Oxidative stress and ion channels in neurodegenerative diseases.

Numerous neurodegenerative diseases result from altered ion channel function and mutations. The intracellular redox status can significantly alter the gating characteristics of ion channels. Abundant neurodegenerative diseases associated with oxidative stress have been documented, including Parkinson's, Alzheimer's, spinocerebellar ataxia, amyotrophic lateral sclerosis, and Huntington's disease. Reactive oxygen and nitrogen species compounds trigger posttranslational alterations that target specific sites within the subunits responsible for channel assembly. These alterations include the adjustment of cysteine residues through redox reactions induced by reactive oxygen species (ROS), nitration, and S-nitrosylation assisted by nitric oxide of tyrosine residues through peroxynitrite. Several ion channels have been directly investigated for their functional responses to oxidizing agents and oxidative stress. This review primarily explores the relationship and potential links between oxidative stress and ion channels in neurodegenerative conditions, such as cerebellar ataxias and Parkinson's disease. The potential correlation between oxidative stress and ion channels could hold promise for developing innovative therapies for common neurodegenerative diseases.

Deep learning-based optic disc classification is affected by optic-disc tilt.

We aimed to determine the effect of optic disc tilt on deep learning-based optic disc classification. A total of 2507 fundus photographs were acquired from 2236 eyes of 1809 subjects (mean age of 46 years; 53% men). Among all photographs, 1010 (40.3%) had tilted optic discs. Image annotation was performed to label pathologic changes of the optic disc (normal, glaucomatous optic disc changes, disc swelling, and disc pallor). Deep learning-based classification modeling was implemented to develop optic-disc appearance classification models with the photographs of all subjects and those with and without tilted optic discs. Regardless of deep learning algorithms, the classification models showed better overall performance when developed based on data from subjects with non-tilted discs (AUC, 0.988 ± 0.002, 0.991 ± 0.003, and 0.986 ± 0.003 for VGG16, VGG19, and DenseNet121, respectively) than when developed based on data with tilted discs (AUC, 0.924 ± 0.046, 0.928 ± 0.017, and 0.935 ± 0.008). In classification of each pathologic change, non-tilted disc models had better sensitivity and specificity than the tilted disc models. The optic disc appearance classification models developed based all-subject data demonstrated lower accuracy in patients with the appearance of tilted discs than in those with non-tilted discs. Our findings suggested the need to identify and adjust for the effect of optic disc tilt on the optic disc classification algorithm in future development.

KCa2 and KCa3.1 Channels in the Airways: A New Therapeutic Target.

K+ channels are involved in many critical functions in lung physiology. Recently, the family of Ca2+-activated K+ channels (KCa) has received more attention, and a massive amount of effort has been devoted to developing selective medications targeting these channels. Within the family of KCa channels, three small-conductance Ca2+-activated K+ (KCa2) channel subtypes, together with the intermediate-conductance KCa3.1 channel, are voltage-independent K+ channels, and they mediate Ca2+-induced membrane hyperpolarization. Many KCa2 channel members are involved in crucial roles in physiological and pathological systems throughout the body. In this article, different subtypes of KCa2 and KCa3.1 channels and their functions in respiratory diseases are discussed. Additionally, the pharmacology of the KCa2 and KCa3.1 channels and the link between these channels and respiratory ciliary regulations will be explained in more detail. In the future, specific modulators for small or intermediate Ca2+-activated K+ channels may offer a unique therapeutic opportunity to treat muco-obstructive lung diseases.

KCa 2.2 (KCNN2): A physiologically and therapeutically important potassium channel.

