Strong Increase Research Articles

Projected Changes in Dry and Wet Spells over West Africa during Monsoon Season Using Markov Chain Approach

This study examines projected changes in dry and wet spell probabilities in West Africa during the July–August–September monsoon season using a Markov chain approach. Four simulations of regional climate models from the CORDEX-Africa program were used to analyze projected changes in intraseasonal variability. The results show an increase in the probability of having a dry day, a dry day preceding a wet day, and a dry day preceding a dry day, and a decrease in the probability of wet days in the Sahel region under anthropogenic forcing scenarios RCP4.5 and RCP8.5. The decrease in wet days is stronger in the far future and under the RCP8.5 scenario (up to −30%). The study also finds that the probability of consecutive dry days (lasting at least 7 days and 10 days) is expected to increase in western Sahel, central Sahel, and the Sudanian Area under both scenarios, with stronger increases in the RCP8.5 scenario. In contrast, a decrease is expected over the Guinea Coast, with the changes being more important under the RCP4.5. Dry spell probabilities increasing in the Sahel areas and in the northern Sudanian Area is linked to the increase in the very wet days (R95P) in the daily rainfall intensity index (SDII). These changes in dry and wet spell probabilities are important for water management decisions and risk reduction in the energy and agricultural sectors. This study also highlights the need for decision-makers to implement mitigation and adaptation policies to minimize the adverse effects of climate change.

Axonal organelle buildup from loss of AP-4 complex function causes exacerbation of amyloid plaque pathology and gliosis in Alzheimer's disease mouse model.

Lysosomes and related precursor organelles robustly build up in swollen axons that surround amyloid plaques and disrupted axonal lysosome transport has been implicated in worsening Alzheimer's pathology. Our prior studies have revealed that loss of Adaptor protein-4 (AP-4) complex function, linked primarily to Spastic Paraplegia (HSP), leads to a similar build of lysosomes in structures we term "AP-4 dystrophies". Surprisingly, these AP-4 dystrophies were also characterized by enrichment of components of APP processing machinery, β-site cleaving enzyme 1 (BACE1) and Presenilin 2. Our studies examining whether the abnormal axonal lysosome build up resulting from AP-4 loss could lead to amyloidogenesis revealed that the loss of AP-4 complex function in an Alzheimer's disease model resulted in a strong increase in size and abundance of amyloid plaques in the hippocampus and corpus callosum as well as increased microglial association with the plaques. Interestingly, we found a further increase in enrichment of the secretase, BACE1, in the axonal swellings of the plaques of Alzheimer model mice lacking AP-4 complex compared to those having normal AP-4 complex function, suggestive of increased amyloidogenic processing under this condition. Additionally, the exacerbation of plaque pathology was region-specific as it did not increase in the cortex. The burden of the AP-4 linked axonal dystrophies/AP-4 dystrophies was higher in the corpus callosum and hippocampus compared to the cortex, establishing the critical role of AP-4 -dependent axonal lysosome transport and maturation in regulating amyloidogenic amyloid precursor protein processing.Significance Statement A major pathological feature of Alzheimer's disease is the accumulation of axonal lysosomes near sites of amyloid plaques. Lysosome accumulation is thought to contribute to amyloid production. In fact, a genetic perturbation that arrests lysosomes in axons exacerbates amyloid plaque pathology. The mechanisms that control axonal lysosome abundance as well the molecular composition of axonal endolysosomes that produce Abeta, however, are not fully understood. Axonal lysosome build-up is emerging as a common pathology in other neurodegenerative disorders such as Hereditary Spastic Paraplegia (HSP), but its relevance to amyloid production is unknown. We find that a model of HSP caused by loss of AP-4 adaptor complex lead to axonal lysosome buildup that differs in some of its content, but still contributes to amyloidogenesis. This demonstrates that different perturbations leading to changes in heterogeneous pool of axonal lysosomes can converge on a common pathology.

Multiscale Elasticity of Epoxy Networks by Rheology and Brillouin Light Spectroscopy.

