Permanent Ocean, Land, Permanent Ice, and Transient Sea Ice—is used to investigate the influence of surface type on low‐level Arctic cloud liquid water path (LWP) seasonality. The results show significant variations in the Arctic low‐level cloud LWP by surface type linked to differences in thermodynamic state. Subdividing the Transient Ice region  by melt/freeze season onset dates reveals a complex influence of sea ice variations on low cloud LWP seasonality. We find that lower tropospheric stability is the primary factor affecting the seasonality of cloud LWP. Our results suggest that variations in sea ice melt/freeze onset have a significant influence on the seasonality of low‐level cloud LWP by modulating the lower tropospheric thermal structure and not by modifying the surface evaporation rate in late spring and midsummer. We find no significant dependence of the May low‐level cloud LWP peak on the melt/freeze onset dates, whereas and September/October low‐level cloud LWP maximum shifts later in the season for earlier melt/later freeze onset regions. The Arctic low cloud LWP seasonality is controlled by several surface‐atmosphere interaction processes; the importance of each varies seasonally due to the thermodynamic properties of sea ice. Our results demonstrate that when analyzing Arctic cloud‐sea ice interactions, a seasonal perspective is critical.Using CALIPSO‐CloudSat‐Clouds and the Earth's Radiant Energy System‐Moderate Resolution Imaging Spectrometer data set, this study documents the seasonal variation of sea ice, cloud, and atmospheric properties in the Arctic (70°N–82°N) for 2007–2010. A surface‐type stratification—consisting  The Arctic low cloud liquid water path seasonal cycle exhibits a surface‐type dependenceSea ice affects liquid water path seasonality by modulating lower tropospheric stabilityRegions of earlier sea ice melt and later freeze onset show a larger cloud liquid water path variance Note that the sum of area percentage of ocean and sea ice  for a grid box can vary because of the limited sampling. Each 2° Land, which is consistent with the terrain boundary  A Transient Ice grid points possess a pronounced seasonal variation in SIC. Next, we consider spatial patterns of the onset date of sea ice melt and freeze to characterize the differences in the seasonal variations of Arctic sea ice coverage and their potential relationship with Arctic low‐level clouds. We define the onset date of sea ice melt at a grid point as the day after which its SIC shows a negative daily tendency for more than 80% of the time with a total decrease of SIC exceeding 15% within a 1‐month period. This condition guarantees a significant change in sea ice cover around the melt onset dates and also eliminates the influence of sea ice regrowth after a short‐lived melting event or due to divergence/convergence of the ice pack. Similarly, the onset date of sea ice freeze is defined as the day after which SIC shows an increasing daily tendency for more than 80% of the time with the total increase of SIC exceeding 15% within a 1‐month period.By definition, only Note that the melt and freeze onset dates defined in this study differ slightly from previous studies  of the SIC within a target region. Figures Transient Ice grid points. It is seen that regardless of an early or late sea ice melt onset date, most regions have high values of SIC (above 80%) before melt onset and gradually evolve toward a nearly ice‐free state (below 15%) after onset, confirming the effectiveness of our onset date detection methods. It can also been seen that the temporal evolution from sea ice freeze onset to an ice‐covered state is faster (~1–2 months) than that from sea ice melt onset to the minimum sea ice state (~2–3 months), consistent with results shown in Figure We calculated the probability density function (PDF) of 4‐year SIC data over aster ~1– months t4Transient Ice region  but larger than Land (0.15 kg/m2) and Permanent Ice (0.16 kg/m2). In cold months (November through April), low‐level cloud LWP varies little across surface types; Land, Permanent Ice, and Transient Ice surfaces all show a small LWP and weak spatial variability (a narrow width in the PDF). Similar findings have been reported using ground observed and satellite passive radiometer retrieval data  mean greater than 0.2 kg/m2 and a noticeable spatial variability. The temporal evolution of the low‐level cloud LWP over Permanent Ocean shows a continuous increase in the first half of the year (January‐June) and a decrease in the remainder of the year. Other surface types exhibit a strong increase in low‐level cloud LWP during warm months (May through September) and a gradual decrease in LWP after September‐October. It is noted that the Permanent Ice and Transient Ice surfaces show a unique midsummer evolution of LWP, i.e., decreasing from mid‐May to the end of June and then increasing again through mid‐August. This local minimum in the LWP around July is weaker over Transient Ice than over Permanent Ice.Table Transient Ice regions with different sea ice melt  indicate a higher likelihood of the specific LWP values relative to the LWP PDF of all Transient Ice grid points  play a dominant role in the seasonal cycle of LWP? Are these factors modified by the nature of underlying surface?According to previous studies  yet substantial moisture above Permanent Ocean (about 3 cm). Permanent Ocean exhibits the strongest evaporation rate in winter, whereas the other surface types have an evaporation rate close‐to‐zero  and air temperature at 700 hPa (T700hPa), over different surface types. LTS is defined as the difference between the potential temperature at 700 hPa and the surface  and resembles Permanent Ocean in warm months (May‐September). These LTS seasonal variations agree well with the annual cycle of LTS over the Beaufort‐Chukchi Seas seasonal ice zone reported by Liu and Schweiger  and from fall to winter (during freeze season), making them distinctly different from Land or Permanent Ocean. In light of the aforementioned discussions, we expect the seasonal variations of LTS over different surface types to be influenced mainly by the thermodynamic properties of the surface.To assess which temperature, surface skin or atmospheric, controls the seasonal variation of LTS over different surface types, we examine the seasonal evolution of Ts Figure  and T700a Figure . It is ePermanent Ocean surface above freezing  correspond to the seasonal maxima in LWP. The time shift of the autumn LWP decreases toward an earlier/later time over regions where sea ice freeze earlier/later is consistent with the time shift of autumn LTS increase. The inverse relationship between LTS and LWP over Permanent Ice and most of the Transient Ice regions and the correspondence between the seasonal LTS minima and LWP maximum suggest that LTS plays an important role in controlling the seasonality of LWP. Low‐level Arctic clouds in Permanent Ice and Transient Ice regions tend to be decoupled from the surface during the warm season  Land, (iii) Permanent Ice where is covered by sea ice pack all the year round, and (iv) Transient Ice where there is a significant seasonal change in sea ice coverage, namely, covered by sea ice in winter but open water in summer. In addition, we further subdivide the Transient Ice region into four subregions according to sea ice melt/freeze onset dates to explore the influence of sea ice on the Arctic low cloud LWP.This study documents the seasonal variation of sea ice, clouds, and the related atmospheric properties in the Arctic region (70–82°N) for the period 2007–2010. We use a surface‐type stratification to investigate the influence of surface type on the seasonality of Arctic low‐level cloud LWP. Four surface types are defined: (i) Permanent Ocean due to cold temperatures and a lack of water vapor.The annual mean and seasonality of low‐level cloud LWP shows a strong dependence on surface type. Regions with smaller sea ice coverage have a higher surface skin temperature in warm months, stronger evaporation, more lower tropospheric moisture, and weaker LTS; conditions that promote larger low‐level cloud LWP. Regional differences in the annual mean cloud LWP are also affected by other factors, such as air and surface temperature and atmospheric advection from lower latitudes. The seasonal variation of LWP shows a large contrast among different surface types in warm months, whereas in cold months, LWP is close to zero over all surface types except Permanent Ice and Transient Ice regions exhibit a low‐level cloud LWP seasonal cycle with several distinguishing characteristics: (1) small LWP values during cold months, (2) a primary and secondary peak in May and September/October, and (3) a midsummer local minimum value. Stratifying the Transient Ice regions by sea ice melt and freeze onset dates provides several key results: (1) The timing of the May peak in the seasonal variation of low‐level cloud LWP is independent of sea ice melt onset timing; (2) the mid‐summer low‐level areal‐mean cloud LWP values and the width of the PDF are sensitive to melt onset where earlier sea ice melt regions possess larger low‐level cloud