One group of the K+ ion channels, the small-conductance Ca2+ -activated potassium channels (KCa 2.x, also known as SK channels family), is widely expressed in neurons as well as the heart, endothelial cells, etc. They are named small-conductance Ca2+ -activated potassium channels (SK channels) due to their comparatively low single-channel conductance of about ~10 pS. These channels are insensitive to changes in membrane potential and are activated solely by rises in the intracellular Ca2+ . According to the phylogenic research done on the KCa 2.x channels family, there are three channels' subtypes: KCa 2.1, KCa 2.2, and KCa 2.3, which are encoded by KCNN1, KCNN2, and KCNN3 genes, respectively. The KCa 2.x channels regulate neuronal excitability and responsiveness to synaptic input patterns. KCa 2.x channels inhibit excitatory postsynaptic potentials (EPSPs) in neuronal dendrites and contribute to the medium afterhyperpolarization (mAHP) that follows the action potential bursts. Multiple brain regions, including the hippocampus, express the KCa 2.2 channel encoded by the KCNN2 gene on chromosome 5. Of particular interest, rat cerebellar Purkinje cells express KCa 2.2 channels, which are crucial for various cellular processes during development and maturation. Patients with a loss-of-function of KCNN2 mutations typically exhibit extrapyramidal symptoms, cerebellar ataxia, motor and language developmental delays, and intellectual disabilities. Studies have revealed that autosomal dominant neurodevelopmental movement disorders resembling rodent symptoms are caused by heterozygous loss-of-function mutations, which are most likely to induce KCNN2 haploinsufficiency. The KCa 2.2 channel is a promising drug target for spinocerebellar ataxias (SCAs). SCAs exhibit the dysregulation of firing in cerebellar Purkinje cells which is one of the first signs of pathology. Thus, selective KCa 2.2 modulators are promising potential therapeutics for SCAs.

Development and validation of an ultrahigh-performance liquid chromatography-tandem mass spectrometry method to investigate the plasma pharmacokinetics of a KCa 2.2/KCa 2.3 positive allosteric modulator in mice.

RATIONALE: There is currently no treatment for spinocerebellar ataxias (SCAs), which are a group of genetic disorders that often cause a lack of coordination, difficulty walking, slurred speech, tremors, and eventually death. Activation of KCa 2.2/KCa 2.3 channels reportedly exerts beneficial effects in SCAs. Here, we report the development and validation of an analytical method for quantitating a recently developed positive allosteric modulator of KCa 2.2/KCa 2.3 channels (compound 2q) in mouse plasma. METHODS: Mouse plasma samples (10 µL) containing various concentrations of 2q were subjected to protein precipitation in the presence of a structurally similar internal standard (IS). Subsequently, the analytes were separated on a C18 ultrahigh-performance liquid chromatography column and detected by a tandem mass spectrometer. The method was validated using US Food and Drug Administration (FDA) guidelines. Finally, the validated assay was applied to the measurement of the plasma concentrations of 2q in plasma samples taken from mice after single intravenous doses of 2 mg/kg of 2q, and the pharmacokinetic parameters of 2q were determined. RESULTS: The calibration standards were linear (r2 ≥ 0.99) in the range of 1.56-200 nM of 2q with intra- and inter-run accuracy and precision values within the FDA guidelines. The lower limit of quantitation of the assay was 1.56 nM (0.258 pg on the column). The recoveries of 2q and IS from plasma were >94%, with no appreciable matrix effect. The assay showed no significant carryover, and the plasma samples stored at -80°C or the processed samples stored in the autosampler at 10°C were stable for at least 3 weeks and 36 h, respectively. After intravenous injection, 2q showed a bi-exponential decline pattern in the mouse plasma, with a clearance of 30 mL/min/kg, a terminal volume of distribution of 1.93 mL/kg, and a terminal half-life of 45 min. CONCLUSIONS: The developed assay is suitable for preclinical pharmacokinetic-pharmacodynamic studies of 2q as a potential drug candidate for ataxias.

Spatial analysis of the occurrence of the western conifer seed bug Leptoglossus occidentalis (Heteroptera: Coreidae) in Europe based on multiple environmental variables.

