Deciphering Spatial Protein–Protein Interactions in Brain Using Proximity Labeling

Cellular biomolecular complexes including protein–protein, protein–RNA, and protein–DNA interactions regulate and execute most biological functions. In particular in brain, protein–protein interactions (PPIs) mediate or regulate virtually all nerve cell functions, such as neurotransmission, cell–cell communication, neurogenesis, synaptogenesis, and synaptic plasticity. Perturbations of PPIs in specific subsets of neurons and glia are thought to underly a majority of neurobiological disorders. Therefore, understanding biological functions at a cellular level requires a reasonably complete catalog of all physical interactions between proteins. An enzyme-catalyzed method to biotinylate proximal interacting proteins within 10 to 300 nm of each other is being increasingly used to characterize the spatiotemporal features of complex PPIs in brain. Thus, proximity labeling has emerged recently as a powerful tool to identify proteomes in distinct cell types in brain as well as proteomes and PPIs in structures difficult to isolate, such as the synaptic cleft, axonal projections, or astrocyte–neuron junctions. In this review, we summarize recent advances in proximity labeling methods and their application to neurobiology.     

Effects of maternal depression on family food insecurity

We use data from the Early Childhood Longitudinal Study—Birth Cohort to estimate the effects of maternal depression, a condition that is fairly common and can be severe, on food insecurity, a hardship that has increased substantially in the U.S. Using various model specifications, we find convincing evidence that severe maternal depression increases the likelihood that young children experience food insecurity by 23–79%, with estimates depending on model specification and measures of depression and food insecurity. For household food insecurity, the corresponding estimates are 11–69%. We also find that maternal depression increases reliance on several types of public programs, suggesting that the programs play a buffering role.     

Synthesis and elaboration of N-methylpyrrolidone as an acetamide fragment substitute in bromodomain inhibition

N-Methylpyrrolidone is a solvent molecule which has been shown to compete with acetyl-lysine-containing peptides for binding to bromodomains. From crystallographic studies, it has also been shown to closely mimic the acetamide binding motif in several bromodomains, but has not yet been directly pursued as a fragment in bromodomain inhibition. In this paper, we report the elaboration of N-methylpyrrolidone as a potential lead in fragment-based drug design. Firstly, N-methylpyrrolidone was functionalised to provide points for chemical elaboration. Then, the moiety was incorporated into analogues of the reported bromodomain inhibitor, Olinone. X-ray crystallography revealed that the modified analogues showed comparable binding affinity and structural mimicry to Olinone in the bromodomain binding site.     

Formación de cuidadores en un programa de estimulación cognitiva: efectos diferenciales según el tipo de cuidador

Background and objectivesThe ageing population and the increasing dependency associated with it, makes the caregiver a highly relevant figure nowadays. The present study analyzes the socio-demographic differences between family and professional caregivers and their satisfaction and implication in a training program for caregivers.MethodsThe sample consisted of 59 caregivers of older people (37 were family caregivers and 22 professional caregivers) which received and implemented a caregivers training program in their daily care functions. These caregivers were trained in communication skills and cognitive stimulation strategies so they could use them in their daily care activities with the older adults under their care during a period of 3 months. All the participants were assessed with a socio-demographic questionnaire, 2 questionnaires to analyze their satisfaction with their work and the training received and one questionnaire to analyze their ability to detect and react to memory and behavior problems in the older adults they attended.ResultsThe results showed socio-demographic differences, improvements in satisfaction in family caregivers and a greater commitment in their daily work after the treatment in both groups although these effects could be due to different reasons.ConclusionsThe research shows the benefits of carrying out training programs for caregivers as they significantly increase the quality and satisfaction with caregiving. The study also displays the need to adjust such programs taking into account that the socio-demographic characteristics and training needs are different depending on whether de caregiver is a family member or a professional.     

Characteristics of TP53 germline variants and their correlations with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome in Chinese tumor patients

Li-Fraumeni syndrome (LFS), a rare autosomal-dominant inheritance condition, is associated with a family cancer history as well as pathogenic/likely-pathogenic TP53 germline variants (P/LP TP53 GV). The current clinical methods for detecting LFS are limited. Here, we retrospectively investigate P/LP TP53 GV among Chinese cancer patients by next-generation sequencing and evaluate its relationship with a family cancer history. A total of 270 out of 19,226 cancer patients have TP53 GV, including 53 patients with P/LP TP53 GV. Patients with P/LP TP53 GV are mainly found in male with glioma, lung cancer or sarcoma. The median age of diagnosis for P/LP TP53 GV patients is significantly lower than that of non-P/LP TP53 GV patients (31-years vs. 53-years; P < 0.01). One LFS patient and 3 Li-Fraumeni-like syndrome (LFL) patients are among the 26 followed-up P/LP TP53 GV patients. Among 25 types of P/LP TP53 GV, the highest variant frequencies occurred at codon 175 and 248. p.M237I, p.R158H, p.C238Y and p.C275R, are firstly identified among the Chinese LFS/LFL patients. This study reports the (P/LP) TP53 GV characteristics of Chinese pan-cancer patients. These findings suggest analyzing the P/LP TP53 GV in cancer patients is an effective strategy for identifying cancer predisposition syndrome.     

Yeast Translation Elongation Factor-1A Binds Vacuole-localized Rho1p to Facilitate Membrane Integrity through F-actin Remodeling

Rho GTPases are molecular switches that modulate a variety of cellular processes, most notably those involving actin dynamics. We have previously shown that yeast vacuolar membrane fusion requires re-organization of actin filaments mediated by two Rho GTPases, Rho1p and Cdc42p. Cdc42p initiates actin polymerization to facilitate membrane tethering; Rho1p has a role in the late stages of vacuolar fusion, but its mode of action is unknown. Here, we identified eEF1A as a vacuolar Rho1p-interacting protein. eEF1A (encoded by the TEF1 and TEF2 genes in yeast) is an aminoacyl-tRNA transferase needed during protein translation. eEF1A also has a second function that is independent of translation; it binds and organizes actin filaments into ordered cable structures. Here, we report that eEF1A interacts with Rho1p via a C-terminal subdomain. This interaction occurs predominantly when both proteins are in the GDP-bound state. Therefore, eEF1A is an atypical downstream effector of Rho1p. eEF1A does not promote vacuolar fusion; however, overexpression of the Rho1p-interacting subdomain affects vacuolar morphology. Vacuoles were destabilized and prone to leakage when treated with the eEF1A inhibitor narciclasine. We propose a model whereby eEF1A binds to Rho1p-GDP on the vacuolar membrane; it is released upon Rho1p activation and then bundles actin filaments to stabilize fused vacuoles. Therefore, the Rho1p-eEF1A complex acts to spatially localize a pool of eEF1A to vacuoles where it can readily organize F-actin.     

中国蜘蛛分科检索表

蜘蛛的物种多样性是极其丰富的,但目前只有一小部分的蜘蛛种类被描述。世界上已描述的蜘蛛种类已超过40000种,隶属于110个科。在我们居住的小范围内,可能至少有30个科的数百种蜘蛛。就中国而言,估计可能有40000种以上的蜘蛛种类,但目前也只有大约4000种被命名。本检索表首次列出了中国现有67个蜘蛛科的答定特征．以及不同科之间的相似处和不同处。