LWP with larger spatial variance; and (3) the timing of the autumn LWP peak is sensitive to sea ice freeze onset. Our analysis indicates a complex but close relationship between the sea ice and the seasonality of low‐level cloud LWP.The Permanent Ice and Transient Ice region, and (3) variations in LTS explain the warm season differences in the variation of LWP with respect to sea ice melt onset and freeze. Variations in evaporation rate have a smaller contribution than LTS because evaporation rate differences do not contribute to the May LWP maximum and evaporation rate does not explain the midsummer differences in LWP over the regions stratified by sea ice melt onset. Enhanced evaporation rate shows some correspondence to the Autumn LWP maximum in regions except Permanent Ocean. However, the evaporation changes linked to variations in underlying surface makes a minor contribution to the seasonal cycle of the water vapor in the lower troposphere. The seasonal structure of the lower tropospheric water vapor shows little contrast by surface type and does not align with the seasonality of low‐level cloud LWP and thus cannot be a primary controlling factor to its evolution.Variations in LTS is found to be the primary factor controlling the seasonality of cloud LWP and timing of the key turning points of the annual cycle of low‐level cloud LWP. The three primary pieces of evidence include (1) the significant correlation between LTS and LWP across all Arctic regions, (2) the correspondence between the seasonality of LWP and LTS such that the seasonal minima in LTS (May and October) correspond to the seasonal maxima in LWP over 700hPa is much weaker.Despite ruling out the influence of sea ice cover via modifying the surface evaporation, surface characteristics and sea ice melt/freeze onset influence the seasonality of low‐level cloud LWP by modulating the seasonality of LTS and the lower tropospheric thermal structure. The large contrast in the thermal inertia between ocean, sea ice, and land leads to differences in the seasonal variations of surface temperature, especially for the transient ice regions in the transitions between winter to summer (during melt season) and from fall to winter (during freeze season), while the contrast in TPermanent Ice and Transient Ice are explained by the thermodynamic characteristics of the surface and its changes. The May LTS minimum results from the rapid surface skin temperature increase in response to increased solar insolation that results from the low thermal inertia of the ice surface, outpacing the warming in the lower troposphere. The midsummer increase in LTS (which corresponds to a decrease in LWP across Permanent Ice and Transient Ice regions) occurs because the surface temperature becomes constant at 0 °C due to sea ice melt while the air temperature continues to warm. The LTS decrease from late summer to early autumn results from the rapid cooling of the lower troposphere while the high thermal inertia of the water surface maintains a warmer surface skin temperature. The LTS increase in autumn is closely tied to the surface thermal inertia decrease caused by the sea ice freezing. The timing of the LTS increase is highly dependent on the sea ice variation, which explains the significant time shift of autumn LWP decrease over regions with different sea ice freeze onset dates. Therefore, the seasonality of low‐level cloud LWP follows these variations in LTS and is attributed to the thermodynamic characteristics of the surface.The primary features in the seasonality of LTS over The influence of sea ice cover on the probability distribution of cloud LWP, to the best of our knowledge, has not been previously demonstrated. We speculate that the apparent enhancement in the variance in low‐level cloud LWP in midsummer may stem from the conditional availability of surface moisture whereby under specific conditions, the cloud layer can access surface moisture resulting in larger LWP values. Additionally, a surface‐type dependent modulation of surface temperature affecting the thermodynamic structure of the lower troposphere may also play a role.In closing, our results argue that the primary factor controlling the seasonality of low‐level cloud LWP in warm months at different surface types is the variation in lower tropospheric stability controlled by the surface thermodynamic characteristics. The Arctic low cloud LWP seasonality is complex with different processes and atmospheric conditions operating in different months. Taking a seasonal perspective when analyzing Arctic cloud‐sea ice interactions is critical. This refined understanding serves as a useful constraint to assess and improve the representation of the Arctic cloud annual cycle in climate models and increase the fidelity of Arctic climate change projections.Supporting Information S1Click here for additional data file.


N = 90, 11–15 years). Both response and semantic inhibition were associated with counterintuitive science and maths reasoning, when controlling for age, general cognitive ability, and performance in control science and maths trials. Better response inhibition was associated with longer reaction times in counterintuitive trials, while better semantic inhibition was associated with higher accuracy in counterintuitive trials. This novel finding suggests that different aspects of inhibitory control may offer unique contributions to counterintuitive reasoning during adolescence and provides further support for the hypothesis that inhibitory control plays a role in science and maths reasoning.Existing concepts can be a major barrier to learning new counterintuitive concepts that contradict pre-existing experience-based beliefs or misleading perceptual cues. When reasoning about counterintuitive concepts, inhibitory control is thought to enable the suppression of incorrect concepts. This study investigated the association between inhibitory control and counterintuitive science and maths reasoning in adolescents ( The acquisition of abstract concepts reflecting an understanding of how elements in the world relate to one another underpins school-based learning of science and maths . These aInhibitory control, the ability to suppress a prepotent response or irrelevant information, is thought to allow the suppression of naïve theories, incorrect strategies, or misleading perceptual cues during counterintuitive reasoning in science and maths ,12–17. AMost previous research exploring the cognitive processes behind science and maths misconceptions has been performed on children ,16,19–21Inhibitory control has been classified in various ways. Nigg , for exaThe link between science and maths reasoning in general, or counterintuitive reasoning specifically, and inhibitory control has been examined across development using correlational, priming, and neuroimaging studies. Evidence from correlational studies suggests that children with better inhibitory control perform better on science problems requiring counterintuitive reasoning. In the domain of physics, the tubes task had an experimenter drop a ball down one of three opaque tubes that crossed over . Three- In the domain of maths, overlapping strategy use in problem solving is a particular demonstration of the maintenance of multiple concepts and theories over the course of learning, rather than the replacement of old concepts by new concepts. An examination of strategy use in four- and five-year-olds solving maths sums found that even when new, more sophisticated strategies had been learnt, children continued to use old strategies ,41. The A few studies have used priming to probe the role of inhibitory control in counterintuitive maths reasoning. Nine-year-olds performed better on a counterintuitive number conservation trial if they were primed to inhibit through the successful inhibition of an incongruent Stroop trial . Ten-yeaNeuroimaging work on logical and scientific reasoning in adults has consistently shown that the inhibition of pre-existing beliefs, misleading perceptual-biases, and intuitive heuristics during counterintuitive reasoning is associated with the activation of the anterior cingulate cortex and the prefrontal cortex, notably the inferior frontal cortex and dorsolateral prefrontal cortex, thought to reflect the recruitment of greater cognitive control for counterintutive vs. intuitive reasoning ,17,46–49The research summarised above suggests that naïve theories, prior knowledge, and misleading perceptual cues are inhibited during successful science and maths reasoning. Adolescents are faced with increasingly complex, and sometimes counterintuitive, science and maths concepts through compulsory school curricula, while their inhibitory control abilities are still developing. The current study aimed to investigate the association between inhibitory control and counterintuitive science and maths reasoning in 11- to 15-year-olds.A novel science and maths misconceptions task was designed to measure adolescents’ ability to give the correct  answer when faced with problems known to be associated with misconceptions. Only misconceptions relevant to the curriculum for 11- to 14-year-olds (Key Stage 3 