Amyloidogenic Oligomerization Transforms Drosophila Orb2 from a Translation Repressor to an Activator.

Memories are thought to be formed in response to transient experiences, in part through changes in local protein synthesis at synapses. In Drosophila, the amyloidogenic (prion-like) state of the RNA binding protein Orb2 has been implicated in long-term memory, but how conformational conversion of Orb2 promotes memory formation is unclear. Combining in vitro and in vivo studies, we find that the monomeric form of Orb2 represses translation and removes mRNA poly(A) tails, while the oligomeric form enhances translation and elongates the poly(A) tails and imparts its translational state to the monomer. The CG13928 protein, which binds only to monomeric Orb2, promotes deadenylation, whereas the putative poly(A) binding protein CG4612 promotes oligomeric Orb2-dependent translation. Our data support a model in which monomeric Orb2 keeps target mRNA in a translationally dormant state and experience-dependent conversion to the amyloidogenic state activates translation, resulting in persistent alteration of synaptic activity and stabilization of memory.

Proteome plasticity in response to persistent environmental change.

Temperature is a variable component of the environment, and all organisms must deal with or adapt to temperature change. Acute temperature change activates cellular stress responses, resulting in refolding or removal of damaged proteins. However, how organisms adapt to long-term temperature change remains largely unexplored. Here we report that budding yeast responds to long-term high temperature challenge by switching from chaperone induction to reduction of temperature-sensitive proteins and re-localizing a portion of its proteome. Surprisingly, we also find that many proteins adopt an alternative conformation. Using Fet3p as an example, we find that the temperature-dependent conformational difference is accompanied by distinct thermostability, subcellular localization, and, importantly, cellular functions. We postulate that, in addition to the known mechanisms of adaptation, conformational plasticity allows some polypeptides to acquire new biophysical properties and functions when environmental change endures.

Critical role of amyloid-like oligomers of Drosophila Orb2 in the persistence of memory.

A long-standing question in the study of long-term memory is how a memory trace persists for years when the proteins that initiated the process turn over and disappear within days. Previously, we postulated that self-sustaining amyloidogenic oligomers of cytoplasmic polyadenylation element-binding protein (CPEB) provide a mechanism for the maintenance of activity-dependent synaptic changes and, thus, the persistence of memory. Here, we found that the Drosophila CPEB Orb2 forms amyloid-like oligomers, and oligomers are enriched in the synaptic membrane fraction. Of the two protein isoforms of Orb2, the amyloid-like oligomer formation is dependent on the Orb2A form. A point mutation in the prion-like domain of Orb2A, which reduced amyloid-like oligomerization of Orb2, did not interfere with learning or memory persisting up to 24 hr. However the mutant flies failed to stabilize memory beyond 48 hr. These results support the idea that amyloid-like oligomers of neuronal CPEB are critical for the persistence of long-term memory.

A "Prime and Expand" strategy using the multifunctional fusion proteins to generate memory-like NK cells for cell therapy.

Adoptive cellular therapy (ACT) using memory-like (ML) natural killer (NK) cells, generated through overnight ex vivo activation with IL-12, IL-15, and IL-18, has shown promise for treating hematologic malignancies. We recently reported that a multifunctional fusion molecule, HCW9201, comprising IL-12, IL-15, and IL-18 domains could replace individual cytokines for priming human ML NK cell programming ("Prime" step). However, this approach does not include ex vivo expansion, thereby limiting the ability to test different doses and schedules. Here, we report the design and generation of a multifunctional fusion molecule, HCW9206, consisting of human IL-7, IL-15, and IL-21 cytokines. We observed > 300-fold expansion for HCW9201-primed human NK cells cultured for 14 days with HCW9206 and HCW9101, an IgG1 antibody, recognizing the scaffold domain of HCW9206 ("Expand" step). This expansion was dependent on both HCW9206 cytokines and interactions of the IgG1 mAb with CD16 receptors on NK cells. The resulting "Prime and Expand" ML NK cells exhibited elevated metabolic capacity, stable epigenetic IFNG promoter demethylation, enhanced antitumor activity in vitro and in vivo, and superior persistence in NSG mice. Thus, the "Prime and Expand" strategy represents a simple feeder cell-free approach to streamline manufacturing of clinical-grade ML NK cells to support multidose and off-the-shelf ACT.