The response of soft materials to an imposed oscillatory stress is typically frequency dependent, with the most utilized frequency range falling in the range of 10-2-102 rad/s. In contrast to most conventional contact techniques for measuring material elasticity, like tensile or shear rheology and atomic force microscopy, or invasive techniques using probes, such as microrheology, Brillouin light spectroscopy (BLS) offers an optical, noncontact, label-free, submicron resolution and three-dimensional (3D) mapping approach to access the mechanical moduli at GHz frequencies. Currently, the correlation between the experimental viscoelastic (at lower frequencies) and elastic (at higher frequencies) moduli has fundamental and practical relevance, but remains unclear. We utilize a series of solvent-free epoxy polymer networks with variable cross-link density as models to compare the storage modulus, G', (in the MPa range) obtained from shear rheology and the longitudinal modulus, M', (in the GPa range) extracted from BLS. Our results show that G' exhibits a much stronger increase with increasing cross-link density than M' (by a factor of about 3.5). This finding is discussed in the context of the phantom network model for G' and Wood's inverse rule of mixtures for M'. The epoxy polymer network displays an unexpectedly fast hypersonic dispersion compared to its uncross-linked precursor. These results testify the importance of obtaining reliable information about the elasticity of networks and will hopefully trigger further investigations in the direction of bridging the elasticity of soft materials at different scales.

Broadening mechanisms of donor-bound exciton photoluminescence in Ga-doped ZnO nanowires

Donor spins in ZnO NWs have promise for quantum information (QI) applications due to high crystalline quality, narrow excitonic luminescence linewidths, and a direct bandgap of this material. It is important to understand the processes that can lead to inhomogeneous broadening of the excitonic transitions for realization of QI devices. We investigate the effect of Ga dopant concentration on the low temperature photoluminescence (PL) of Ga-doped ZnO nanowires. Spectrometer-resolution-limited donor-bound exciton (D0X) PL lines are observed at low concentrations with linewidths of around 0.1 meV. A clear increase in the Ga D0X line is observed as trace amounts of Ga are added. Above a certain concentration threshold, we observe a strong increase in the lateral growth coupled with a significant tail on the low energy side of the D0X emission, which scales linearly with dopant precursor concentration. We have analyzed this behavior using different models, including a model based on a bound exciton wavefunction overlap with neigbhouring donors and a Stark effect model due to random charged impurities. We rule out both of these models based on PL excitation spectroscopy measurements and show that a simple exponential model of the Urbach form gives the best fit and points to disorder in the more heavily doped shells.

A Cohort Replacement of Household Labour Supply in Germany and the UK

In recent decades, fluctuating unemployment rates and welfare state retrenchment have led to increased levels of economic insecurity in some countries. At the same time, cultural norms and family policies have become more gender-egalitarian. While earlier research related these trends to the decline in the male breadwinner model, little is known about whether recent cohorts who entered adult life against the backdrop of a new socio-economic opportunity structure have established new configurations of household labour supply. Using sequence analysis and cluster analyses across harmonised longitudinal data (GSOEP, BHPS and Understanding Society) for a sample of adults born between 1961 and 1973 in Germany and the United Kingdom (UK), this study introduces an innovative indicator of household labour supply types and new descriptive findings on the cohort replacement of household labour supply in these two countries. Descriptive findings show that recent cohorts in both Germany and the UK are forming more gender-egalitarian households, as reflected by the decline in the male breadwinner model as well as by the rise of 1.5-male breadwinner households in Germany and dual-earner households in the UK. However, the proportion of single and low labour intensity households in recent cohorts has declined in the UK, while there has been no meaningful change in East Germany and a strong increase in West Germany. The evolution of household labour supply types can be attributed to the replacement of cohorts who entered adulthood and established their households under shifting socio-economic contexts and gender ideologies.

Influence of Fresnel effects on the glossiness and perceived depth of depth-scaled glossy objects.

Fresnel effects, that is, shape-dependent changes in the strength of specular reflection from glossy objects, can lead to large changes in reflection strength when objects are scaled along the viewing axis. In an experiment, we scaled sphere-like bumpy objects with fixed material parameters in the depth direction and then measured with and without Fresnel effects how this influences the gloss impression, gloss constancy, and perceived depth. The results show that Fresnel effects in this case lead to a strong increase in gloss with depth, indicating lower gloss constancy than without them, but that they improve depth perception. In addition, we used inverse rendering to investigate the extent to which Fresnel effects in a rendered image limit the possible object shapes in the underlying scene. We found that, for a static monocular view of an unknown object, Fresnel effects by themselves provide only a weak constraint on the overall shape of the object.