for England) were included, based on consultation with curricula ,24 and sBoth response and semantic inhibition were measured to investigate the possible unique influence of these aspects of inhibitory control. Response inhibition was measured using a simple and complex Go/No-Go adapted from Watanabe et al. , to inveIt was hypothesised that better semantic inhibitory control, evidenced by less interference effect on accuracy and reaction time (RT) in the numerical Stroop task, would allow participants to better solve the conflict between their naïve belief or misleading perceptual information and the correct answer, and that they would therefore show more accurate and faster responses on the science and maths misconception problems, relative to non-counterintuitive control problems. It was also hypothesised that better response inhibition, evidenced by higher accuracy in simple and complex No-Go trials, would also be associated with better science and maths misconception performance, by limiting impulsive responses. As science and maths problem solving typically requires the maintenance of some information in working memory, and as misconceptions in particular may elicit competition between, and comparison of, intuitive and counterintuitive responses, it was finally hypothesised that performance in complex No-Go trials would show a greater association with science and maths misconception performance than performance in simple No-Go trials.This project received approval from the Department of Psychological Sciences Ethics Committee, Birkbeck College University of London [reference approval number: 141552].Ninety pupils with no neurological or developmental disorders, from an English secondary school where most students are from minority ethnic heritages, and the proportion of free school meals  is well above average, took part . LettersThe science and maths misconceptions task was administered on a laptop. On each trial, participants read a statement relating to science or maths, and pressed one of two keys to indicate whether they thought the statement was correct or incorrect. There were 48 problem-sets, each addressing one curriculum-related misconception where the intuitive response is incorrect, based on research findings e.g. ,7,54).,54.7,54]Misconception-False problem presented a false statement based on a counterintuitive concept, while a Misconception-True problem presented a true statement based on the same counterintuitive concept. All misconception problems required counterintuitive reasoning; the intuitive response was incorrect. Varying the nature of the statements was necessary to counterbalance left/right answers across the experiment: Including Misconception-False problems only would have led to the correct answer being “Incorrect” on all trials. Note that it was expected that accuracy and RT might be influenced by true or false statement type, since it might be easier to give a correct response when the statement is true.Each problem-set contained four problems . A MiscoControl-False, Control-True)  . EffortsMisconception problems, participants need to inhibit their naïve belief that the weight of objects matters in this situation. The Control problems also refer to the fall of objects, but in this case the concept is that objects fall to the ground if they are not supported. As this is not a misconception participants do not have to inhibit a prior belief. The maths problem-set  and accurately  than those with poorer inhibitory control, who might answer intuitively, or take longer to inhibit the incorrect belief or irrelevant perceptual information.blem-set  refers tMisconception-True/False and Control-True/False problems were matched as well as possible in terms of text and images presented, ensuring all participants saw similar stimuli across conditions, and allowing the comparison of participants’ performance across conditions. See Twenty-six problem-sets were science-based. Biology topics included living organisms, cells, inheritance, genetics, and plants (8 problem-sets). Chemistry topics included pollution, atoms, pure and impure substances, heating, and melting (7 problem-sets). Physics topics included force, the solar system, electricity, gravity, waves, and temperature (11 problem-sets). Maths topics included fractions, decimals, angles, algebra, shape, transformations, statistics, probability, and graphs (22 problem-sets). One hundred and twenty-six problems were accompanied by images  that were sometimes essential for the problem, sometimes provided further explanation, and sometimes simply relevant to keep the task engaging. In all cases the Misconception-False, Misconception-True, Control-False, Control-True). Participants were assigned to a sequence pseudo-randomly, ensuring each age group contained the range of sequences. Stimuli remained on the screen until a response was made, and the task lasted 11 min on average including self-timed breaks every 24 trials. Accuracy and RT were recorded.Two sequences of 96 trials were created by distributing problems such that each sequence contained one misconception trial and one control trial from each problem-set. Two further sequences were created by reversing the presentation order of the original sequences. Each participant thus completed 24 of each of the four problem-set types . For simplicity of reporting, age groups are referred to according to the mean age of the group . Main effects of Age group were followed up with three planned tests assessing differences between 12y and 15y, 13y and 15y, and 14y and 15y, since the greatest differences were anticipated in comparison to the oldest group.Mean RTs are reported for all trials in the science and maths misconceptions task, since RTs for incorrect trials are of interest here, reflecting the time spent to reason about a counterintuitive concept, even if the resulting answer is incorrect. Mean RTs are reported for correct trials only in the inhibitory control tasks . Examination of boxplots across tasks showed outliers, so exclusionary criteria were put in place before analysis commenced. Participants whose mean accuracy or RT was further than ±3.29 standard deviations away from the group mean were excluded from analyses of the task on which they were an outlier, as standardised scores outside that range are cause for concern . Effect N = 87 participants. Two  x two  x two  x four  mixed model repeated measures ANOVAs were performed on accuracy and RT. Three participants were excluded from the simple Go/No-Go task, and two participants were excluded from the complex Go/No-Go tasks  or slow RT , leaving a final asks see . Analysens: 12y: n = 20, 13y: n = 22, 14y: n = 21, 15y: n = 18), leaving a total N = 81. Correlations were run between the variables of interest to examine collinearity and assess associations between measures across the whole sample. Hierarchical multiple regressions investigated whether inhibitory control variables could account for individual differences in science and maths misconception accuracy and RT.Participants excluded from any individual task analysis were also excluded from the regression analyses , RT cost (incongruent minus congruent), congruent accuracy, and congruent RT.Inclusion of separate Go/No-Go and Stroop blocks allowed for investigation of variance explained individually by response and semantic inhibition. Stepwise entry and the inclusion of variables that do not necessarily reflect inhibition (such as Go accuracy or congruent Stroop RT) enabled examination of the possibility that general processing speed or accuracy alone were the most important predictors of performance, rather than inhibition per se.Follow up exploratory regressions were run on science and maths separately, to examine possible discipline-specific effects and to explore whether directions of association were consistent. All follow up models included the control variables and the inhibitory control variables identified in the science and maths combined regressions, using the enter method.In line with the design of this task, participants tended to give the correct answer in control trials, with a mean accuracy of 82.2% , while tA two  x two  x two  x four  mixed model repeated measures ANOVA performed on accuracy showed main effects of Trial type and Statement type, with greater accuracy in control compared to misconception trials, and true compared to false statements . There wF = 11.33, p = .001, ηp2 = .120, compared to misconception trials, F = 28.57, p < .001, ηp2 = .256. There was an additional significant interaction between Discipline and Statement type, whereby the difference between true and false statements was significant for science trials, F = 84.75, p < .001, ηp2 = .505, but not maths trials, p = .629  = 20.50, p < .001, ηp2 = .198, with longer RTs for false trials  with age, WASI Vocabulary and Matrix Reasoning raw scores, and science and maths control RT as predictors, was significant, explaining 84% of the variance. Only science and maths control RT was a significant predictor of misconception accuracy. Complex No-Go accuracy was selected in model 2b, uniquely accounting for 1% of the variance. Greater complex