The western conifer seed bug (WCSB) Leptoglossus occidentalis (Heidemann) (Heteroptera: Coreidae) is a pest insect that causes significant losses of coniferous trees worldwide. In this study, we sought to project the potential distribution of the WCSB based on dual CLIMEX modeling and random forest (RF) analysis to obtain basic data for WCSB monitoring strategies. The CLIMEX model, a semimechanistic niche model that responds to climate-based environmental parameters, is a species distribution model that focuses on regional climatic suitability. Given that this model can be used to select areas that are likely to reflect the climatically favorable spread of species, which we initially used CLIMEX to evaluate the potential distribution of the WCSB. The RF algorithm was used to predict the potential occurrence of WCSB and to evaluate the relative importance of environmental variables for WCSB occurrence. Using the RF model, land cover was found to be the most important variable for classifying the presence/pseudo-absence of the WCSB, with an accuracy of 77.1%. Climatic suitability for the WCSB was predicted to be 2.4-fold higher in Southern Europe than in Western Europe, and the WCSB was predicted to occur primarily near coniferous forests. Given that CLIMEX and RF analyses yielded different prediction results, using the findings of both models may compensate for the shortcomings of these models when used independently. Consequently, to ensure greater prediction reliability, we believe that it would be beneficial to base predictions on the combined potential distribution data obtained using both modeling approaches.

Loss-of-function KCa2.2 mutations abolish channel activity.

Small-conductance Ca2+-activated potassium channels subtype 2 (KCa2.2, also called SK2) are operated exclusively by a Ca2+-calmodulin gating mechanism. Heterozygous genetic mutations of KCa2.2 channels have been associated with autosomal dominant neurodevelopmental disorders including cerebellar ataxia and tremor in humans and rodents. Taking advantage of these pathogenic mutations, we performed structure-function studies of the rat KCa2.2 channel. No measurable current was detected from HEK293 cells heterologously expressing these pathogenic KCa2.2 mutants. When coexpressed with the KCa2.2_WT channel, mutations of the pore-lining amino acid residues (I360M, Y362C, G363S, and I389V) and two proline substitutions (L174P and L433P) dominant negatively suppressed and completely abolished the activity of the coexpressed KCa2.2_WT channel. Coexpression of the KCa2.2_I289N and the KCa2.2_WT channels reduced the apparent Ca2+ sensitivity compared with the KCa2.2_WT channel, which was rescued by a KCa2.2 positive modulator.

Channelopathy of small- and intermediate-conductance Ca2+-activated K+ channels.

Small- and intermediate-conductance Ca2+-activated K+ (KCa2.x/KCa3.1 also called SK/IK) channels are gated exclusively by intracellular Ca2+. The Ca2+ binding protein calmodulin confers sub-micromolar Ca2+ sensitivity to the channel-calmodulin complex. The calmodulin C-lobe is constitutively associated with the proximal C-terminus of the channel. Interactions between calmodulin N-lobe and the channel S4-S5 linker are Ca2+-dependent, which subsequently trigger conformational changes in the channel pore and open the gate. KCNN genes encode four subtypes, including KCNN1 for KCa2.1 (SK1), KCNN2 for KCa2.2 (SK2), KCNN3 for KCa2.3 (SK3), and KCNN4 for KCa3.1 (IK). The three KCa2.x channel subtypes are expressed in the central nervous system and the heart. The KCa3.1 subtype is expressed in the erythrocytes and the lymphocytes, among other peripheral tissues. The impact of dysfunctional KCa2.x/KCa3.1 channels on human health has not been well documented. Human loss-of-function KCa2.2 mutations have been linked with neurodevelopmental disorders. Human gain-of-function mutations that increase the apparent Ca2+ sensitivity of KCa2.3 and KCa3.1 channels have been associated with Zimmermann-Laband syndrome and hereditary xerocytosis, respectively. This review article discusses the physiological significance of KCa2.x/KCa3.1 channels, the pathophysiology of the diseases linked with KCa2.x/KCa3.1 mutations, the structure-function relationship of the mutant KCa2.x/KCa3.1 channels, and potential pharmacological therapeutics for the KCa2.x/KCa3.1 channelopathy.

Spatial ensemble modeling for predicting the potential distribution of Lymantria dispar asiatica (Lepidoptera: Erebidae: Lymantriinae) in South Korea.

