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Microsatellite repeat expansions within genes contribute to a number of neurological diseases1,2. The accumulation of toxic proteins and RNA molecules with repetitive sequences, and/or sequestration of RNA-binding proteins by RNA molecules containing expanded repeats are thought to be important contributors to disease aetiology3-9. Here we reveal that the adenosine in CAG repeat RNA can be methylated to N1-methyladenosine (m1A) by TRMT61A, and that m1A can be demethylated by ALKBH3. We also observed that the m1A/adenosine ratio in CAG repeat RNA increases with repeat length, which is attributed to diminished expression of ALKBH3 elicited by the repeat RNA. Additionally, TDP-43 binds directly and strongly with m1A in RNA, which stimulates the cytoplasmic mis-localization and formation of gel-like aggregates of TDP-43, resembling the observations made for the protein in neurological diseases. Moreover, m1A in CAG repeat RNA contributes to CAG repeat expansion-induced neurodegeneration in Caenorhabditis elegans and Drosophila. In sum, our study offers a new paradigm of the mechanism through which nucleotide repeat expansion contributes to neurological diseases and reveals a novel pathological function of m1A in RNA. These findings may provide an important mechanistic basis for therapeutic intervention in neurodegenerative diseases emanating from CAG repeat expansion.

Objective: The objective of this study is to investigate the heavy metal content in sediment and various organs of Hunan lotus seed in a planting area, as well as to explore the characteristics of heavy metal accumulation and transfer in Hunan lotus seed. Methods: A typical planting area in Hunan Province was selected for this research. The contents of Cd, Cr, Pb, Ni, Cu, Zn and Mn were measured using an inductively coupled plasma emission spectrometer. The bioconcentration factor （BCF） and transfer factor （TF） were used to evaluate the heavy metal accumulation and transfer ability of Hunan lotus seed. Results: The average content of Cd, Cr, Pb, Ni, Cu, Zn, and Mn in the sediment were 0.73, 176.28, 40.48, 27.61, 28.07, 95.57 and 311.68 mg/kg, respectively. Compared with the limit values of NY/T 391—2021, the exceeding rates of Cd, Cr, and Pb content are 100%, 75%, and 10%, respectively. The highest concentrations and contents of these 7 heavy metals were Cd, Cu and Zn in the lotus core, Cr and Pb in the root, Ni in the lotus-seed kernel and Mn in the leaves, with an average content of 0.20, 13.64, 78.58, 14.66, 2.23, 1.11 and 924.03 mg/kg, respectively. The BCFMn values for both stems and leaves exceeded 1. The TFCu values for all organs were greater than 1. Conclusion: This study reveals that there is serious pollution from Cd within the study area. The content of heavy metals in different organs of Hunan lotus seed is different. Lotus stems and leaves has strong enrichment of Mn, and Cu had strong transfer ability in Hunan lotus seed.

Voltage-gated sodium channels located in axon initial segments (AIS) trigger action potentials (AP) and play pivotal roles in the excitability of cortical pyramidal neurons. The differential electrophysiological properties and distributions of NaV1.2 and NaV1.6 channels lead to distinct contributions to AP initiation and propagation. While NaV1.6 at the distal AIS promotes AP initiation and forward propagation, NaV1.2 at the proximal AIS promotes the backpropagation of APs to the soma. Here, we show the small ubiquitin-like modifier (SUMO) pathway modulates Na+ channels at the AIS to increase neuronal gain and the speed of backpropagation. Since SUMO does not affect NaV1.6, these effects were attributed to SUMOylation of NaV1.2. Moreover, SUMO effects were absent in a mouse engineered to express NaV1.2-Lys38Gln channels that lack the site for SUMO linkage. Thus, SUMOylation of NaV1.2 exclusively controls INaP generation and AP backpropagation, thereby playing a prominent role in synaptic integration and plasticity.