No-Go accuracy was associated with higher misconception RT. No Stroop variables were selected by the model.p-values were at trend and the coefficients were in the same direction as the combined analyses. Complex Go/No-Go accuracy was not a significant predictor of science (model 5) or maths (model 6) misconception RT. This time the coefficient was positive for maths, as with the combined analyses, but negative for science.Follow up exploratory regressions  examinedIn summary, the regression analyses revealed unique roles for response and semantic inhibition in reasoning about science and maths misconceptions. Both response inhibition (complex No-Go accuracy) and semantic inhibition (Stroop RT cost) were predictors of performance when science and maths misconceptions were combined. Proficiency in semantic inhibition was more important for predicting misconception accuracy, while proficient response inhibition was more important for predicting longer RTs when addressing misconception problems.The current study investigated the role of inhibitory control in counterintuitive science and maths reasoning in adolescence. It was hypothesised that better inhibitory control would be associated with better performance in science and maths misconception problems, when controlling for performance on related problems, age, and general cognitive ability. Ninety adolescents were tested on response and semantic inhibition and a novel science and maths misconceptions task. Both response and semantic inhibition were associated with performance in science and maths misconception trials, beyond performance in control trials and individual differences in general cognitive ability or age. This was the first study to consider the unique roles of response and semantic inhibition in this context, demonstrating that response inhibition may be more related to RTs in counterintuitive reasoning, while semantic inhibition may be more related to accuracy. General performance on the science and maths misconceptions task will be considered first, followed by inhibitory control findings; finally the association between inhibitory control and science and maths misconception performance will be discussed.As anticipated, accuracy was lower and RTs slower for misconception trials, indicating that reasoning about counterintuitive curriculum-related concepts leads to misconceptions in this age group, even in the oldest participants who should have a good understanding of these concepts having covered them all at school. Only small age effects were observed, in line with standardised assessment findings that only small improvements are made in maths within this age range .The reduction in accuracy in false trials compared to true trials was greater for misconception than control trials, which may be due to increased cognitive demand in false trials. To arrive at the correct response, the participant must first read the statement and detect an error, then possibly generate the true statement internally before deciding that the statement presented is false. This may explain why it is easier to answer a true statement correctly, especially if it is counterintuitive. This pattern of performance was observed in science trials only, which may be explained by the inclusion in maths of nine problem-sets containing equations, where both true and false trials require a mental calculation, which should limit any specific increase in cognitive demand for false trials. It should also be noted that a higher proportion of science trials were accompanied by a picture (79% vs. 50%) which cannot be ruled out as a source of difference between the two disciplines.Overall, these findings support the previous literature that misconceptions due to intuitive reasoning exist in this age range ,54. AlthThe inhibitory control tasks showed a degree of improvement with age, echoing findings in the literature . Some meBoth response and semantic inhibition were associated with science and maths misconception performance when controlling for age, general cognitive ability, and control performance. In line with our first hypothesis, a smaller difference in RT between incongruent and congruent Stroop trials, suggesting less interference and better semantic inhibition, was associated with higher accuracy on misconception trials. These results fit with the proposal that semantic inhibition may allow suppression of naïve beliefs or irrelevant perceptual information in order to reach the correct answer to counterintuitive problems. Note that while the Stroop task was selected to measure semantic inhibition, it requires suppression of a motor response to some extent , so thisThe ability to withhold a response in the complex Go/No-Go was associated with longer RTs on misconception trials. Therefore, contrary to our hypothesis, good response inhibition is not associated with better performance in the science and maths misconceptions task. However, a possible interpretation is that good response inhibition may afford more time for consideration of the response, with a less impulsive pattern of responding. Individuals may not necessarily eventually choose the correct response, but they may be able to spend more time thinking about their response and evaluate competing alternative answers.The complex Go/No-Go measured inhibitory control within the context of a cognitive load. The regression model’s selection of a complex rather than simple Go/No-Go variable implicates individual differences in the ability to manage combined response inhibition and working memory demands. The use of this ability is exemplified by a maths misconception problem that requires counting items and calculating probabilities, and holding this information in mind while considering how it applies to the statement. This account is consistent with suggestions that beliefs must be held in working memory during reasoning, before the incorrect response is inhibited . Future The discipline-specific analyses had reduced power due to the smaller number of trials, in addition to the different number of pictures within the stimuli, so must be interpreted cautiously. There were also fewer maths problems than science problems. The results overall suggest that misconceptions in science and maths show similar associations to semantic inhibition, with potentially different associations with response inhibition: Higher complex No-Go accuracy was associated with shorter responses in science but longer response in maths. However, these exploratory analyses did not reach significance so further research would be necessary to determine discipline-specific associations. Further distinctions could also be made within disciplines. For example, although not focusing on counterintuitive reasoning, previous research found an association between numerical dot comparison inhibition and procedural maths but not conceptual or factual maths in adolescents .It is possible that the completion of the inhibitory control tasks before the science and maths task may have led to increased inhibitory control use in the latter due to practice effects. Nonetheless, short breaks between tasks, which included talking to the researcher, may have dissipated any such effects. Further, any effect will have applied to all participants, and there remains poorer accuracy in misconception problems compared to control problems.Finally, future work should consider the possibility that different types of inhibition specifically allow the suppression of different types of misconception. The current study did not categorise types of misconception, and contained a mixture of those due to misleading perceptual cues, previously held beliefs, and prior experiences. While the focus here was on covering a broad set of problems, it would be interesting to establish specific links between types of inhibitory control and misconceptions of different origins. Further, intervention studies could assess the impact of inhibitory control training in the context of science and maths learning. This would help to establish the extent to which the association between inhibitory control and counterintuitive reasoning is a causal one; something that the current paper could not address directly. The evidence so far suggests that encouraging learners to inhibit their immediate responses might lead to improved counterintuitive reasoning in science and maths.The associations seen in this novel study suggest that both response inhibition and semantic inhibition play a role in counterintuitive science and maths reasoning problems that are curriculum-related. The results are in line with the idea that inhibition is required to overcome misleading perceptual cues  or old tS1 Fig(TIF)Click here for additional data file.S2 FigMisconception trials accuracy was near chance at 54.7%, participants did not consistently guess across all problems.The range of mean accuracy observed suggests that although the mean overall (TIF)Click here for additional data file.S1 FileThis file contains the method and results of the inhibitory control tasks, and further accuracy analyses from the science and maths misconceptions task.(DOCX)Click here for additional data file.