The spongy moth, Lymantria dispar, is a pest that damages various tree species throughout North America and Eurasia, has recently emerged in South Korea, threatening local forests and landscapes. The establishment of effective countermeasures against this species' outbreak requires predicting its potential distribution with climate change. In this study, we used species distribution models (CLIMEX and MaxEnt) to predict the potential distribution of the spongy moth and identify areas at risk of exposure to a sustained occurrence of the pest by constructing an ensemble map that simultaneously projected the outcomes of the two models. The results showed that the spongy moth could be distributed over the entire country under the current climate, but the number of suitable areas would decrease under a climate change scenario. This study is expected to provide basic data that can predict areas requiring intensive control and monitoring in advance with methodologically improved modeling technique.

Subtype-Selective Positive Modulation of KCa2.3 Channels Increases Cilia Length.

Small-conductance Ca2+-activated potassium (KCa2.x) channels are gated exclusively by intracellular Ca2+. The activation of KCa2.3 channels induces hyperpolarization, which augments Ca2+ signaling in endothelial cells. Cilia are specialized Ca2+ signaling compartments. Here, we identified compound 4 that potentiates human KCa2.3 channels selectively. The subtype selectivity of compound 4 for human KCa2.3 over rat KCa2.2a channels relies on an isoleucine residue in the HA/HB helices. Positive modulation of KCa2.3 channels by compound 4 increased flow-induced Ca2+ signaling and cilia length, while negative modulation by AP14145 reduced flow-induced Ca2+ signaling and cilia length. These findings were corroborated by the increased cilia length due to the expression of Ca2+-hypersensitive KCa2.3_G351D mutant channels and the reduced cilia length resulting from the expression of Ca2+-hyposensitive KCa2.3_I438N channels. Collectively, we were able to associate functions of KCa2.3 channels and cilia, two crucial components in the flow-induced Ca2+ signaling of endothelial cells, with potential implications in vasodilation and ciliopathic hypertension.

Channelopathy-causing mutations in the S45A/S45B and HA/HB helices of KCa2.3 and KCa3.1 channels alter their apparent Ca2+ sensitivity.

Small- and intermediate-conductance Ca2+-activated potassium (KCa2.x and KCa3.1, also called SK and IK) channels are activated exclusively by a Ca2+-calmodulin gating mechanism. Wild-type KCa2.3 channels have a Ca2+ EC50 value of ∼0.3 µM, while the apparent Ca2+ sensitivity of wild-type KCa3.1 channels is ∼0.27 µM. Heterozygous genetic mutations of KCa2.3 channels have been associated with Zimmermann-Laband syndrome and idiopathic noncirrhotic portal hypertension, while KCa3.1 channel mutations were reported in hereditary xerocytosis patients. KCa2.3_S436C and KCa2.3_V450L channels with mutations in the S45A/S45B helices exhibited hypersensitivity to Ca2+. The corresponding mutations in KCa3.1 channels also elevated the apparent Ca2+ sensitivity. KCa3.1_S314P, KCa3.1_A322V and KCa3.1_R352H channels with mutations in the HA/HB helices are hypersensitive to Ca2+, whereas KCa2.3 channels with the equivalent mutations are not. The different effects of the equivalent mutations in the HA/HB helices on the apparent Ca2+ sensitivity of KCa2.3 and KCa3.1 channels may imply distinct modulation of the two channel subtypes by the HA/HB helices. AP14145 reduced the apparent Ca2+ sensitivity of the hypersensitive mutant KCa2.3 channels, suggesting the potential therapeutic usefulness of negative gating modulators.

Subtype-selective positive modulation of KCa 2 channels depends on the HA/HB helices.