Kohn-Sham Density in a Slater Orbital Basis Set.

Finite, atom-centered Slater basis sets are used to determine approximate Kohn-Sham molecular orbitals. This is achieved by minimizing the kinetic energy plus the sum-squared difference between the Kohn-Sham density and the full configuration interaction density. As a result of the finite basis, a weight factor is introduced to balance the two minimization components. Results herein show that this can be done systematically, without sensitive dependence on the choice of scaling factor. In addition, the algorithm is applied to the LiH diatomic for fractional electron counts, where stretching the bond introduces significant reorganization of the electron density. The analysis will show the correct KS orbital structure and reveal the effects of correlation and electron locality on the KS solutions.

The cryptic metabolites and anti-phytopathogenic activities from Nigrospora lacticolonia and Penicillium rubens uncovered by the synergism with host Paris polyphylla, monoculture, and co-culture.

The synergism of host Paris polyphylla medium, the monoculture, and the coculture led to seventeen new metabolites, including eight sesquiterpenes, 1-7 having uncommon structural motifs compared to similar caryophyllene derivatives, 8 with an unprecedented bicyclic framework, and three xyloketals (13-15) with unprecedented frameworks from Nigrospora lacticolonia; one polyketide, 17 with novel bicyclo [2.2.2] undecane skeleton, and five polyketide-terpenoid hybrids, 20 (one novel sulfated), 21-24 from Penicillium rubens. The structures were determined mainly by the NMR, HRESIMS, ECD calculation, and single-crystal X-ray diffraction. Nine cryptic compounds (2-4, 5, 12-15, 17) were produced by the inductions of host medium and the coculture. The compounds 13 from N. lacticolonia, 24-26, 28, 29, and 31 from P. rubens indicated significant antiphytopathogenic activities against N. lacticolonia with MICs at 2-4 µg/mL. Moreover, compounds 22-26, 28, 29, and 31 from P. rubens showed antifungal activities against P. rubens with MICs at 2-4 µg/mL. The synergistic effects of host medium and the coculture can induce the structural diversity of metabolites.

Association of changes in frailty status with the risk of all-cause mortality and cardiovascular death in older people: results from the Chinese Longitudinal Healthy Longevity Survey (CLHLS).

BACKGROUND: Few studies have investigated the association between changes in frailty status and all-cause mortality, inconsistent results were reported. What's more, studies that evaluated the effect of changes of frailty on cardiovascular death in older population are scanty. Therefore, the present study aims to investigate the association of such changes with the risk of all-cause mortality and cardiovascular death in older people, using data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). METHODS: A total of 2805 older participants from two consecutive waves (i.e. 2011 and 2014) of the CLHLS were included for analysis. Based on the changes in frailty status from wave 2011 to wave 2014, participants were categorized into 4 subgroups, including sustained pre/frailty, robustness to pre/frailty, pre/frailty to robustness and sustained robustness. Study outcomes were all-cause mortality and cardiovascular death, and Cox regression analysis examined the association of changes in frailty status with outcomes. RESULTS: From wave 2011 to wave 2014, 33.2% of the participants had frailty transitions. From wave 2014 to wave 2018, there were 952 all-cause mortalities and 170 cardiovascular deaths during a follow-up of 9530.1 person-years, and Kaplan-Meier analysis demonstrated that cumulative incidences of the two outcomes were significantly lower in more robust participants (all log-rank p < 0.001). Compared with the subgroup of sustained pre/frailty, the fully adjusted HRs of all-cause mortality were 0.61 (95% CI: 0.51-0.73, p < 0.001), 0.51 (95% CI: 0.42-0.63, p < 0.001) and 0.41 (0.34-0.49, p < 0.001) in the subgroup of robustness to pre/frailty, the subgroup of pre/frailty to robustness, and the subgroup of sustained robustness, respectively. The fully adjusted HRs of cardiovascular death were 0.79 (95% CI: 0.52-1.19, p = 0.256) in the subgroup of robustness to pre/frailty, 0.45 (95% CI: 0.26-0.76, p = 0.003) in the subgroup of pre/frailty to robustness and 0.51 (0.33-0.78, p = 0.002) in the subgroup of sustained robustness when comparing to the subgroup of sustained pre/frailty, respectively. Stratified analysis and extensive sensitivity analyses revealed similar results. CONCLUSIONS: Frailty is a dynamic process, and improved frailty and remaining robust are significantly associated with lower risk of all-cause mortality and cardiovascular death in older people.