Ambra1, a pro-autophagic gene crucial for brain development. We show that heterozygous Ambra1 mice (Ambra+/−) are characterized by loss of hippocampal parvalbumin interneurons, decreases in the inhibition/excitation ratio, and altered social behaviors that are solely restricted to the female gender. Loss of parvalbumin interneurons in Ambra1+/− females is further linked to reductions of the inhibitory drive onto principal neurons and alterations in network oscillatory activity, CA1 synaptic plasticity, and pyramidal neuron spine density. Parvalbumin interneuron loss is underlined by increased apoptosis during the embryonic development of progenitor neurons in the medial ganglionic eminence. Together, these findings identify an Ambra1-dependent mechanism that drives inhibition/excitation imbalance in the hippocampus, contributing to abnormal brain activity reminiscent of neurodevelopmental disorders.Imbalances between excitatory and inhibitory synaptic transmission cause brain network dysfunction and are central to the pathogenesis of neurodevelopmental disorders. Parvalbumin interneurons are highly implicated in this imbalance. Here, we probed the social behavior and hippocampal function of mice carrying a haploinsufficiency for The online version of this article (10.1007/s12035-018-0911-5) contains supplementary material, which is available to authorized users. Neurodevelopmental disorders including autism and schizophrenia are disease spectrums with considerable overlapping phenotypes, including deficits in cognition and complex information processing, and behaviors such as anxiety and impaired social interaction –6. GenetAmbra1 gene encodes the activating molecule in Beclin1-regulated autophagy -e14.5 -1,4benzoxazin-6-yl]-1-naphthalenylmethanone mesylate; Tocris) to block GABA release from cholecystokinin (CCK) basket cells.eIPSCs  were recorded using pipettes filled with (in mM): 140 CsCl, 1 MgClFor all the recordings, the stimulating electrode was a monopolar glass electrode filled with aCSF and stimuli (100 μs duration every 30 s) were applied with an ISO-Flex stimulus isolator . For the input/output curves of eEPSCs and eIPSCs, the stimulus intensity referred to as 1× was determined as the intensity that elicited a response between 15 and 20 pA. Stimulation was increased in a multiplicative manner to develop the input/output curves. Overall, stimulus intensity ranged from 20 to 110 μA. Paired-pulse ratios (PPR) were calculated using pairs of afferent stimuli at half-maximal intensity at different paired-pulse intervals and are expressed as peak of the second/first current.AMPAR-mediated whole-cell currents (− 70 mV) were recorded in the presence of bath-applied AMPA  and cyclothiazide, to prevent fast receptor desensitization , together with D-AP5  and lidocaine . NMDAR-mediated currents (+ 40 mV) were recorded in NMDA , glycine , NBQX , and lidocaine . The experiments were performed in the presence of picrotoxin .Miniature excitatory (mEPSCs) and inhibitory (mIPSCs) postsynaptic currents from hippocampal pyramidal neurons were recorded in voltage-clamp mode (at − 70 mV) using the same solutions and drugs as for evoked currents, in the presence of bath-applied lidocaine . Single events were detected with Mini Analysis  and analyzed for amplitude and inter-event interval (IEI). For the recording segments chosen for analysis, both parameters were tested for time stability using Spearman’s rank order correlation test  and segmFor Golgi-Cox staining, mice were perfused transcardially with 0.9% saline and samples were impregnated in a Golgi-Cox solution  at room temperature for 6 days. On the 7th day, brains were transferred in 30% sucrose solution and sectioned with a vibratome. Coronal sections (100 μm) were stained through consecutive steps in water (1 min), ammonium hydroxide (30 min), water (1 min), developer solution , and water (1 min). Sections were then dehydrated through successive steps in alcohol at rising concentrations  and covered with slide coverslips. Spine analysis was performed on dendritic segments of basal and apical dendrites of CA1 pyramidal neurons. Neurons were first identified with a light microscope (Leica DMLB) under a ×20 objective. Subsequently, quantification of dendritic spines was done online under ×100 magnification using a Qimaging Qicam Fast1394 camera connected to the microscope. From each brain, five neurons were selected and on each neuron, five 30–100 μm dendritic segments were randomly selected for spine counts. Only protrusions with a clear connection of the head of the spine to the shaft of the dendrite were counted as spines using the Neurolucida software . Analysis of dendritic spine size was carried out after random selection of spines, by measuring spine head diameter parallel to the dendrite using the ImageJ software. Spine head width values were expressed as cumulative frequencies.t test (WT versus Ambra1+/−). P < 0.05 indicates statistical significance . Details on statistical analysis can be found in figure legends.Analysis was performed using Prism (GraphPad Software v5). Behavioral data for social interaction were analyzed with two-way ANOVAs with genotype and vocalization numbers or sniffing duration as independent factors, followed by Tukey’s post-hoc test. Behavioral data from the three-chamber task were analyzed with one-way ANOVAs (Str versus Obj and Fam versus non-Fam). Cumulative frequencies of spine head diameters were compared with the Kolmogorov-Smirnov test. Ambra1 protein levels were compared with two-way ANOVAs for genotype and gender, with Bonferroni’s post-hoc test. All other data were analyzed using two-tailed unpaired The target number of samples in each group for immunohistochemical, immunofluoscent, stereological, electrophysiological, biochemical, behavioral, and morphological experiments was determined on the basis of numbers reported in published studies.+/− females, Ambra1+/− males), a random number was assigned for each animal; randomization for the animals used in experiments was achieved using a random number table. A similar method was used for unfamiliar C57BL/6J female mice used in the behavioral tests.All randomization was performed by an experimenter. Following separation of all available animals into four groups based on genotype and sex .+/− mice display social deficits, we performed female-female and male-female social interaction tests and analyzed the ultrasonic emissions and sniffing responses of the test animals. During the female-female social interaction test, Ambra1+/− females emitted fewer ultrasonic vocalizations  enzymes, vesicular GABA transporter (VGAT) and the proteins PV, calbindin (CB), and calretinin (CR), used for classifying interneurons into three subsets based on calcium-binding protein expression [+/− females showed significant reductions in the levels of GAD67 and PV  to induce gamma-oscillations in vitro [+/− female mice, we observed a reduction in the power of CCh-induced gamma-oscillations in the frequency range of 25–45 Hz in female , or in the stratum pyramidale  from CA1 principal cells  of CA3-CA1 synapses by stimulating the Schaffer collaterals and recording field excitatory postsynaptic potentials (fEPSPs) in the CA1 dendritic region. LTP was significantly higher in Ambra1 WT Fig. , in agre+/− female mice by measuring spine density and head diameter in Golgi-stained CA1 pyramidal neurons . Our data suggest that Ambra1 haploinsufficiency in Ambra1+/− female mice might contribute to perturbations in the pruning, formation, or recycling of pyramidal neuron dendritic spines, leading to an overall increase in spine numbers, stronger bicuculline-induced epileptiform activity, and enhanced synaptic plasticity following high-frequency stimulation.In line with the increased apical dendrite spine density in Ambra1ity Fig. h. We didAmbra1 heterozygosity reduces the protein expression of both female and male Ambra1+/− embryos compared to WT siblings , the la+/− mice affects females more. Moreover, our data from e10.5 embryos, showing no gender difference in Ambra1 levels, point to a causal role of sex steroid hormones in the differential expression of the protein between genders [A striking outcome of this study is the fact that the described deficits are restricted to females. This is surprising considering that neurodevelopmental diseases such as ASDs and schizophrenia are diagnosed more frequently in males, although recent studies argue that many biases may influence this ratio, including an under-diagnosis in females . A hint  genders .+/− mice? The majority of hippocampal PV interneurons are generated from e11 to e17 in the MGE and migrate tangentially to reach the hippocampus [+/− mice at e13.5, when most interneurons of the CA1 and CA3 are generated [+/− interneurons to apoptotic cell death. In fact, Ambra1 is pivotal for the elimination of damaged mitochondria [Which factors might underlie PV interneuron loss in Ambra1pocampus , 62, 65.enerated , stronglchondria , a form chondria , PV intechondria , 69, andchondria , 70.Our work supports the notion that alterations in the function and/or number of PV interneurons, with the consequent changes in the brain inhibition/excitation ratio, might underlie behaviors that are reminiscent of neurodevelopmental disorders. We conclude that Ambra1 is differentially expressed between male and female brains following gonadal differentiation, and the haploinsufficiency condition is more damaging in female embryos, requiring a greater Ambra1 expression to complete physiological interneuron development.ESM 1(PDF 376 kb)