Engagement of peroxisome proliferator-activated receptor gamma (PPARγ) and mammalian target of rapamycin (mTOR) in the triclosan-induced disruption of Cyp450 enzyme activity in an in vitro model of mouse embryo fibroblasts (3T3-L1).

Triclosan (TCS) is commonly used worldwide due to its bactericidal and antifungal properties. There are data suggesting the involvement of aryl hydrocarbon receptors (AhR) and peroxisome proliferator-activated receptors (PPARγ). Since the effect of TCS on mouse fibroblasts has not been described so far, we decided to investigate the mechanism of action of this compound in the mouse embryonic fibroblast cell line (3T3-L1). Our results showed that high µM concentrations of TCS increased caspase-3 activity and decreased cell viability after 24-h exposure. The molecular analysis confirmed that 1µM TCS decreased Ki67 mRNA expression and PCNA protein expression with a similar tendency to that of AhR. The analyses of mRNA levels after treatment with αNF or βNF alone and αNF in combination with TCS showed an increase in Ki67 mRNA expression. TCS alone increased AhR mRNA but had different effects on Cyp1a1 and Cyp1b1 expression. These results suggest the involvement of the PPARγ pathway in the inhibition of Cyp1b1 by TCS. After the TCS exposure, we observed a decrease in PPARγ, and this effect was enhanced in the presence of an AhR agonist and antagonist. These results support the theory about the interaction between the AhR and PPARγ pathways. In the experiments, the strongest increase in PI3K protein expression was observed in the group treated simultaneously with TCS and βNF. Changes in the PI3K level were reflected in changes in the examined mTOR protein. TCS caused a decrease in both mTOR and Cyp1b1 after 24hours, while opposite effects were observed after 48hours. Given the crucial role of Cyp1b1, PPARγ, and mTOR in cellular metabolism, we can conclude that TCS is able to disrupt a number of cellular processes. Our data suggest that TCS reduces the metabolism of this xenobiotic in mouse preadipocytes.

Energy Needs and Trends Assessment for the Urban Commune of N’zérékoré, Republic of Guinea

Nowadays, one of the major problems facing large cities is the adaptation of energy needs with their rapid demographic growth. In most cases, there is a disconnect between the rapid demographic increases and the updating of energy needs. The major cities of the Republic of Guinea are confronted to a significant challenge due to insufficient energy supply for their sustainable development, and the urban commune of N’zérékoré is a clear example of this. The city is experiencing substantial rapid demographic growth, which requires a long-term assessment of its energy needs for its sustainable development. In this paper, a model for projecting energy demand over 10 years for the urban commune of N'zérékoré taking into account its demographic evolution was developed. An estimate of energy needs was made based on the projected population growth from 2024 to 2060. The results show that the urban commune's current energy consumption is estimated at 53.89 MW, or 38.8 GWh per month, while the projected energy demand for the same year amounts to 51.6 GWh. Population growth continuously drives a strong increase in energy demand, if production remains unchanged, by 2060 the commune’s energy need would reach 1,595.16 GWh, resulting in a deficit of 1,543.56 GWh.

Nanostructured Hydrogels of Carboxylated Cellulose Nanocrystals Crosslinked by Calcium Ions

Bio-based eco-friendly cellulose nanocrystals (CNCs) gain an increasing interest for diverse applications. We report the results of an investigation of hydrogels spontaneously formed by the self-assembly of carboxylated CNCs in the presence of CaCl2 using several complementary techniques: rheometry, isothermal titration calorimetry, FTIR-spectroscopy, cryo-electron microscopy, cryo-electron tomography, and polarized optical microscopy. Increasing CaCl2 concentration was shown to induce a strong increase in the storage modulus of CNC hydrogels accompanied by the growth of CNC aggregates included in the network. Comparison of the rheological data at the same ionic strength provided by NaCl and CaCl2 shows much higher dynamic moduli in the presence of CaCl2, which implies that calcium cations not only screen the repulsion between similarly charged nanocrystals favoring their self-assembly, but also crosslink the polyanionic nanocrystals. Crosslinking is endothermic and driven by increasing entropy, which is most likely due to the release of water molecules surrounding the interacting COO− and Ca2+ ions. The hydrogels can be easily destroyed by increasing the shear rate because of the alignment of rodlike nanocrystals along the direction of flow and then quickly recover up to 90% of their viscosity in 15 s, when the shear rate is decreased.