BACKGROUND AND PURPOSE: In the activated state of small-conductance Ca2+ -activated potassium (KCa 2) channels, calmodulin interacts with the HA/HB helices and the S4-S5 linker. CyPPA potentiates KCa 2.2a and KCa 2.3 channel activity but not the KCa 2.1 and KCa 3.1 subtypes. EXPERIMENTAL APPROACH: Site-directed mutagenesis, patch-clamp recordings and in silico modelling were utilised to explore the structural determinants for the subtype-selective modulation of KCa 2 channels by CyPPA. KEY RESULTS: Mutating residues in the HA (V420) and HB (K467) helices of KCa 2.2a channels to their equivalent residues in KCa 3.1 channels diminished the potency of CyPPA. CyPPA elicited prominent responses on mutant KCa 3.1 channels with an arginine residue in the HB helix substituted for its equivalent lysine residue in the KCa 2.2a channels (R355K). KCa 2.1 channels harbouring a three-amino-acid insertion upstream of the cognate R438 residues in the HB helix showed no response to CyPPA, whereas the deletion mutant (KCa 2.1_ΔA434/Q435/K436) became sensitive to CyPPA. In molecular dynamics simulations, CyPPA docked between calmodulin C-lobe and the HA/HB helices widens the cytoplasmic gate of KCa 2.2a channels. CONCLUSION AND IMPLICATIONS: Selectivity of CyPPA among KCa 2 and KCa 3.1 channel subtypes relies on the HA/HB helices.

Structure-Activity Relationship Study of Subtype-Selective Positive Modulators of KCa2 Channels.

A series of modified N-cyclohexyl-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methylpyrimidin-4-amine (CyPPA) analogues were synthesized by replacing the cyclohexane moiety with different 4-substituted cyclohexane rings, tyrosine analogues, or mono- and dihalophenyl rings and were subsequently studied for their potentiation of KCa2 channel activity. Among the N-benzene-N-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-4-pyrimidinamine derivatives, halogen decoration at positions 2 and 5 of benzene-substituted 4-pyrimidineamine in compound 2q conferred a ∼10-fold higher potency, while halogen substitution at positions 3 and 4 of benzene-substituted 4-pyrimidineamine in compound 2o conferred a ∼7-fold higher potency on potentiating KCa2.2a channels, compared to that of the parent template CyPPA. Both compounds retained the KCa2.2a/KCa2.3 subtype selectivity. Based on the initial evaluation, compounds 2o and 2q were selected for testing in an electrophysiological model of spinocerebellar ataxia type 2 (SCA2). Both compounds were able to normalize the abnormal firing of Purkinje cells in cerebellar slices from SCA2 mice, suggesting the potential therapeutic usefulness of these compounds for treating symptoms of ataxia.

Differential modulation of SK channel subtypes by phosphorylation.

Small-conductance Ca2+-activated K+ (SK) channels are voltage-independent and are activated by Ca2+ binding to the calmodulin constitutively associated with the channels. Both the pore-forming subunits and the associated calmodulin are subject to phosphorylation. Here, we investigated the modulation of different SK channel subtypes by phosphorylation, using the cultured endothelial cells as a tool. We report that casein kinase 2 (CK2) negatively modulates the apparent Ca2+ sensitivity of SK1 and IK channel subtypes by more than 5-fold, whereas the apparent Ca2+ sensitivity of the SK3 and SK2 subtypes is only reduced by ∼2-fold, when heterologously expressed on the plasma membrane of cultured endothelial cells. The SK2 channel subtype exhibits limited cell surface expression in these cells, partly as a result of the phosphorylation of its C-terminus by cyclic AMP-dependent protein kinase (PKA). SK2 channels expressed on the ER and mitochondria membranes may protect against cell death. This work reveals the subtype-specific modulation of the apparent Ca2+ sensitivity and subcellular localization of SK channels by phosphorylation in cultured endothelial cells.

Hydrophobic interactions between the HA helix and S4-S5 linker modulate apparent Ca2+ sensitivity of SK2 channels.