Results demonstrate that strong (weak) EAWMres weakens (enhances) the positive rainfall anomalies in southeastern China induced by El Niño, because anomalous downward motion over the western North Pacific (WNP) associated with El Niño is weakened (strengthened) by strong (weak) EAWMres. The modulated convective activity over the WNP, on the one hand, changes the anomalous local Hadley circulation associated with El Niño. When El Niño is combined with strong (weak) EAWMres, anomalous local Hadley circulation is weak (strong) and the resultant anomalous upward motion is weak (strong) over southeastern China, leading to small (larger) positive rainfall anomalies there. On the other hand, the modulated WNP convective activity induces different low-level atmospheric responses to El Niño. During an El Niño winter with strong (weak) EAWMres, the weak (strong) anomalous suppressed convection produces a weak (strong) and insignificant (significant) anomalous low-level WNP anticyclone, resulting in correspondingly insignificant (significant) rainfall anomalies in southeastern China. Results from a linear baroclinic model further suggest that the different low-level atmospheric responses over WNP are mainly induced by different diabatic heating associated with El Niño under different EAWMres conditions.The present study investigates the modulation of the East Asian winter monsoon (EAWM) in the impacts of El Niño on the wintertime rainfall anomalies in southeastern China. Here, the variability of the EAWM that is independent of ENSO is considered, which is referred to as EAWM Many of these previous studies have been focused on the summer precipitation because it is of great importance to the agriculture and industry10. However, the wintertime precipitation in East Asia has received less concern. During the East Asian winter, the climatological rainfall belt lies in southeastern China and southern Japan, where has a concentration of population, advanced infrastructure, developed industry and large scope of agriculture. Strong interannual variability of the rainfall belt often caused large societal and economic impacts13. For example, the extreme severe snowstorm in the winter of 2007/2008 in southeastern China had damaged 8381 power towers and 2018 transformer stations, and deprived 129 lives15. Severe drought occurred persistently from the winter of 2011 to the succeeding spring in southern China, leading to 1.09 billion economic loss16. Therefore, it is getting ever more important to understand the interannual variability of the wintertime rainfall in southeastern China.The East Asian monsoon system dominates the seasonal variation of climate over East Asia and favors abundant rainfall in summer but infrequent precipitation in winter17, El Niño-Southern Oscillation (ENSO)20, the Tibetan Plateau thermal state16, the warm pool ocean heat content21, and low-latitude systems including the Bay of Bengal trough and the Northwestern Pacific subtropical high19, etc. Among the factors that impact the southeastern China rainfall in winter, the EAWM and ENSO play the most important role on interannual time scales. The EAWM features with northeasterlies near the surface along the coastal eastern Asia27. A weak EAWM is often accompanied by southeasterly wind anomalies along the coast of East Asia, which transport warm and moist air from the tropical ocean northward to southeastern China, further induces moisture convergence and results in above-normal rainfall there, and vice versa29. ENSO is the most important tropical air-sea couple system on interannual time scales, which can influence the climate in the East Asia region via Gill-type response in terms of tropical Rossby waves31. During an El Niño (La Niña) winter, positive (negative) rainfall anomalies in southeastern China are often observed due to an anomalous lower-tropospheric anticyclone (cyclone) over the western North Pacific (WNP) induced by El Niño (La Niña)32.The winter precipitation in East Asia is affected by many factors. For example, the East Asian winter monsoon (EAWM) system30. On the other hand, a strong EAWM can act as a trigger for an El Niño event through inducing westerly wind anomalies over the equatorial western Pacific33. The respective impacts of ENSO and EAWM on the wintertime rainfall in China has been investigated by Zhou and Wu29. They found that the independent EAWM dominantly exerts its impact on rainfall anomalies in eastern China, while the independent ENSO dominantly in southern China. ENSO-induced climate anomalies are not steady worldwide36. Especially, recent studies have noticed that the relationship between ENSO and the climate variability in East Asia is not stable. This unsteady relationship may be caused by many factors, such as different flavors of ENSO and extra-tropical influences. Compared with the traditional eastern Pacific El Niño, the central Pacific El Niño  tends to cause less precipitation anomalies in southern China from winter to the subsequent summer due to a weaker and southwestward shift of WNP anticyclone38. Wang et al.39 showed that ENSO has a significant (hardly any) impact on the EAWM during a negative (positive) phase of Pacific Decadal Oscillation (PDO). Jia and Ge40 reported that the influence of the EAWM as well as ENSO on the wintertime precipitation in southeastern China is strong during the period of 1980–1998, but weak in 1999–2015.The interaction between ENSO and the EAWM makes their impacts on the wintertime precipitation in southeastern China complex. On the one hand, an El Niño (La Niña) is often accompanied by a weak (strong) EAWM as anomalous southerly (northerly) winds to the northwest of an El Niño-induced anticyclone (cyclone) impair (favor) the southward penetrating of cold waves30. However, the WNP anticyclone (cyclone), as well as the relationship between ENSO and the climate in southern East Asia, can be modulated by extra-tropical factors. For instance, Kim et al.41 reported that a negative PDO or a positive Atlantic Multidecadal Oscillation (AMO) phase tends to drive a westward shift of the WNP anticyclone, resulting in a stronger connection between ENSO and the climate of East Asia. It is difficult to recognize the influence of EAWM on the WNP anticyclone (cyclone) associated with ENSO due to the interaction between ENSO and the EAWM. However, there is evidence that a weak (strong) EAWMres, which represents the variation of the EAWM that is linear independent of ENSO, is associated with an anomalous anticyclonic (cyclonic) circulation over the WNP near the Philippine Sea36. Feng and Chen42 demonstrated that EAWMres modulates the impacts of El Niño (La Niña) on the following East Asian summer monsoon through changing the intensity and domain of the El Niño-induced western North Pacific anticyclone (WNPAC). Hence, we wonder whether the EAWM could interfere with the impacts of ENSO on wintertime rainfall in southeastern China. This study aims to address this issue. Additionally, it is reported that the relationship between La Niña and the winter rainfall anomalies in China is insignificant43. Hence, we will focus on the rainfall anomalies induced by El Niño in this study.It is widely accepted that ENSO exerts its impacts on the wintertime rainfall in southeastern China through yielding an anomalous lower tropospheric anticyclone (cyclone) over the WNP near the Philippine Seares in modulating the impacts of El Niño on the wintertime rainfall anomalies in China. In section 2(b) and (c), possible mechanisms are elucidated by the observational analysis and the experiments with a linear baroclinic model (LBM), respectively. The summary is provided in section 3. Descriptions of data, methods, and the linear baroclinic model are given in section 4.The rest of the paper is organized as follows: Section 2(a) documents roles of EAWMres on the rainfall anomalies in China associated with El Niño, Fig. res , and the El Niño winters with weak EAWMres . The pattern of rainfall anomalies in all the El Niño events  EAWMres tends to suppress (enhance) anomalous rainfall response to El Niño in southeastern China.To investigate the modulation effects of EAWMnts Fig.  is charaver Fig. . In contver Fig. , anomalover Fig.  indicateet al.20 is employed to confirm the robustness of our results. This East Asian monsoon index is calculated by the 3-month running mean of meridional wind anomalies at 850 hPa