Search

Although the molecular composition and architecture of synapses have been widely explored, much less is known about what genetic programs directly activate synaptic gene expression and how they are modulated. Here, using Caenorhabditis elegans dopaminergic neurons, we reveal that EGL-43/MECOM and FOS-1/FOS control an activity-dependent synaptogenesis program. Loss of either factor severely reduces presynaptic protein expression. Both factors bind directly to promoters of synaptic genes and act together with CUT homeobox transcription factors to activate transcription. egl-43 and fos-1 mutually promote each others expression, and increasing the binding affinity of FOS-1 to the egl-43 locus results in increased presynaptic protein expression and synaptic function. EGL-43 regulates the expression of multiple transcription factors, including activity-regulated factors and developmental factors that define multiple aspects of dopaminergic identity. Together, we describe a robust genetic program underlying activity-regulated synapse formation during development.

Insulin-mechanistic target of rapamycin (mTOR) signaling drives anabolic growth during organismal development; its late-life dysregulation contributes to aging and limits lifespans. Age-related regulatory mechanisms and functional consequences of insulin-mTOR remain incompletely understood. Here, we identify LPD-3 as a megaprotein that orchestrates the tempo of insulin-mTOR signaling during C. elegans aging. We find that an agonist insulin, INS-7, is drastically overproduced from early life and shortens lifespan in lpd-3 mutants. LPD-3 forms a bridge-like tunnel megaprotein to facilitate non-vesicular cellular lipid trafficking. Lipidomic profiling reveals increased hexaceramide species in lpd-3 mutants, accompanied by up-regulation of hexaceramide biosynthetic enzymes, including HYL-1. Reducing the abundance of HYL-1, insulin receptor/DAF-2 or mTOR/LET-363, normalizes INS-7 levels and rescues the lifespan of lpd-3 mutants. LPD-3 antagonizes SINH-1, a key mTORC2 component, and decreases expression with age. We propose that LPD-3 acts as a megaprotein brake for organismal aging and that its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways.

Abstract We investigate the exclusive $$J/\psi $$ J / ψ production at the future Electron-ion collider in China by utilizing the eSTARlight event generator. We model the cross-section and kinematics by fitting to the world data of $$J/\psi $$ J / ψ photoproduction. Projected statistical uncertainties on $$J/\psi $$ J / ψ production are based on the design of a central detector, which consists of a tracker and vertex subsystem. The precision of the pseudo-data allows us to probe the near-threshold mechanism, e.g. the re-scattering effect. The significance of the forward amplitudes is discussed as well. The design and optimization of the detector enhance the potential for exploring the near-threshold region and the realm of high four-momentum transfer squared, which is of particular interest on several physics topics.

BACKGROUND: Chinese American family caregivers of persons with dementia experience high rates of psychosocial distress and adverse health outcomes. Due to their immigrant and minority status, they face substantial obstacles to care and support, including stigma and misperception of dementia, limited knowledge and use of welfare and services, and poor social support. Few interventions have been developed or tested for this vulnerable population. OBJECTIVE: This study aims to pilot-test the Wellness Enhancement for Caregivers (WECARE) intervention, a culturally tailored program delivered via WeChat, a social media app highly popular in the Chinese population. The 7-week WECARE was designed specifically for Chinese American dementia caregivers to improve their caregiving skills, reduce stress, and enhance psychosocial well-being. Feasibility, acceptability, and preliminary efficacy of the WECARE were assessed in this pilot. METHODS: A total of 24 Chinese American family caregivers of persons with dementia were recruited for a pre-post 1-arm trial of the WECARE. By subscribing to the WECARE official account, participants received interactive multimedia programs on their WeChat account multiple times a week for 7 weeks. A backend database automatically delivered program components and tracked user activities. Three online group meetings were organized to facilitate social networking. Participants completed a baseline and a follow-up survey. Feasibility was assessed by the follow-up rate and curriculum completion rate; acceptability was assessed by user satisfaction and perceived usefulness of the program; and efficacy was assessed with pre-post differences in 2 primary outcomes of depressive symptoms and caregiving burden. RESULTS: The intervention was completed by 23 participants with a retention rate of 96%. Most of them (n=20, 83%) were older than 50 years and the majority (n=17, 71%) were female. The backend database revealed that the mean curriculum completion rate was 67%. Participants also reported high rates of user satisfaction and perceived usefulness of the intervention and high ratings of weekly programs. The intervention led to significant improvement in participants psychosocial health outcomes; their depressive symptoms reduced from 5.74 to 3.35 with an effect size of -0.89 and caregiving burden decreased from 25.78 to 21.96 with an effect size of -0.48. CONCLUSIONS: This pilot study suggests that WeChat-based WECARE intervention was feasible and acceptable; it also demonstrated initial efficacy in improving psychosocial well-being in Chinese American dementia caregivers. Further research with a control group is needed to assess its efficacy and effectiveness. The study highlights the need for more culturally appropriate mobile health interventions for Chinese American family caregivers of persons with dementia.