The human voltage-gated proton channel (hHv1) is important for control of intracellular pH. We designed C6, a specific peptide inhibitor of hHv1, to evaluate the roles of the channel in sperm capacitation and in the inflammatory immune response of neutrophils [R. Zhao et al., Proc. Natl. Acad. Sci. U.S.A. 115, E11847–E11856 (2018)]. One C6 binds with nanomolar affinity to each of the two S3–S4 voltage-sensor loops in hHv1 in cooperative fashion so that C6-bound channels require greater depolarization to open and do so more slowly. As depolarization drives hHv1 sensors outwardly, C6 affinity decreases, and inhibition is partial. Here, we identified residues essential to C6–hHv1 binding by scanning mutagenesis, five in the hHv1 S3–S4 loops and seven on C6. A structural model of the C6–hHv1 complex was then generated by molecular dynamics simulations and validated by mutant-cycle analysis. Guided by this model, we created a bivalent C6 peptide (C62) that binds simultaneously to both hHv1 subunits and fully inhibits current with picomolar affinity. The results help delineate the structural basis for C6 state-dependent inhibition, support an anionic lipid-mediated binding mechanism, and offer molecular insight into the effectiveness of engineered C6 as a therapeutic agent or lead.

Parkinson’s disease (PD) is the second most common neurodegenerative disease with complex pathogenesis. Although HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) is upregulated in PD, its exact role in HOTAIRM1 is seldom reported. The purpose of this study is to research the effect of HOTAIRM1 on 1-methyl-4-phenylpyridonium (MPP+)-induced cytotoxicity and oxidative stress in SH-SY5Y cells.

Study objectiveTo determine the effect of dexmedetomidine on acute kidney injury (AKI) following endovascular aortic repair (EVAR) for Stanford type B aortic dissection (TBAD).DesignRandomized, double-blind, placebo-controlled, pilot study.SettingUniversity Hospital.Patients102 TBAD patients undergoing EVAR procedures were enrolled. Patients with dissection involving aortic arch or renal artery were excluded.InterventionsPatients were randomly assigned, in a 1:1 ratio, to a dexmedetomidine group (intravenous dexmedetomidine 0.4 μg/kg/h immediately after anesthesia induction and 0.1 μg/kg/h after extubation, which was maintained until 24 h) or a normal saline control group.MeasurementsThe primary outcome was the incidence of AKI within the first two days after surgery, based on the Acute Kidney Injury Network (AKIN) criteria. The secondary outcomes included serum cystatin C and estimated glomerular filtration rate on postoperative days 1, 2, and 7, and in-hospital need for renal replacement therapy (RRT). Long-term outcomes included RRT and all-cause mortality.Main resultsNinety-eight patients completed the study (dexmedetomidine, n = 48; control, n = 50). AKIN stage 1 AKI occurred in 3/48 (6.3%) patients receiving dexmedetomidine, compared with 11/50 (22%) patients receiving normal saline (odds ratio = 0.24, 95% CI: 0.07 to 0.89, P = 0.041). This difference remained significant after adjusting for baseline covariates (adjusted odds ratio = 0.21, 95% CI: 0.05 to 0.84; P = 0.028). Dexmedetomidine led to a lower serum cystatin C on postoperative day 1 (median [IQR] mg/L: 1.31 [1.02-1.72] vs. 1.58 [1.28-1.96]). There were no between-group differences in other secondary or long-term outcomes. During the follow-up (median = 28.4 months), 1 patient in the dexmedetomidine group and 3 patients in the control group required RRT.ConclusionsDexmedetomidine reduced the incidence of AKI in TBAD patients after EVAR procedures. The long-term benefits of dexmedetomidine in this patient population warrant further investigation.Trial registrationChiCTR-IPR-15006372.

Human voltage-gated proton channels (hHv1) extrude protons from cells to compensate for charge and osmotic imbalances due metabolism, normalizing intracellular pH and regulating protein function. Human albumin (Alb), present at various levels throughout the body, regulates oncotic pressure and transports ligands. Here, we report Alb is required to activate hHv1 in sperm and neutrophils. Dose-response studies reveal the concentration of Alb in semen is too low to activate hHv1 in sperm whereas the higher level in uterine fluid yields proton efflux, allowing capacitation, the acrosomal reaction, and oocyte fertilization. Likewise, Alb activation of hHv1 in neutrophils is required to sustain production and release of reactive oxygen species during the immune respiratory burst. One Alb binds to both voltage sensor domains (VSDs) in hHv1, enhancing open probability and increasing proton current. A computational model of the Alb-hHv1 complex, validated by experiments, identifies two sites in Alb domain II that interact with the VSDs, suggesting an electrostatic gating modification mechanism favoring the active "up" sensor conformation. This report shows how sperm are triggered to fertilize, resolving how hHv1 opens at negative membrane potentials in sperm, and describes a role for Alb in physiology that will operate in the many tissues expressing hHv1.