averaged over the area of 20–30°N, 110–130°E and shows a good relationship with El Niño. By using this index, very similar results are obtained compared to Fig. res has a significant modulation effect on the winter rainfall anomalies in China associated with El Niño.Another East Asian monsoon index defined by Zhang 32. Zhang et al.20 first proposed the explanation of the WNPAC as a Rossby wave response to the suppressed convection over the tropical western Pacific. Recently, Zhang et al.45 further reviewed the association of El Niño with the WNPAC and the possible mechanisms. On the one hand, the anomalous subsidence over the tropical western Pacific results in a weakened local Hadley cell which can affect the meridional East Asian monsoon circulation. On the other hand, a WNPAC is generated in response to the diabatic cooling over the tropical western Pacific, which may transport moisture to southern China and increase rainfall there. To understand how the EAWMres modulates the impacts of El Niño events, we diagnosed the 500 hPa vertical p-velocity motion and 850 hPa divergent winds as shown in Fig. 32. Meanwhile, anomalous rising and correspondent convergent winds in the lower troposphere are seen over southeastern China  EAWMres often carries northerly (southerly) wind anomalies to penetrate southward to lower latitudes42. Therefore, convective activity around the Philippines is enhanced (suppressed) by strong (weak) EAWMres, which weakens (intensifies) the El Niño-induced suppressed convection around the Philippines.During an El Niño event, suppressed convective activities and associated diabatic cooling over the tropical western Pacific play important roles in linking El Niño to the rainfall anomalies in East Asiaina Fig. . This rened Fig. . There aned Fig. . Compari32. However, when an El Niño event happens with a strong EAWMres, the WNPAC is much weakened  and the El Niño with weak EAWMres (EN&wEAWM).This study investigated the modulation effect of the EAWM on the relationship between El Niño and the rainfall anomalies in southeastern China through composite analysis and a simple linear baroclinic model simulation. The El Niño winters were divided into two groups based on the intensity of EAWMres. Nearly no significant rainfall anomalies are observed in southeastern China in the EN&sEAWM winters. In contrast, in the EN&wEAWM winters, positive precipitation anomalies are increased and cover a larger domain of southeastern China. The magnitude of precipitation anomalies in the EN&wEAWM winters is about twice of that in the all El Niño winters. The result indicates that the strong (weak) EAWMres weakens (enhances) the impacts of El Niño on the winter rainfall in southeastern China.An El Niño event often causes above-normal winter rainfall in southeastern China. However, the rainfall anomalies associated El Niño show totally different features after considering the condition of EAWMres on the rainfall is suggested to be induced by its modulation on the anomalous downward motion around the WNP associated with El Niño. Strong EAWMres carries northerly wind anomalies to penetrate southward deeply and causes anomalous upward motion over the WNP, whereas weak EAWMres has the opposite effect on the WNP convective activity. Hence, the El Niño-induced downward motion over the WNP is weakened (strengthened) by strong (weak) EAWMres in the case of EN&sEAWM (EN&wEAWM). This modulated convective activity over the WNP tends to influence the local Hadley circulation associated with El Niño. In the EN&sEAWM winters, the local Hadley circulation becomes much weaker. In contrast, in the EN&wEAWM winters, the local Hadley circulation becomes much stronger. The changes in the local Hadley circulation induce much stronger anomalous upward motion in the EN&wEAWM winters than the EN&sEAWM winters. Hence, significantly excessive rainfall anomalies are observed in the EN&wEAWM winters.The effect of EAWMres during the El Niño events yield different responses of the WNPAC. In the EN&sEAWM winters, the WNPAC response is weak due to weak convective anomalies over the WNP, leading to weak rainfall response. In the EN&wEAWM winters, strengthened suppressed convection over the WNP induces a much stronger WNPAC, which corresponds to excessive rainfall in southeastern China by transporting plentiful moisture.On the other hand, the convective activities modulated by the EAWMThe effect of anomalous convective heating over the WNP is further validated by experiments with a dry linear baroclinic model. The result demonstrates that the intensity of low-level anomalous WNPAC is dominantly controlled by the magnitude of anomalous diabatic heating over the WNP. The numerical results are largely consistent with the observations, suggesting that the difference in the diabatic heating anomalies in the EN&sEAWM and EN&wEAWM winters account for the different atmosphere circulation anomalies over the WNP.47. The CRU data are provided by the Centre for Environmental Data Analysis from their web site http://catalogue.ceda.ac.uk. The monthly mean atmospheric data used in this study are from the National Centers for Environmental Prediction (NCEP) /National Center for Atmospheric Research (NCAR) and available at the website of NOAA/OAR/ESRL PSD https://www.esrl.noaa.gov/psd. This NCEP/NCAR dataset has a 2.5° × 2.5° horizontal resolution and 17 vertical levels extending from 1000 to 10 hPa and covers the period from 1948 to the present48. The monthly mean Sea Surface Temperature (SST) data on 1° × 1° grids are provided by the Met Office Hadley Center (https://www.metoffice.gov.uk), covering the period from the year of 1870 to present49. The National Oceanic and Atmospheric Administration (NOAA) reconstructed precipitation (PREC) data, provided also by the NOAA/OAR/ESRL PSD, are used to analyze the rainfall anomalies over oceans, which is constructed on a 2.5° × 2.5° latitude/longitude grid across the global spanning from 1948 to the present50. The time period of 1948–2015 that all the datasets cover is considered in this study. To exclude the impacts of interdecadal change, the variability longer than 7 years has been removed from the original datasets through a Lanczos filter51.The Climatic Research Unit (CRU) Time-series (TS) version 4.00 rainfall data is employed in this study, which has a horizontal resolution of 0.5° latitude by 0.5° longitude and spans the time period from 1901 to 2015The historical El Niño/La Niña episodes selected in this study are based on the criterion defined by the Climate Prediction Center (CPC). An El Niño (La Niña) event is identified when the Oceanic Niño Index (ONI) is greater (less) than 0.5 °C (−0.5 °C) for 5 consecutive overlapping seasons, and the ONI is defined as 3-month-mean of the SST anomalies over the Niño 3.4 region . Therefore, 24 El Niño events during the period of 1948–2015 are finally picked out.et al.52. Specifically, an EAWM index, which is defined by the 850 hPa meridional wind anomaly averaged over the area 27, is used to estimate the strength of EAWM. As the El Niño episode is selected based on the SST anomalies in Nino 3.4 region, the ENSO signal is determined by the Nino 3.4 index here. Then, the ENSO-related EAWM (EAWMEN) index is computed by a linear regression of EAWM index upon the Nino3.4 index. The ENSO-unrelated EAWM index, which is referred to as EAWMres, is finally obtained by the total EAWM index minus the EAWMEN index. Here, a positive (negative) EAWMres index represents a weak (strong) EAWMres winter. On the basis of the EAWMres index, the El Niño events are sorted into two groups (Table res (EN&sEAWM); and (2) El Niño with weak EAWMres (EN&wEAWM).To isolate the EAWM component that is independent of ENSO influence, we followed the method proposed by Ma 20–40°N, 00–140°E253. The experiments are set in a T42 resolution on horizontal and 20 levels in the vertical on σ surface. To analyze the steady atmospheric response to a diabatic heating anomaly, a dry model and time integration method is employed. The basic state and the external forcing in the LBM are computed from the NCEP/NCAR reanalysis data and PREC precipitation data, respectively.The Linear Baroclinic Model (LBM) Package is used in this study, which is developed by the Center for Climate System Research (CCSR), University of Tokyo and the National Institute for Environmental Studies (NIES)