AIM: Small-conductance Ca2+ -activated potassium (SK) channels are activated exclusively by increases in intracellular Ca2+ that binds to calmodulin constitutively associated with the channel. Wild-type SK2 channels are activated by Ca2+ with an EC50 value of ~0.3 µmol/L. Here, we investigate hydrophobic interactions between the HA helix and the S4-S5 linker as a major determinant of channel apparent Ca2+ sensitivity. METHODS: Site-directed mutagenesis, electrophysiological recordings and molecular dynamic (MD) simulations were utilized. RESULTS: Mutations that decrease hydrophobicity at the HA-S4-S5 interface lead to Ca2+ hyposensitivity of SK2 channels. Mutations that increase hydrophobicity result in hypersensitivity to Ca2+ . The Ca2+ hypersensitivity of the V407F mutant relies on the interaction of the cognate phenylalanine with the S4-S5 linker in the SK2 channel. Replacing the S4-S5 linker of the SK2 channel with the S4-S5 linker of the SK4 channel results in loss of the hypersensitivity caused by V407F. This difference between the S4-S5 linkers of SK2 and SK4 channels can be partially attributed to I295 equivalent to a valine in the SK4 channel. A N293A mutation in the S4-S5 linker also increases hydrophobicity at the HA-S4-S5 interface and elevates the channel apparent Ca2+ sensitivity. The double N293A/V407F mutations generate a highly Ca2+ sensitive channel, with an EC50 of 0.02 µmol/L. The MD simulations of this double-mutant channel revealed a larger channel cytoplasmic gate. CONCLUSION: The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca2+ sensitivity of SK2 channels.

Forecasting Spring Flight of Ips subelongatus (Coleoptera: Curculionidae: Scolytinae) in Japanese larch Larix kaempferi (Pinales: Pinaceae) Forests in the Republic of Korea.

Ips subelongatus is a species of bark beetle experiencing population outbreaks in Korea. In this study, a predictive model and empirical prediction were used to forecast the spring flight of these beetles in Japanese larch forests. The number of beetles caught in pheromone traps was investigated in larch forests thinned in 2009, 2010, 2012, or 2013. Data from the sites thinned in 2009, 2010, or 2012 were used in the predictive model based on a degree-day model that was validated using data from the site thinned in 2013. The lower threshold temperature for flight (LTF) and a thermal sum for the spring flight of I. subelongatus were estimated. The empirical prediction that beetles initiate their flight when daily maximum temperatures reach 16 or 20°C was tested using daily maximum temperature and the beetles caught. The LTF was estimated as 5.97°C, with 42.95 degree-days required for initiation of spring flight. The median flight dates were estimated with a discrepancy from 1 to 3 d by the predictive model. Using the empirical prediction, differences between the day when daily maximum temperature reached 16 or 20°C and flight peak days ranged from 4 to 45 d. These results demonstrate that the predictive model is more suitable than the empirical prediction for predicting the spring flight of I. subelongatus. Overwintering I. subelongatus adults seem to need to gain a determined thermal sum before initiating spring flight rather than merely waiting for the daily maximum temperature to exceed a critical temperature.

Structural basis for broad substrate specificity of UDP-glucose 4-epimerase in the human milk oligosaccharide catabolic pathway of Bifidobacterium longum.

Infant gut-associated bifidobacteria has a metabolic pathway that specifically utilizes lacto-N-biose I (Gal-ß1,3-GlcNAc) and galacto-N-biose (Gal-ß1,3-GalNAc) from human milk and mucin glycans. UDP-glucose 4-epimerase (GalE) from Bifidobacterium longum (bGalE) catalyzes epimerization reactions of UDP-Gal into UDP-Glc and UDP-GalNAc into UDP-GlcNAc with the same level of activity that is required to send galacto-hexoses into glycolysis. Here, we determined the crystal structures of bGalE in three ternary complex forms: NAD+/UDP, NAD+/UDP-GlcNAc, and NAD+/UDP-Glc. The broad specificity of bGalE was explained by structural features of the binding pocket for the N-acetyl or C2 hydroxy group of the substrate. Asn200 is located in a pocket of the C2 group, and its side chain adopts different conformations in the complex structures with UDP-Glc and UDP-GlcNAc. On the other side, Cys299 forms a large pocket for the C5 sugar ring atom. The flexible C2 pocket and the large C5 pocket of bGalE are suitable for accommodating both the hydroxy and N-acetyl groups of the substrate during sugar ring rotation in the catalytic cycle. The substrate specificity and active site structure of bGalE were distinct from those of Esherichia coli GalE but similar to those of human GalE.