The global burden, risk and inequality of maternal obstructed labor and uterine rupture from 1990 to 2019.

BACKGROUND: Obstructed labor (OL) and uterine rupture (UR) are common obstetric complications. This study explored the burden, risk factors, decomposition, and health inequalities associated with OL and UR to improve global maternal health. METHODS: This was a cross-sectional analysis study including data on OL and UR from the Global Burden of Diseases, and Risk Factors Study (GBD) 2019. The main outcome measures included the number and age-standardized rate (ASR) of incidence, disability-adjusted life years (DALYs), prevalence, and deaths. RESULTS: The global burden of OL and UR has declined, with a decrease in incidence (number in 2019: 9,410,500.87, 95%UI 11,730,030.94 to 7,564,568.91; ASR in 2019: 119.64 per 100,000, 95%UI 149.15 to 96.21; estimated annual percentage change [EAPC] from 1990 to 2019: -1.34, 95% CI -1.41 to -1.27) and prevalence over time. However, DALYs (number in 2019: 999,540.67, 95%UI 1,209,749.35 to 817,352.49; ASR in 2019: 12.92, 95%UI 15.63 to 10.56; EAPC from 1990 to 2019: -0.91, 95% CI -1.26 to -0.57) and deaths remain significant. ASR of DALYs increased for the 10-14 year-old age group (2.01, 95% CI 1.53 to 2.5), the 15-19 year-old age group (0.07, 95% CI -0.47 to 0.61), Andean Latin America (3.47, 95% CI 3.05 to 3.89), and Caribbean (4.16, 95% CI 6 to 4.76). Iron deficiency was identified as a risk factor for OL and UR, and its impact varied across different socio-demographic indices (SDIs). Decomposition analysis showed that population growth primarily contributed to the burden, especially in low SDI regions. Health inequalities were evident, the slope and intercept for DALYs were - 47.95 (95% CI -52.87 to -43.02) and - 29.29 (95% CI -32.95 to -25.63) in 1990, 39.37 (95%CI 36.29 to 42.45) and 24.87 (95%CI 22.56 to 27.18) in 2019. Concentration indices of ASR-DALYs were - 0.2908 in 1990 and - 0.2922 in 2019. CONCLUSION: This study highlights the significant burden of OL and UR and emphasizes the need for continuous efforts to reduce maternal mortality and morbidity. Understanding risk factors and addressing health inequalities are crucial for the development of effective interventions and policies to improve maternal health outcomes globally.

Association of frailty status with overall survival in elderly hypertensive patients: based on the Chinese Longitudinal Healthy Longevity Survey.