Cells adapt to cold by increasing levels of unsaturated phospholipids and membrane fluidity through conserved homeostatic mechanisms. Here we report an exceptionally large and evolutionarily conserved protein LPD-3 in C. elegans that mediates lipid trafficking to confer cold resilience. We identify lpd-3 mutants in a mutagenesis screen for genetic suppressors of the lipid desaturase FAT-7. LPD-3 bridges the endoplasmic reticulum (ER) and plasma membranes (PM), forming a structurally predicted hydrophobic tunnel for lipid trafficking. lpd-3 mutants exhibit abnormal phospholipid distribution, diminished FAT-7 abundance, organismic vulnerability to cold, and are rescued by Lecithin comprising unsaturated phospholipids. Deficient lpd-3 homologues in Zebrafish and mammalian cells cause defects similar to those observed in C. elegans. As mutations in BLTP1, the human orthologue of lpd-3, cause Alkuraya-Kucinskas syndrome, LPD-3 family proteins may serve as evolutionarily conserved highway bridges critical for ER-associated non-vesicular lipid trafficking and resilience to cold stress in eukaryotic cells.

BACKGROUND: Racial/ethnic minority and immigrant caregivers of persons with dementia experience high rates of psychosocial stress and adverse health outcomes. Few culturally tailored mobile health (mHealth) programs were designed for these vulnerable populations. OBJECTIVE: This study reports the development of a culturally tailored mHealth program called Wellness Enhancement for Caregivers (WECARE) to improve caregiving skills, reduce distress, and improve the psychosocial well-being of Chinese American family caregivers of persons with dementia. METHODS: Community-based user-centered design principles were applied in the program development. First, the structure and curriculum of the WECARE program were crafted based on existing evidence-based interventions for caregivers with input from 4 experts. Second, through working closely with 8 stakeholders, we culturally adapted evidence-based programs into multimedia program components. Lastly, 5 target users tested the initial WECARE program; their experience and feedback were used to further refine the program. RESULTS: The resulting WECARE is a 7-week mHealth program delivered via WeChat, a social media app highly popular in Chinese Americans. By subscribing to the official WECARE account, users can receive 6 interactive multimedia articles pushed to their WeChat accounts each week for 7 weeks. The 7 major themes include (1) facts of dementia and caregiving; (2) the enhancement of caregiving skills; (3) effective communication with health care providers, care partners, and family members; (4) problem-solving skills for caregiving stress management; (5) stress reduction and depression prevention; (6) the practice of self-care and health behaviors; and (7) social support and available resources. Users also have the option of joining group chats for peer support. The WECARE program also includes a back-end database that manages intervention delivery and tracks user engagement. CONCLUSIONS: The WECARE program represents one of the first culturally tailored social media-based interventions for Chinese American caregivers of persons with dementia. It demonstrates the use of community-based user-centered design principles in developing an mHealth intervention program in underserved communities. We call for more cultural adaptation and development of mHealth interventions for immigrant and racial/ethnic minority caregivers of persons with dementia.

Objective: To achieve rapid, quantitative and high-throughput detection of aminoglycoside antibiotic residues in pork. Methods: Square-array aligned SERS substrates based on Au nanoflowers （AuNFs） were prepared using PP synthetic paper as a substrate. Pork samples were pre-treated by QuEChERs method and subjected to SRES. Results: Using 4-mercaptobenzoic acid as the SERS probe molecule, the substrate exhibited good homogeneity, SERS enhancement effect, reproducibility and stability. the SERS signal intensities at the characteristic peaks at 475, 619 cm-1 showed good linear relationships with the logarithms of the concentrations of gentamicin sulphate and neomycin sulphate, respectively （R2 of 0.991 6 and 0.990 7, respectively）. The limits of detections （LODs） were as low as 1×10-9, 1×10-8 mol/L, respectively, and were successfully applied to the rapid, quantitative and high-throughput determination of aminoglycoside antibiotics in pork. Conclusion: The experimental method provides an economical, efficient, time-saving and highly sensitive way for the application of SERS technology for the detection of antibiotic residues in real meat samples.