Estimating Flight Distance of Platypus koryoensis (Coleoptera: Curculionidae) by Mark-Release-Recapture and Its Validation by Field Observation.

Korean oak wilt (KOW) is vectored by the beetle Platypus koryoensis (Murayama) (Coleoptera: Curculionidae), a native species of Korea, whose dispersal distance is a key factor determining the spread of damage by KOW. To estimate dispersal distance at stand level, we conducted a mark-release-recapture (MRR) experiment and validated its results using an independent data. Sticky traps were attached to the trunks of oak trees up to 48.8 m from the release point. Beetles were marked with different three fluorescent powders by date and released, and the number of recaptured beetles was counted 90 min after release. To validate the flight distance, annual mean dispersal distance of P. koryoensis population was analyzed using GPS coordinates of oak trees with the symptom of KOW recorded in the field from 2012 to 2014 in independent oak stands that have been damaged by KOW since 2012. The beetles were recaptured only on the day they were released, suggesting that the beetles only make one flight. The percentage of recaptured beetles was 6.0 ± 1.6%. The mean dispersal distance was 18.0 ± 1.3 m, and more than 85% of recaptured beetles were caught within 25 m. Annual movement distances in infested stands were 24.1 and 19.9 m from 2012 to 2013 and 2013 to 2014, respectively, similar to the dispersal distance obtained from our MRR experiment. Our results showed that the dispersal distance of P. koryoensis estimated by MRR is a useful process for predicting the spread of areas damaged by KOW.

A family of finite-temperature electronic phase transitions in graphene multilayers.

Suspended Bernal-stacked graphene multilayers up to an unexpectedly large thickness exhibit a broken-symmetry ground state whose origin remains to be understood. We show that a finite-temperature second-order phase transition occurs in multilayers whose critical temperature (T c) increases from 12 kelvins (K) in bilayers to 100 K in heptalayers. A comparison of the data with a phenomenological model inspired by a mean-field approach suggests that the transition is associated with the appearance of a self-consistent valley- and spin-dependent staggered potential that changes sign from one layer to the next, appearing at T c and increasing upon cooling. The systematic evolution with thickness of several measured quantities imposes constraints on any microscopic theory aiming to analyze the nature of electronic correlations in this system.

A V-to-F substitution in SK2 channels causes Ca2+ hypersensitivity and improves locomotion in a C. elegans ALS model.

Small-conductance Ca2+-activated K+ (SK) channels mediate medium afterhyperpolarization in the neurons and play a key role in the regulation of neuronal excitability. SK channels are potential drug targets for ataxia and Amyotrophic Lateral Sclerosis (ALS). SK channels are activated exclusively by the Ca2+-bound calmodulin. Previously, we identified an intrinsically disordered fragment that is essential for the mechanical coupling between Ca2+/calmodulin binding and channel opening. Here, we report that substitution of a valine to phenylalanine (V407F) in the intrinsically disordered fragment caused a ~6 fold increase in the Ca2+ sensitivity of SK2-a channels. This substitution resulted in a novel interaction between the ectopic phenylalanine and M411, which stabilized PIP2-interacting residue K405, and subsequently enhanced Ca2+ sensitivity. Also, equivalent valine to phenylalanine substitutions in SK1 or SK3 channels conferred Ca2+ hypersensitivity. An equivalent phenylalanine substitution in the Caenorhabditis elegans (C. elegans) SK2 ortholog kcnl-2 partially rescued locomotion defects in an existing C. elegans ALS model, in which human SOD1G85R is expressed at high levels in neurons, confirming that this phenylalanine substitution impacts channel function in vivo. This work for the first time provides a critical reagent for future studies: an SK channel that is hypersensitive to Ca2+ with increased activity in vivo.