Industrial reform policies: does marketization enhance productivity more than privatization?

Abstract Placing state-owned firms into the private sector is understood to yield productivity gains, but this effect is seldom decomposed into changes in ownership (privatization) and changes in firm characteristics to match privately owned firms without changing ownership (marketization). This article presents an empirical assessment of Chinese firm-level data using a counterfactual design approach to identify if the Chinese ‘grasp the large and let go of the small’ industrial policy reform initiative reduced the efficiency gap between state-owned and non-state-owned enterprises and whether any gains were associated with privatization or marketization. Our empirical results show that marketization was associated with stronger increases in productivity than was privatization, suggesting that industrial reforms should consolidate assets, enhance cash flows, and reduce the need for external liquidity rather than focusing on changing ownership.

A preliminary investigation on the protective effects of β-glucan and mannan induced trained immunity in pufferfish Takifugu obscurus

Immune stimuli are able to trigger long-term protective effects through mechanisms of trained immunity, which has attracted increasing attention. Although the existence of trained immunity has evidenced in teleost fish, while there were no such reports in pufferfish (Takifugu obscurus) so far. Therefore, the present study aimed to evaluate the induction of β-glucan and mannan on the trained immunity and their protective efficacy against Vibrio harveyi re-stimulation in pufferfish. β-glucan and mannan induction of trained immunity in head-kidney primary leukocytes is accompanied by a strong increase in immediate ROS burst, cumulative NO production and lactate concentrations after V. harveyi re-stimulation. In addition, β-glucan and mannan-treated pufferfish exhibited reduced bacterial loads in multiple tissues, a rapid and long-term elevated inflammatory response in head kidney during secondary V. harveyi infection. Notably, immune receptors dectin-1 and dectin-2, and cytokines tnfsf14 and il-1β exhibited comparatively upregulation to the β-glucan training, while NK-lysin and faslg showed stronger response to the mannan training post V. harveyi stimulation, implying the different signaling pathway activated post β-glucan and mannan training. Subsequent markers for immune training including abundance of genes encoding glycolytic enzymes (hk1, pfkla, and ldha) and transcription factors (mtor and hif-1α), as well as increased acetylation levels were elevated in the β-glucan and mannan trained pufferfish, depicting heightened glycolysis following β-glucan and mannan training. These results collectively demonstrated that β-glucan and mannan both induced protective responses against V. harveyi infection probably through mediating distinct signaling pathway in pufferfish, and studies are underway to harness its potential applicability for prime and boost vaccination strategies.

Multifaceted Assessment of Agricultural Extension in Conflict Affected Areas of Mindanao, Philippines

Agricultural extension in conflict affected areas has received limited research attention. Yet agricultural extension undertaken within a group–based facilitation framework can have many benefits via livelihood improvement, human and social capital development. In this paper, an extension model adapted for conflict affected areas is briefly described and then assessed from multiple viewpoints – physical, economic, lifestyle, social capital and environmental. This was done in two case study sites in conflict affected areas of Mindanao, Philippines. Major positive physical, economic and lifestyle changes were revealed at both case study sites, as were changes in knowledge, attitude, skills, and aspirations and social capital. Some positive environmental aspects were also noted. Income and savings were up 64 and 108 percent respectively, with those income changes being reflected in additional expenditures on basic items such as food clothing and education. Knowledge, attitudes skills and aspirations (which can be regarded as intermediate steps towards livelihood improvement) all increased substantially. Various social capital indicators were judged to have improved. From an environmental perspective, there were decreases in charcoal production and slash and burn activity. Tree planting and soil fertility increased. Most of these assessment parameters, but especially social capital with its implication for trust and human interaction, are relevant to peace building. With the passage of the Bangsamoro Organic Law, there is expected to be a strong increase within the Philippines and internationally in funding the promotion of agricultural livelihood activities in Mindanao. The multifaced assessment of benefits is somewhat unique and the resulting quantification of the benefits demonstrates that additional funding and more diverse applications could be warranted.

