Nicotinamide mononucleotide adenylyltransferase uses its NAD+ substrate-binding site to chaperone phosphorylated Tau.

Funder: Science and Technology Commission of Shanghai Municipality; FundRef: http://dx.doi.org/10.13039/501100003399Funder: Dr. John T. MacDonald Foundation; FundRef: http://dx.doi.org/10.13039/100010239Tau hyper-phosphorylation and deposition into neurofibrillary tangles have been found in brains of patients with Alzheimer's disease (AD) and other tauopathies. Molecular chaperones are involved in regulating the pathological aggregation of phosphorylated Tau (pTau) and modulating disease progression. Here, we report that nicotinamide mononucleotide adenylyltransferase (NMNAT), a well-known NAD+ synthase, serves as a chaperone of pTau to prevent its amyloid aggregation in vitro as well as mitigate its pathology in a fly tauopathy model. By combining NMR spectroscopy, crystallography, single-molecule and computational approaches, we revealed that NMNAT adopts its enzymatic pocket to specifically bind the phosphorylated sites of pTau, which can be competitively disrupted by the enzymatic substrates of NMNAT. Moreover, we found that NMNAT serves as a co-chaperone of Hsp90 for the specific recognition of pTau over Tau. Our work uncovers a dedicated chaperone of pTau and suggests NMNAT as a key node between NAD+ metabolism and Tau homeostasis in aging and neurodegeneration

Critical thinking disposition of medical students in Anhui Province, China: a cross-sectional investigation

Abstract Objective To investigate the critical thinking disposition of medical undergraduates. Methods This cross-sectional study was performed on 426 students from four majors, including preventive medicine, maternal and children’s health care medicine, health inspection and quarantine, and food quality and safety. The survey was completed in May 2019 using the California Critical Thinking Dispositions Inventory-Chinese version (CTDI-CV). Results A total of 435 questionnaires were distributed and 426 valid questionnaires were collected, with an effective rate of 97.93%. The CTDI-CV overall average score was 262.02 ± 34.74 points indicating an ambivalent disposition in medical undergraduate students. Only one of the subscales (maturity in judgment) had mean scores of 43.35 ± 8.23 indicating the positive disposition of students. Among them, males scored 257.42 ± 35.06 lower than females’ 264.82 ± 34.32, the difference was statistically significant. The target scores of preventive medicine, maternal and children’s health medicine, health inspection and quarantine, and food quality and safety were 265.17 ± 30.10, 260.26 ± 37.05, 271.73 ± 33.55, and 252.11 ± 39.87, respectively. The difference was statistically significant. Among the three dimensions of seeking truth, open mind, and cognitive maturity, the scores of males were 38.26 ± 7.48, 38.78 ± 6.46 and 41.03 ± 8.69, which were lower than females’ 39.97 ± 7.11, 40.48 ± 6.48 and 44.91 ± 7.60, respectively. The scores of food quality and safety students were 37.23 ± 7.08, 36.61 ± 7.41 and 40.57 ± 8.60, respectively, which were lower than the preventive medicine (39.98 ± 7.07, 40.60 ± 5.96 and 44.44 ± 6.97, respectively). Conclusion Most medical students were found to have an ambivalent disposition which meant they were not disposed toward critical thinking. These findings suggested that more effective teaching methods should be taken to facilitate critical thinking disposition and problem-solving ability

Phytophthora effector targets a novel component of small RNA pathway in plants to promote infection

A broad range of parasites rely on the functions of effector proteins to subvert host immune response and facilitate disease development. The notorious Phytophthora pathogens evolved effectors with RNA silencing suppression activity to promote infection in plant hosts. Here we report that the Phytophthora Suppressor of RNA Silencing 1 (PSR1) can bind to an evolutionarily conserved nuclear protein containing the aspartate-glutamate-alanine-histidine-box RNA helicase domain in plants. This protein, designated PSR1-Interacting Protein 1 (PINP1), regulates the accumulation of both microRNAs and endogenous small interfering RNAs in Arabidopsis. A null mutation of PINP1 causes embryonic lethality, and silencing of PINP1 leads to developmental defects and hypersusceptibility to Phytophthora infection. These phenotypes are reminiscent of transgenic plants expressing PSR1, supporting PINP1 as a direct virulence target of PSR1. We further demonstrate that the localization of the Dicer-like 1 protein complex is impaired in the nucleus of PINP1-silenced or PSR1-expressing cells, indicating that PINP1 may facilitate small RNA processing by affecting the assembly of dicing complexes. A similar function of PINP1 homologous genes in development and immunity was also observed in Nicotiana benthamiana. These findings highlight PINP1 as a previously unidentified component of RNA silencing that regulates distinct classes of small RNAs in plants. Importantly, Phytophthora has evolved effectors to target PINP1 in order to promote infection

Specific binding of Hsp27 and phosphorylated Tau mitigates abnormal Tau aggregation-induced pathology

Amyloid aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles is closely associated with Alzheimer’s disease (AD). Several molecular chaperones have been reported to bind Tau and impede its pathological aggregation. Recent findings of elevated levels of Hsp27 in the brains of patients with AD suggested its important role in pTau pathology. However, the molecular mechanism of Hsp27 in pTau aggregation remains poorly understood. Here, we show that Hsp27 partially co-localizes with pTau tangles in the brains of patients with AD. Notably, phosphorylation of Tau by microtubule affinity regulating kinase 2 (MARK2), dramatically enhances the binding affinity of Hsp27 to Tau. Moreover, Hsp27 efficiently prevents pTau fibrillation in vitro and mitigates neuropathology of pTau aggregation in a Drosophila tauopathy model. Further mechanistic study reveals that Hsp27 employs its N-terminal domain to directly interact with multiple phosphorylation sites of pTau for specific binding. Our work provides the structural basis for the specific recognition of Hsp27 to pathogenic pTau, and highlights the important role of Hsp27 in preventing abnormal aggregation and pathology of pTau in AD

Natural variation in a CENTRORADIALIS homolog contributed to cluster fruiting and early maturity in cotton

Abstract Background Plant architecture and the vegetative-reproductive transition have major impacts on the agronomic success of crop plants, but genetic mechanisms underlying these traits in cotton (Gossypium spp.) have not been identified. Results We identify four natural mutations in GoCEN-D t associated with cluster fruiting (cl) and early maturity. The situ hybridization shows that GhCEN is preferentially expressed in cotton shoot apical meristems (SAM) of the main stem and axillary buds. Constitutive GhCEN-Dt overexpression suppresses the transition of the cotton vegetative apex to a reproductive shoot. Silencing GoCEN leads to early flowering and determinate growth, and in tetraploids causes the main stem to terminate in a floral bud, a novel phenotype that exemplifies co-adaptation of polyploid subgenomes and suggests new research and/or crop improvement approaches. Natural cl variations are enriched in cottons adapted to high latitudes with short frost-free periods, indicating that mutants of GoCEN have been strongly selected for early maturity. Conclusion We show that the cotton gene GoCEN-Dt, a homolog of Antirrhinum CENTRORADIALIS, is responsible for determinate growth habit and cluster fruiting. Insight into the genetic control of branch and flower differentiation offers new approaches to develop early maturing cultivars of cotton and other crops with plant architecture appropriate for mechanical harvesting