Synapses are specialized cellular junctions essential for communication between neurons. Synapse loss occurs in many neurodegenerative diseases. Harnessing our molecular knowledge of the development and maintenance of synapses, Suzuki et al. present the first comprehensive attempt to use a synthetic protein to bridge the pre- and postsynaptic membranes1. They show that this powerful approach can stimulate the formation of pre- and postsynaptic specializations in vitro, rescue synaptic deficits of mutant mice in vivo, and ameliorate synapse loss and behavioral abnormalities in both Alzheimer's disease and spinal cord injury mouse models.

The structural and functional complexity of multicellular biological systems, such as the brain, are beyond the reach of human design or assembly capabilities. Cells in living organisms may be recruited to construct synthetic materials or structures if treated as anatomically defined compartments for specific chemistry, harnessing biology for the assembly of complex functional structures. By integrating engineered-enzyme targeting and polymer chemistry, we genetically instructed specific living neurons to guide chemical synthesis of electrically functional (conductive or insulating) polymers at the plasma membrane. Electrophysiological and behavioral analyses confirmed that rationally designed, genetically targeted assembly of functional polymers not only preserved neuronal viability but also achieved remodeling of membrane properties and modulated cell type-specific behaviors in freely moving animals. This approach may enable the creation of diverse, complex, and functional structures and materials within living systems.

Cellular differentiation requires both activation of target cell transcriptional programs and repression of non-target cell programs. The Myt1 family of zinc finger transcription factors contributes to fibroblast to neuron reprogramming in vitro. Here, we show that ztf-11 (Zinc-finger Transcription Factor-11), the sole Caenorhabditis elegans Myt1 homolog, is required for neurogenesis in multiple neuronal lineages from previously differentiated epithelial cells, including a neuron generated by a developmental epithelial-to-neuronal transdifferentiation event. ztf-11 is exclusively expressed in all neuronal precursors with remarkable specificity at single-cell resolution. Loss of ztf-11 leads to upregulation of non-neuronal genes and reduced neurogenesis. Ectopic expression of ztf-11 in epidermal lineages is sufficient to produce additional neurons. ZTF-11 functions together with the MuvB corepressor complex to suppress the activation of non-neuronal genes in neurons. These results dovetail with the ability of Myt1l (Myt1-like) to drive neuronal transdifferentiation in vitro in vertebrate systems. Together, we identified an evolutionarily conserved mechanism to specify neuronal cell fate by repressing non-neuronal genes.

Synaptic vesicle and active zone proteins are required for synaptogenesis. The molecular mechanisms for coordinated synthesis of these proteins are not understood. Using forward genetic screens, we identified the conserved THO nuclear export complex (THOC) as an important regulator of presynapse development in C. elegans dopaminergic neurons. In THOC mutants, synaptic messenger RNAs are retained in the nucleus, resulting in dramatic decrease of synaptic protein expression, near complete loss of synapses, and compromised dopamine function. CRE binding protein (CREB) interacts with THOC to mark synaptic transcripts for efficient nuclear export. Deletion of Thoc5, a THOC subunit, in mouse dopaminergic neurons causes severe defects in synapse maintenance and subsequent neuronal death in the substantia nigra compacta. These cellular defects lead to abrogated dopamine release, ataxia, and animal death. Together, our results argue that nuclear export mechanisms can select specific mRNAs and be a rate-limiting step for neuronal differentiation and survival.

Proper morphogenesis of dendrites plays a fundamental role in the establishment of neural circuits. The molecular mechanism by which dendrites grow highly complex branches is not well understood. Here, using the Caenorhabditis elegans PVD neuron, we demonstrate that high-order dendritic branching requires actin polymerization driven by coordinated interactions between two membrane proteins, DMA-1 and HPO-30, with their cytoplasmic interactors, the RacGEF TIAM-1 and the actin nucleation promotion factor WAVE regulatory complex (WRC). The dendrite branching receptor DMA-1 directly binds to the PDZ domain of TIAM-1, while the claudin-like protein HPO-30 directly interacts with the WRC. On dendrites, DMA-1 and HPO-30 form a receptor-associated signaling complex to bring TIAM-1 and the WRC to close proximity, leading to elevated assembly of F-actin needed to drive high-order dendrite branching. The synergistic activation of F-actin assembly by scaffolding distinct actin regulators might represent a general mechanism in promoting complex dendrite arborization.