Is the mechanism of "fast sound" the same in liquids with long-range interactions and disparate mass metallic alloys?

We present abinitio simulations of a large system of 2400 particles of molten NaCl to investigate the behavior of collective mode dispersion beyond the hydrodynamic regime. In particular, we aim to explain the unusually strong increase in the apparent speed of sound with wave number, which significantly exceeds the typical positive sound dispersion of 10%-25% observed in simple liquids. We compare dispersions of "bare" acoustic and optic modes in NaCl with abinitio simulations of other ionic melts such as CuCl and LiBr, metallic liquid alloys such as Pb44Bi56 and Li4Tl, and the regular Lennard-Jones KrAr liquid simulated by classical molecular dynamics. Analytical expressions for the "bare" acoustic and optic branches of collective excitations help us to identify the impact of the high-frequency optic branch on the emergence of "fast sound" in binary melts. Our findings show that in ionic melts, the high-frequency speed of sound is much larger than in the simple Lennard-Jones liquids and metallic melts, leading to an observed strong viscoelastic increase in the apparent speed of sound-more than double its adiabatic value.

Field versus controlled environmental experiments to evaluate the heat stress response of barley (Hordeum vulgare L.)

The complexity of heat stress hinders both the exploration of the genetic basis of stress response and breeding of genotypes with increased stress tolerance. Our main goal was to analyze and compare the possibilities of evaluating heat stress responses of barley cultivars in field sowing and controlled environmental experiments. For this purpose, a four-year field-sown experiment was carried out at one location in a panel of 190 winter and facultative barleys. In parallel, a subset of 28 cultivars were included into controlled environmental tests, where their reactions were determined to single heat stress treatment applied at heading and to combined heat stresses applied at first node appearance and then at heading. Based on the grain-yield related parameters, seven distinct clusters of the cultivars could be established with specific reaction patterns across the years. There was one year with close to optimal weather conditions and one year, when heat stress occurred during flowering and grain setting, making it possible to evaluate the heat stress responses of the 190 barley genotypes. In the heat stress prone 2022 year, the general trends were a strong reduction in the reproductive tiller number and a slight reduction in the fertility. In several groups, these negative effects were compensated with significant increases in grain number per ears and with strong increases in the average grain weight. Under controlled conditions, heat stress significantly reduced most of the grain-yield related traits. Among the more tolerant genotypes, two basic response types could be distinguished. One group was able to better preserve the grain number and weight in the main ear under heat stress, while the other was more able to allocate resources into the side tillers during the recovery period. In the combined heat stress, the average trait values were similar to those in the single stress or even lower, and there was no general priming effect clearly detectable. In the case of the 28 genotypes, there were significant correlations between the stress-induced changes in grain-yield related traits measured under field and under controlled conditions, underlining the possibility of combining the information originating from the two different environments.

Stronger Westerly Wind Bursts in a Warming Climate: The Effects of the Pacific Warming Pattern, the Madden–Julian Oscillation, and Tropical Cyclones

Abstract Westerly wind bursts (WWBs) in the western–central equatorial Pacific are critical in El Niño–Southern Oscillation (ENSO) dynamics. Understanding how they may change with global warming has important implications for future projections of El Niño. In this study, we investigate how the enhanced eastern equatorial Pacific warming pattern, emerging in future climate projections, can influence WWB characteristics in an atmospheric general circulation model, CAM6. Changes in three main factors affecting WWBs—El Niño-conditions mean westerly wind stress anomalies, the Madden–Julian oscillation (MJO), and tropical cyclones (TCs)—are analyzed. We find that during El Niño onset (December–April), the WWB wind stress intensity remains largely unchanged but WWBs shift westward by about 20° of longitude. In contrast, during El Niño development (May–November), the WWB intensity increases by 41% or 79% in two warming scenarios considered [shared socioeconomic pathways (SSP5-8.5) and SSP2-4.5, respectively], which is mainly caused by a higher frequency of TC occurrence in the central tropical Pacific within 15°N/S. Further, we find that westerly wind speed anomalies associated with El Niño and the MJO also increase during El Niño development. However, as trade winds weaken in the central-eastern equatorial Pacific, the mean strength of the resulting westerly wind stress anomalies does not change much, and no significant eastward shift of WWBs is observed. Thus, our atmospheric model simulations suggest a strong TC-driven increase in WWB wind stress anomalies during El Niño development and hence a more important role of TCs in WWB generation, which in a coupled system could lead to stronger ENSO events, enhanced TC–ENSO coupling, and even greater intensification of WWBs.