BACKGROUND: Hypertension and frailty often coexist in older people. The present study aimed to evaluate the association of frailty status with overall survival in elderly hypertensive patients, using data from the Chinese Longitudinal Healthy Longevity Survey. METHODS: A total of 10,493 elderly hypertensive patients were included in the present study (median age 87.0 years, 58.3% male). Frailty status was assessed according to a 36-item frailty index (FI), which divides elderly individuals into four groups: robustness (FI ≤ 0.10), pre-frailty (0.10 < FI ≤ 0.20), mild-frailty (0.20 < FI ≤ 0.30), and moderate-severe frailty (FI > 0.30). The study outcome was overall survival time. Accelerated failure time model was used to evaluate the association of frailty status with overall survival. RESULTS: During a period of 44,616.6 person-years of follow-up, 7327 (69.8%) participants died. The overall survival time was decreased with the deterioration of frailty status. With the robust group as reference, adjusted time ratios (TRs) were 0.84 (95% confidence interval [CI]: 0.80-0.87) for the pre-frailty group, 0.68 (95% CI: 0.64-0.72) for the mild frailty group, and 0.52 (95% CI: 0.48-0.56) for the moderate-severe frailty group, respectively. In addition, restricted cubic spline analysis revealed a nearly linear relationship between FI and overall survival (p for non-linearity = 0.041), which indicated the overall survival time decreased by 17% with per standard deviation increase in FI (TR = 0.83, 95% CI: 0.82-0.85). Stratified and sensitivity analyses suggested the robustness of the results. CONCLUSIONS: The overall survival time of elderly hypertensive patients decreased with the deterioration of frailty status. Given that frailty is a dynamic and even reversible process, early identification of frailty and active intervention may improve the prognosis of elderly hypertensive patients.

Prognostic value of albumin to fibrinogen ratio for mortality in patients with hypertrophic cardiomyopathy.

BACKGROUND: Albumin to fibrinogen ratio (AFR), a new inflammatory marker, has emerged as a useful indicator to predict adverse outcomes for several diseases. However, whether AFR could be a new useful indicator to predict mortality in HCM patients remains to be evaluated. The study explored the predictive value of AFR for HCM-related death in adult HCM patients. METHODS: A total of 404 HCM patients were eventually enrolled in the study according to the inclusion criteria. Patients were divided into two groups based on the median of baseline AFR. The association between AFR and HCM-related death was analyzed. RESULTS: During a median follow-up of 4.75 years, HCM-related death was observed in 45 patients (11.1%). The incidence of HCM-related death was significantly higher in the low AFR group (log-rank p < 0.001). With the high AFR group as reference, the unadjusted hazard ratio (HR) for HCM-related death was 2.97 (95% confidence interval [CI]: 1.53-5.75, p = 0.001) in the low AFR group, and after adjusting for potentially confounding variables, the adjusted HR for low AFR group was 3.15 (95% CI: 1.56-6.37, p = 0.001). No significant interactions between AFR and other variables were observed in subgroup analysis. Sensitivity analyses in patients with normal albumin and fibrinogen showed similar results. CONCLUSION: AFR is an independent prognostic factor for HCM-related death, adult HCM patients with a lower AFR have a higher risk of HCM-related death.

Neuron-Glial Antigen 2 Participates in Liver Fibrosis via Regulating the Differentiation of Bone Marrow Mesenchymal Stem Cell to Myofibroblast.

Neuron-glial antigen 2 (NG2, gene name: Cspg4) has been characterized as an important factor in many diseases. However, the pathophysiological relevance of NG2 in liver disease specifically regarding bone marrow mesenchymal stem cell (BMSC) differentiation to myofibroblast (MF) and the molecular details remain unknown. Human liver tissues were obtained from patients with different chronic liver diseases, and mouse liver injury models were induced by feeding a methionine-choline-deficient and high-fat diet, carbon tetrachloride administration, or bile duct ligation operation. NG2 expression was increased in human and mouse fibrotic liver and positively correlated with MF markers α-smooth muscle actin (αSMA) and other fibrotic markers in the liver. There was a co-localization between NG2 and αSMA, NG2 and EGFP (BMSC-derived MF) in the fibrotic liver determined by immunofluorescence analysis. In vitro, TGFß1-treated BMSC showed a progressive increase in NG2 levels, which were mainly expressed on the membrane surface. Interestingly, there was a translocation of NG2 from the cell membrane into cytoplasm after the transfection of Cspg4 siRNA in TGFß1-treated BMSC. siRNA-mediated inhibition of Cspg4 abrogated the TGFß1-induced BMSC differentiation to MF. Importantly, inhibition of NG2 in vivo significantly attenuated the extent of liver fibrosis in methionine-choline-deficient and high fat (MCDHF) mice, as demonstrated by the decreased mRNA expression of fibrotic parameters, collagen deposition, serum transaminase levels, liver steatosis and inflammation after the administration of Cspg4 siRNA in MCDHF mice. We identify the positive regulation of NG2 in BMSC differentiation to MF during liver fibrosis, which may provide a promising target for the treatment of liver disease.

