities, as well as the organization and structure of microbial co-occurrence networks, varied during the green tide. The decline phase may be favorable to the bacterial and archaeal diversity and richness. The bacterial community, as well as the archaeal community, showed clear variations between the outbreak and decline phases. A simpler and less connected microbial co-occurrence network was observed during the outbreak phase compared with the decline phase. Flavobacteriales and Rhodobacterales separately dominated the bacterial community during the outbreak and decline phase, and Marine Group II (MGII) dominated the archaeal community during the green tide. Combined with microbial co-occurrence network analysis, Flavobacteriales, Rhodobacterales and MGII may be important organisms during the green tide. Temperature, chlorophyll a content and salinity may have an important impact on the variations in bacterial and archaeal communities during the green tide.

In addition to inhabiting extreme territories, Archaea are widely distributed in common environments spanning from terrestrial to aquatic environments. This study investigated and compared archaeal community structures from three different habitats (representing distinct environments): agriculture soils (from farming system trials FST, PA, United States), freshwater biofilms (from White Clay Creek, PA, United States), and estuary water (Chesapeake Bay, United States). High-throughput sequencing of 16S rRNA genes indicated that Thaumarchaeota, Euryarchaeota, Nanoarchaeota, Crenarchaeota, and Diapherotrites were the commonly found dominant phyla across these three environments. Similar to Bacteria, distinct community structure and distribution patterns for Archaea were observed in soils vs. freshwater vs. estuary. However, the abundance, richness, evenness, and diversity of archaeal communities were significantly greater in soils than it was in freshwater and estuarine environments. Indicator species (or amplicon sequence variants, ASVs) were identified from different nitrogen and carbon cycling archaeal groups in soils (Nitrososphaerales, Nitrosotaleales, Nitrosopumilales, Methanomassiliicoccales, Lainarchaeales), freshwater biofilms (Methanobacteria, Nitrososphaerales) and Chesapeake Bay (Marine Group II, Nitrosopumilales), suggesting the habitat-specificity of their biogeochemical contributions to different environments. Distinct functional aspects of Archaea were also confirmed by functional predictions (PICRUSt2 analysis). Further, co-occurrence network analysis indicated that only soil Archaea formed stable modules. Keystone species (ASVs) were identified mainly from Methanomassiliicoccales, Nitrososphaerales, Nitrosopumilales. Overall, these results indicate a strong habitat-dependent distribution of Archaea and their functional partitions within the local environments.

Abstract Introduction Alzheimer's disease (AD) is an age‐related neurodegenerative disorder. One of the pathological features of AD is neuronal loss in brain regions associated with cognition, particularly the hippocampus. An enriched environment (EE) can facilitate neuronal plasticity and improve behaviors such as emotion, motor function, and cognition in AD. Methods After APP/PS1 mice were exposed to EE at an early stage (2 months of age), elevated plus maze performance and contextual fear conditioning were tested, and neurogenesis and the extent of activation in the hippocampus were observed. Results The results showed that, compared with that in the mice that experienced a standard environment, the cognition of the mice exposed to EE, as measured by contextual fear conditioning, was not statistically significant. However, based on their performance in the elevated plus maze, the index was increased in the mice, especially the APP/PS1 mice, exposed to EE. Consistent with the behavioral changes, the APP/PS1 mice exposed to EE showed an increased number of c‐Fos‐positive neurons and elevated neurogenesis in the dentate gyrus (DG) area. In addition, the activation of newborn neurons did not occur in the other three groups. Conclusions These results indicate that the activation of newborn neurons may participate in the improvement of behavioral performance in APP/PS1 mice after EE.

Netrin-1 and its receptors play crucial roles in inducing axonal growth and neuronal migration during neuronal development. Their profound impacts then extend into adulthood to encompass the maintenance of neuronal survival and synaptic function. Increasing amounts of evidence highlight several key points: (1) Diminished Netrin-1 levels exacerbate pathological progression in animal models of Alzheimer’s disease and Parkinson’s disease, and potentially, similar alterations occur in humans. (2) Genetic mutations of Netrin-1 receptors increase an individuals’ susceptibility to neurodegenerative disorders. (3) Therapeutic approaches targeting Netrin-1 and its receptors offer the benefits of enhancing memory and motor function. (4) Netrin-1 and its receptors show genetic and epigenetic alterations in a variety of cancers. These findings provide compelling evidence that Netrin-1 and its receptors are crucial targets in neurodegenerative diseases. Through a comprehensive review of Netrin-1 signaling pathways, our objective is to uncover potential therapeutic avenues for neurodegenerative disorders.