Increase in PUFA and protein, and decrease in carbohydrate intake improves liver fat in 12 months and the role of weight loss as a mediator: A randomized controlled trial

Recently, a beneficial effect of high intake of unsaturated fatty acids (UFA) and protein on intrahepatic lipids (IHL) was demonstrated over 12 months within a randomized controlled trial (the NutriAct trial). We now aimed to explore the specific macronutrient components driving this IHL improvement within this trial in middle-aged and elderly subjects (50-80y) at risk for age-related diseases. The NutriAct trial (n=502) analyzed the effect of a high-protein and high-UFA diet on age related diseases including fatty liver disease. Individuals who completed 3-day food records with available IHL data both at baseline and at month 12 were included in this analysis. The impact of each macronutrient (E%) on IHL (measured by magnetic resonance spectroscopy) was analyzed by linear regression analyses and mediation analysis. Adherence in the intervention group was defined as intake at month 12 of ≥1g protein/kg bodyweight or ≥25%E UFA intake; in the control group it was defined as intake of ≥15%E protein or ≥17%E UFA. 248 participants were included in the analyses (34% male, median age 66y). Although BMI changed similarly in both groups within 12 months (mean change-0.41kg/m2 in the control and-0.70kg/m2 in the intervention group, p within groups <0.001, p between groups=0.09), IHL improved more strongly in the compliant intervention participants than in compliant controls (estimate of relative change 0.21% (95% CI 0.01, 0.40), p=0.03). Participants with stronger increase in protein and PUFA intake and a greater decrease in carbohydrate intake showed a stronger improvement in IHL (estimate for linear relative change-0.04% (95%CI -0.06,-0.02), estimate 4th quartile vs. 1st quartile-0.40% (95%CI -0.65,-0.16), and 0.32% (95%CI 0.05, 0.59), respectively). These associations were partially mediated by BMI changes. Increase in PUFA intake was also directly associated with IHL improvement independently of BMI changes (estimate for linear relative change-0.03% (95%CI -0.05,-0.01)). Beneficial effects of increased protein and decreased carbohydrate intake on IHL are mediated by BMI changes in middle-aged and elderly subjects. The effect of high PUFA intake on IHL improvement was partly independent of weight loss. These results give insight into the understanding of a macronutrient specific effect on IHL changes in a long-term dietary intervention. The trial was registered at German Clinical Trials Register (drks.de) as DRKS00010049.

Stabilizing Metal Halide Perovskite Films via Chemical Vapor Deposition and Cryogenic Electron Beam Patterning.

Halide perovskites are hailed as semiconductors of the 21st century. Chemical vapor deposition (CVD), a solvent-free method, allows versatility in the growth of thin films of 3- and 2D organic-inorganic halide perovskites. Using CVD grown methylammonium lead iodide (MAPbI3) films as a prototype, the impact of electron beam dosage under cryogenic conditions is evaluated. With 5 kV accelerating voltage, the dosage is varied between 50 and 50000 µC cm-2. An optimum dosage of 35 000 µC cm-2 results in a significant blue shift and enhancement of the photoluminescence peak. Concomitantly, a strong increase in the photocurrent is observed. A similar electron beam treatment on chlorine incorporated MAPbI3, where chlorine is known to passivate defects, shows a blue shift in the photoluminescence without improving the photocurrent properties. Low electron beam dosage under cryogenic conditions is found to damage CVD grown 2D phenylethlyammoinum lead iodide films. Monte Carlo simulations reveal differences in electron beam interaction with 3- and 2D halide perovskite films.

De Novo Production of the Bioactive Phenylpropanoid Artepillin C Using Membrane-Bound Prenyltransferase in Komagataella phaffii.