Development of a MOF-based SPE method combined with GC-MS for simultaneous determination of alachlor, acetochlor and pretilachlor in field soil.

In this work, a rapid, highly selective, reusable and effective method was developed for simultaneous determination of alachlor, acetochlor and pretilachlor in field soil by GC-MS coupled with MIL-101 based SPE. Main factors affecting the SPE by using MIL-101 were optimized. Moreover, by comparing with the other commercial materials such as C18, PSA and Florisil, the MIL-101(Cr) exhibited excellent adsorption performance, which aimed at amide herbicides. On the other hand, method validation displayed excellent method performance, achieving good linearities with r2 ≥ 0.9921, limits of detection between 0.25-0.45 µg kg-1, enrichment factors ≥ 89, matrix effect in the range of ± 20%, recoveries between 86.3% and 102.4%, and RSD lower than 4.38%. The developed method was successfully applied to the determination of amide herbicides in soil taken from the wheat, corn and soybean field at different depths, where the concentration of alachlor, acetochlor and pretilachlor were in the range of 0.62-8.04 µg kg-1. It was demonstrated that the more depth of soil, the lower of three amide herbicides. This finding could be proposed a novel method to detect the amide herbicides in the agriculture and food industry.

Pest Biological Control: Goals Throughout My Life.

This autobiography documents the life and accomplishments of Li Liying. Born into a poor family in China, she eventually became director of Guangdong Entomological Institute. After graduating middle school (1949), she was admitted to the Agronomy Faculty at Beijing Agricultural University but was shortly after redirected by the Chinese Government to Timiryazev Agricultural Academy, Moscow, Russia. The last year of her study at Timiryazev Agricultural Academy was a pivotal experience. She had the opportunity to conduct fieldwork on cotton pest control and became aware of the harmful practice of aerially spraying highly toxic organophosphates with workers present. She decided to dedicate herself to finding safer alternatives and became a leader in the development of mass-rearing techniques for insects beneficial to agriculture. She traveled to laboratories in several foreign countries to foster collaboration and exchange of ideas among colleagues. She is recognized for her service to entomological societies, teaching at universities, and love of entomology.

On end-point distribution for directed polymers and related problems for randomly forced Burgers equation.

In this paper, we study several problems related to the theory of randomly forced Burgers equation. Our numerical analysis indicates that despite the localization effects the quenched variance of the endpoint distribution for directed polymers in the strong disorder regime grows as the polymer length [Formula: see text]. We also present numerical results in support of the 'one force-one solution' principle. This article is part of the theme issue 'Scaling the turbulence edifice (part 2)'.

New metabolic health definition might not be a reliable predictor for mortality in the nonobese Chinese population.