Background/Aims: Chronic stress can lead to cognitive impairment. Senescence-accelerated mouse prone 8 (SAMP8) is a naturally occurring animal model that is useful for investigating the neurological mechanisms of Alzheimer's disease. Here we investigated the impact and mechanisms of chronic stress on cognition in male SAMP8 mice. Methods: Male 6-month- old SAMP8 and SAMR1 (senescence-accelerated mouse resistant 1) mice strains were randomly divided into 4 groups. Mice in the unpredictable chronic mild stress (UCMS) groups were exposed to diverse stressors for 4 weeks. Then, these mice performed Morris water maze (MWM) test to assess the effect of UCMS on learning and memory. To explore the neurological mechanisms of UCMS on cognition in mice, we evaluated changes in the expression of postsynaptic density 95 (PSD95) and synaptophysin (SYN), which are essential proteins for synaptic plasticity. Five mice from each group were randomly chosen for reverse transcription polymerase chain reaction (RT-PCR) and western blotting analysis of SYN and PSD95. Results: The Morris water maze experiment revealed that the cognitive ability of the SAMP8 mice decreased with brain aging, and that chronic stress aggravated this cognitive deficit. In addition, chronic stress decreased the mRNA and protein expression of SYN and PSD95 in the hippocampus of the SAMP8 mice; however, the SAMR1 mice were unaffected. Conclusion: Our results demonstrate that decreased cognition and synaptic plasticity are related to aging. Moreover, we show that chronic stress aggravated this cognitive deficit and decreased SYN and PSD95 expression in the SAMP8 mice. Furthermore, the SAMP8 mice were more vulnerable to the detrimental effects of chronic stress on cognition than the SAMR1 mice. Our results suggest that the neurological mechanisms of chronic stress on cognition might be associated with a decrease in hippocampal SYN and PSD95 expression, which is critical for structural synaptic plasticity.

Chronic high-frequency repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that has recently received increasing interests as a therapeutic procedure for neurodegenerative diseases. To identify the metabolism mechanism underlying the improving effects of rTMS, we observed that high frequency (25Hz) rTMS for 14 days could reverse the decline of the performance of the passive avoidance task in aged mice. We further investigated the metabolite profiles in the prefrontal cortex (PFC) in those mice and found that rTMS could also reverse the metabolic abnormalities of gamma-aminobutyric acid, N-acetyl aspartic, and cholesterol levels to the degree similar to the young mice. These data suggested that the rTMS could ameliorate the age-related cognitive impairment and improving the metabolic profiles in PFC, and potentially can be used to improve cognitive decline in the elderly.

Rare (RVs) and common variants of the RET gene contribute to Hirschsprung disease (HSCR; congenital aganglionosis). While RET common variants are strongly associated with the commonest manifestation of the disease (males; short-segment aganglionosis; sporadic), rare coding sequence (CDS) variants are more frequently found in the lesser common and more severe forms of the disease (females; long/total colonic aganglionosis; familial).Here we present the screening for RVs in the RET CDS and intron/exon boundaries of 601 Chinese HSCR patients, the largest number of patients ever reported. We identified 61 different heterozygous RVs (50 novel) distributed among 100 patients (16.64%). Those include 14 silent, 29 missense, 5 nonsense, 4 frame-shifts, and one in-frame amino-acid deletion in the CDS, two splice-site deletions, 4 nucleotide substitutions and a 22-bp deletion in the intron/exon boundaries and 1 single-nucleotide substitution in the 5' untranslated region. Exonic variants were mainly clustered in RET the extracellular domain. RET RVs were more frequent among patients with the most severe phenotype (24% vs. 15% in short-HSCR). Phasing RVs with the RET HSCR-associated haplotype suggests that RVs do not underlie the undisputable association of RET common variants with HSCR. None of the variants were found in 250 Chinese controls.