Water homeostasis is fundamental for cell survival. Transport of water across cellular membranes is governed by aquaporins—tetrameric integral membrane channels that are highly conserved throughout the prokaryotic and eukaryotic kingdoms. In eukaryotes, specific regulation of these channels is required and is most commonly carried out by shuttling the protein between cellular compartments (trafficking) or by opening and closing the channel (gating). Structural and functional studies have revealed phosphorylation as a ubiquitous mechanism in aquaporin regulation by both regulatory processes. In this review we summarize what is currently known about the phosphorylation-dependent regulation of mammalian aquaporins. Focusing on the water-specific aquaporins (AQP0–AQP5), we discuss how gating and trafficking are controlled by phosphorylation and how phosphorylation affects the binding of aquaporins to regulatory proteins, thereby highlighting structural details and dissecting the contribution of individual phosphorylated residues when possible. Our aim is to provide an overview of the mechanisms behind how aquaporin phosphorylation controls cellular water balance and to identify key areas where further studies are needed. Phosphorylation is the most studied post-translational protein modification, allowing for simple and reversible regulation of protein function. It is estimated that around 30% of human proteins are phosphorylated at some point in their lifetime . ProteinFor the ubiquitous membrane-bound water channels known as aquaporins (AQPs), phosphorylation is an important regulatory mechanism. In eukaryotes, this allows water flow across cellular membranes to be tightly regulated in response to various external and internal signals, thereby maintaining the desired water balance of the organism . Fast reAll AQPs share the same structural features with four monomers assembling as a tetramer . Each moThirteen AQPs (AQP0-12) have been identified in mammals, which are expressed and regulated in a tissue-dependent manner ,8. A majPhosphorylation of AQPs can be readily identified in cells, tissues, as well as cell lysates and purified proteins using phosphospecific antibodies . However2 are used to facilitate the specific enrichment of phosphopeptides. In rats, phosphoproteomics has been studied extensively and the results can be found in the CPR PTm Resource, an online database of more than 30,000 identified protein phosphorylation sites, including those in aquaporins, across 14 different rat tissues . O. O47]. O269 instead of RRXS/T), it may nevertheless be phosphorylated by PKA . Of. Of49]. d by PKA ,49. The role of the two remaining phosphorylation sites, S261 and S264, has not been completely elucidated. In contrast to S256 and T269, AVP stimulates the dephosphorylation of S261 by protein phosphatase 2C , and AQPAs for S256 and T269, AVP stimulates phosphorylation of S264, which is suggested to sit in a casein kinase type I phosphorylation site (SXXS where the first S is phosphorylated) or a PKC site ,49. S264A few studies have tried to elucidate the role of specific phosphatases in AQP2 trafficking. In PKA-phosphorylated endosomes isolated from rat kidney collecting duct the AQP2 could be dephosphorylated, in vitro, by the addition of protein phosphatase 2B  . CalcineThe effect of phosphorylation on AQP4 function was first suggested already 20 years ago  and has a receptor (V1aR), activates a signalling cascade ending with PKC activation. Indeed, oocytes co-expressing both AQP4 and V1aR, were sensitive to AVP and upon AVP treatment, the water permeability was reduced two-fold. In addition to PKC, PKA has also been proposed to regulate AQP4 internalization. Gastric cells expressing rat AQP4 were treated with histamine, resulting in reversible internalization of AQP4 which co-localized with late endosomes but not with lysosomes [Phosphorylation of S180 by PKC has been shown to lead to increased AQP4 internalization. Upon treatment with PKC activators, the water content of rat brain was significantly reduced ex vivo, an effect that correlated with AQP4 downregulation . PKC actysosomes . While tysosomes .Contradicting these results, studies in HEK293-cells did not show a difference in constitutive expression or hypotonicity-triggered translocation of AQP4 S180A or S180D, nor any effect of PKC-inhibitors. Instead, it was shown that AQP4 plasma membrane targeting was dependent on PKA, as hypotonicity-induced translocation of AQP4 to the plasma membrane was abolished by PKA inhibitors (but not by PKC inhibitors) in both HEK293 cells and primary astrocytes. The PKA-phosphorylation event was attributed to S276 in the C-terminus, since a S276A mutant did not translocate to the membrane following a hypotonic trigger. The corresponding phospho-mimicking mutant S276D could reach the membrane also in the presence of PKA inhibitors, suggesting that phosphorylation at other PKA-sites is not necessary for translocation to occur. Interestingly, directly upstream of this phosphorylation site a putative CaM-binding site was identified. CaM is known to modulate the water permeability of AQP4, however it is not known whether this happens through direct binding or indirectly through protein kinase activation .Other studies have shown that phosphorylation of S276 has the opposite effect on AQP4 trafficking. This residue has also been identified as a casein kinase II consensus site and a S276D mutant has been shown to have 5-fold increased affinity to the μ3A subunit of the AP3 complex in a yeast two-hybrid assay, with S276 immediately preceding the tyrosine-based binding site. This interaction plays an important role in targeting proteins for lysosomal degradation following clathrin-mediated endocytosis. Moreover, the same mutant showed an increased co-localization with lysosomes in MDCK cells. Neither the delivery rate to the plasma membrane nor protein internalization rate was affected by this phosphorylation, suggesting it plays a role in intracellular sorting of AQP4 .In summary, studies of phosphorylation-dependent trafficking of AQP4 have generated conflicting results and more work will be needed to dissect the roles of individual kinases and phosphorylation sites. It seems clear that there are multiple pathways that regulate AQP4 membrane abundance and that the existence of these pathways, and/or the cross-talk between them, may differ depending on the experimental conditions or the cell type used.AQP5 is highly expressed in salivary, sweat, lacrimal glands, as well as lungs and airways and plays a key role in secretion of isotonic fluids . SimilarSeveral studies have probed the individual roles of S156 and T259 in PKA-dependent AQP5 trafficking. In MDCK-II cells, S156 as well as the immediately preceding consensus phosphorylation site S152 was mutated to alanines, with the mutant exhibiting only slightly increased trafficking to the plasma membrane . This waTaken together, these studies support the biphasic response on AQP5 trafficking following cAMP-stimulation, with the short-term effect causing a decrease in AQP5 membrane abundance through phosphorylation of a different target and the long-term effect resulting in increased AQP5 membrane levels, involving direct phosphorylation of S156. Structural studies of the AQP5 S156E-mutant showed that, contradictory to what was originally proposed from the crystal structure of wild-type AQP5 , phosphoThe AQPs constitute one of the best characterized families of integral membrane proteins in terms of the structure. While this has led to a thorough understanding of the structural basis for transport and selectivity, much remains to be learnt about how different AQPs can be specifically regulated, despite sharing a conserved structural fold. The regions important for AQP regulation are most often found outside the highly conserved transmembrane core domains, in the loops and termini. These regions are often highly flexible, and the structural details and their involvement in regulation may be difficult to deduce from a static structure. In fact they are often missing from AQP structures, due to disorder.Located within the loops and termini, phosphorylation sites play crucial roles in the differential regulation of human AQP isoforms. Through phosphorylation/dephosphorylation, the structures and properties of these regions are altered, changing their ability to bind the regulatory proteins that control the phosphorylation-dependent regulatory events, including translocation to and from the plasma membrane, targeting degradation and, in the case of gating, whether the AQP is open and closed. It seems likely that the flexibility is one of the key properties that allow these regions to play such prominent roles in AQP regulation and they may often lack a stable secondary structure in the absence of an interacting partner. In this respect, obtaining structural information for AQPs in complexes with regulatory proteins will be crucial in order to understand the roles of these regions and specific phosphorylation sites in AQP regulation.An additional layer of complexity in AQP regulation becomes apparent when considering an even higher level of regulation: The regulation of kinases and phosphatases themselves. Much remains to be determined, regarding which specific enzymes are involved and how they are regulated. Such information would significantly aid in our understanding of the cross-talk between different kinases and phosphatases when regulating AQPs with multiple phosphorylation sites, or when several AQPs are present and differentially regulated within the same cell.