BACKGROUND: Recently, a new metabolic health (MH) definition was developed from NHANES-III. In the origin study, the definition may stratify mortality risks in people who are overweight or normal weight. We aimed to investigate the association between the new MH definition and all-cause mortality in a nonobese Chinese population. METHODS: The data were collected in 1992 and then again in 2007 from the same group of 1157 participants. The association between the new MH definition and all-cause mortality were analyzed by Cox regression models with overlap weighting according to propensity score (PS) as primary analysis. RESULTS: At baseline in 1992, 920 (79.5%) participants were categorized as MH, and 237 (20.5%) participants were categorized as metabolically unhealthy (MUH) based on this new definition. During a median follow-up of 15 years, all-cause mortality occurred in 17 (1.85%) participants in MH group and 13 (5.49%) in MUH group, respectively. In the crude sample, Kaplan-Meier analysis demonstrated a significantly higher all-cause mortality in MUH group when compared to MH group (log-rank p = 0.002), and MUH was significantly associated with increased all-cause mortality when compared to MH with HR at 3.04 (95% CI: 1.47-6.25, p = 0.003). However, Kaplan-Meier analysis with overlap weighting showed that the cumulative incidence of all-cause mortality was not significantly different between MH and MUH groups (adjusted p = 0.589). Furthermore, in the primary multivariable Cox analysis with overlap weighting, adjusted HR for all-cause mortality was 1.42 (95% CI: 0.49-4.17, p = 0.519) in MUH group in reference to MH group. Other additional PS analyses also showed the incidence of all-cause mortality was not significantly different between the two groups. CONCLUSION: The new MH definition may be not appropriate for mortality risk stratification in non-obese Chinese people. Further investigations are needed.

circRNAs and their relationship with breast cancer: a review.

BACKGROUND: Recently, an increasing number of studies have been conducted on circular RNAs (circRNAs) that have demonstrated their different roles in a variety of biological processes. Moreover, a large number of circRNAs have been shown to be involved in the occurrence and development of breast cancer (BC). MAIN BODY: Both functional and mechanistic experiments have shown that circular RNAs (circRNAs) can act as competing endogenous RNAs by sponging miRNAs, encoding proteins, and regulating parental genes. In doing so, circRNAs modulate the proliferation, migration, apoptosis, and invasion of BC cells in vitro as well as tumor growth and metastasis in vivo. Moreover, scores of circRNAs have been demonstrated to be related to clinicopathological features, prognosis, and treatment sensitivity in patients with BC; many circRNAs have shown potential as biomarkers for diagnosis, drug sensitivity, and prognosis prediction. Furthermore, researchers have focused on circRNAs as potential therapeutic targets. CONCLUSION: In this review, we briefly summarize the functions and categories of circRNAs, their different roles in BC, and recent research and therapeutic progress related to circRNAs.

Sphingosine 1-phosphate/microRNA-1249-5p/MCP-1 axis is involved in macrophage-associated inflammation in fatty liver injury in mice.

Monocyte chemotactic protein-1 (MCP-1) is one of the most representative inflammatory cytokines, and has been proved to be markedly increased in injured liver and sphingosine 1-phosphate (S1P)-treated macrophages. However, microRNAs (miRNAs) targeting MCP-1 and the role of miRNA/MCP-1 axis in S1P-mediated liver inflammation remain largely unknown. Here, we demonstrate that MCP-1 expression is increased in the liver and isolated liver macrophages of MCDHF mice. Moreover, there is a positive correlation between the hepatic levels of S1P and MCP-1. We then predict miRNAs targeting MCP-1 by bioinformatics analysis and select miRNA-1249-5p (miR-1249-5p) from the intersection of TargetScan database and downregulated miRNAs in the injured liver. S1P significantly upregulates the expression of MCP-1 and decreases miR-1249-5p expression in macrophages. MiR-1249-5p directly targets 3'-UTR of MCP-1 and negatively regulates its expression in S1P-treated macrophages. Administration of miR-1249-5p agomir decreases hepatic MCP-1 levels and attenuates liver inflammation in MCDHF mice. Protein-protein interaction network by STRING displays that S1P system is closely associated with MCP-1/CCR2 axis in the network of inflammation. In conclusion, we characterize the vital role of miR-1249-5p in negatively regulating MCP-1 expression in vitro and in vivo, which may open new perspectives for pharmacological treatment of liver disease.