Artepillin C is a diprenylated phenylpropanoid with various pharmacological benefits for human health. Its natural occurrence is limited to a few Asteraceae plants, such as Baccharis species, necessitating a stable supply through synthetic biology. In Saccharomyces cerevisiae, the utilization of aromatic substrates within the cell was limited, resulting in very low production of artepillin C. In this study, we used AcPT1, a p-coumaric acid (p-CA)-specific diprenyltransferase, in Komagataella phaffii to produce artepillin C. Detailed studies revealed that the critical bottleneck in K. phaffii was the supply of prenyl diphosphates, not phenylpropanoid flux. By enhancing the prenyl substrate pathway through overexpression of isopentenyl diphosphate isomerase and a truncated HMG-CoA reductase, we achieved a strong increase in artepillin C production. A major part of artepillin C was accumulated in yeast cells. One of the advantages of K. phaffii is its superior growth and ability to achieve high cell density cultivation compared to that of S. cerevisiae. Therefore, fed-batch cultivation with glycerol was performed. As a result, the dry cell weight (DCW) reached 61.0 g/L, and the intracellular amount of de novo produced artepillin C reached 187.3 μg/DCW. Analysis of intermediates revealed that the supply of p-CA constituted a bottleneck in artepillin C production in the engineered strain. By enhancing the p-CA supply, the intracellular accumulation of artepillin C reached 1200 μg/DCW even in batch cultivation. Moreover, the total intra- and extracellular amounts of artepillin C reached 12.5 mg/L, marking the highest de novo synthesis amount of artepillin C reported thus far, even under batch cultivation conditions.

Axonal organelle buildup from loss of AP-4 complex function causes exacerbation of amyloid plaque pathology and gliosis in Alzheimer's disease mouse model.

Lysosomes and related precursor organelles robustly build up in swollen axons that surround amyloid plaques and disrupted axonal lysosome transport has been implicated in worsening Alzheimer's pathology. Our prior studies have revealed that loss of Adaptor protein-4 (AP-4) complex function, linked primarily to Spastic Paraplegia (HSP), leads to a similar build of lysosomes in structures we term "AP-4 dystrophies". Surprisingly, these AP-4 dystrophies were also characterized by enrichment of components of APP processing machinery, β-site cleaving enzyme 1 (BACE1) and Presenilin 2. Our studies examining whether the abnormal axonal lysosome build up resulting from AP-4 loss could lead to amyloidogenesis revealed that the loss of AP-4 complex function in an Alzheimer's disease model resulted in a strong increase in size and abundance of amyloid plaques in the hippocampus and corpus callosum as well as increased microglial association with the plaques. Interestingly, we found a further increase in enrichment of the secretase, BACE1, in the axonal swellings of the plaques of Alzheimer model mice lacking AP-4 complex compared to those having normal AP-4 complex function, suggestive of increased amyloidogenic processing under this condition. Additionally, the exacerbation of plaque pathology was region-specific as it did not increase in the cortex. The burden of the AP-4 linked axonal dystrophies/AP-4 dystrophies was higher in the corpus callosum and hippocampus compared to the cortex, establishing the critical role of AP-4 -dependent axonal lysosome transport and maturation in regulating amyloidogenic amyloid precursor protein processing.

The profound influence of the North Atlantic Ocean on Northeast Asia: A comprehensive multi‐model study

AbstractWe assess the effects of the North Atlantic Sea surface temperature multidecadal variability on Northeast Asia using a set of sensitivity experiments (with a total of 530 ensemble members). We show that a warming of the North Atlantic Ocean leads to a strong and robust increase in temperature over Northeast Asia, which is replicated by a large majority of ensemble members. We show that the effect of the North Atlantic on Northeast Asia is model and season‐dependent. We focus on two seasons, for which response to the North Atlantic Ocean is the most robust (autumn) and the less robust (spring) as indicated by the number of models that simulate a statistically significant change in surface air temperature. We use a clustering method to identify the sources of differences between models in simulating the effects of warming in the North Atlantic. We find that the primary mechanism linking the North Atlantic to Northeast Asia is a perturbation of the circumglobal teleconnection pattern (i.e., of the upper tropospheric atmospheric circulation), which allows modulation of the near‐surface atmospheric circulation and an increase in temperature over East Asia. A second mechanism is related to the influence of the North Atlantic on the Pacific Ocean and the resulting effects on atmospheric circulation over Northeast Asia.