Neutrophil recruitment mediated by sphingosine 1-phosphate (S1P)/S1P receptors during chronic liver injury.

Excessive neutrophils are recruited to damaged tissue and cause collateral injury under chronic inflammatory conditions. Sphingosine 1-phosphate (S1P) modulates kinds of physiological and pathological actions by inducing recruitment of various cell types through S1P receptors (S1PRs). This study aimed to detect the S1P/S1PRs-mediated effects on neutrophil recruitment during chronic liver inflammation. In present study, increased neutrophils originated from bone marrow (BM) were detected in liver tissue of BDL-treated mice. Hepatic sphingosine kinase 1 (SphK, S1P rate-limiting enzyme) or S1P levels positively correlated with neutrophil marker expression in liver of mice and patients. In vitro, expression of S1PR1, S1PR2 and S1PR3 were detected in both mouse BM neutrophils and differentiated human neutrophil-like (dHL60) cells. S1P powerfully boosted the migration and cytoskeletal remodeling of BM neutrophils through S1PR1 or S1PR2. Different from BM neutrophils, the migration and cytoskeletal remodeling of dHL60 cells were mediated by S1PR2 or S1PR3. S1PR2 blockade obviously attenuates neutrophil infiltration in bile duct ligation (BDL)-induced mouse liver injury. In conclusion, S1P/S1PRs system plays a pivotal role in neutrophil recruitment.

Both HuR and miR-29s regulate expression of CB1 involved in infiltration of bone marrow monocyte/macrophage in chronic liver injury.

Bone marrow-derived monocytes/macrophages (BMMs) play a vital role in liver inflammation and fibrogenesis. Cannabinoid receptor 1 (CB1) mediates the recruitment of BMMs into the injured liver. In this study, we revealed the molecular mechanisms under CB1-mediated BMM infiltration. Carbon tetrachloride (CCl4 ) was employed to induce mouse liver injury. In vivo, human antigen R (HuR) was upregulated in macrophages of injured liver. HuR messenger RNA (mRNA) expression was positively correlated with CB1 and F4/80 mRNA expression. Furthermore, we detected the binding between HuR and CB1 mRNA in CCl4 -treated livers. In vitro, HuR modulated arachidonyl-2'-chloroethylamide (ACEA, CB1 agonist)-induced BMM migration by regulating CB1 expression. HuR promoted CB1 expression via binding to CB1 mRNA. ACEA promoted the association between HuR and CB1 mRNA via inducing HuR nucleoplasmic transport. In the cytoplasm, HuR competed with the miR-29 family to improve CB1 expression and BMM migration. In conclusion, our results prove that HuR regulates CB1 expression and influences ACEA-induced BMM migration by competing with miR-29 family.

Molecular Basis of Orb2 Amyloidogenesis and Blockade of Memory Consolidation.

Amyloids are ordered protein aggregates that are typically associated with neurodegenerative diseases and cognitive impairment. By contrast, the amyloid-like state of the neuronal RNA binding protein Orb2 in Drosophila was recently implicated in memory consolidation, but it remains unclear what features of this functional amyloid-like protein give rise to such diametrically opposed behaviour. Here, using an array of biophysical, cell biological and behavioural assays we have characterized the structural features of Orb2 from the monomer to the amyloid state. Surprisingly, we find that Orb2 shares many structural traits with pathological amyloids, including the intermediate toxic oligomeric species, which can be sequestered in vivo in hetero-oligomers by pathological amyloids. However, unlike pathological amyloids, Orb2 rapidly forms amyloids and its toxic intermediates are extremely transient, indicating that kinetic parameters differentiate this functional amyloid from pathological amyloids. We also observed that a well-known anti-amyloidogenic peptide interferes with long-term memory in Drosophila. These results provide structural insights into how the amyloid-like state of the Orb2 protein can stabilize memory and be nontoxic. They also provide insight into how amyloid-based diseases may affect memory processes.