Conditions Of High Demand Research Articles

Endoplasmic reticulum stress in the salivary glands of patients with primary and associated Sjögren’s disease, and non-Sjögren’s sicca syndrome: a comparative analysis and the influence of chloroquine

BackgroundEndoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are adaptive mechanisms for conditions of high protein demand, marked by an accumulation of misfolded proteins in the endoplasmic reticulum (ER). Rheumatic autoimmune diseases (RAD) are known to be associated with chronic inflammation and an ERS state. However, the activation of UPR signaling pathways is not completely understood in Sjögren’s disease (SD). This study evaluated the expression of ERS-related genes in glandular tissue of patients with primary SD (pSD), associated SD (aSD) with other autoimmune diseases, and non-Sjögren sicca syndrome (NSS).MethodsIn a cross-sectional study, minor salivary gland biopsies were obtained from 44 patients with suspected SD and 13 healthy controls (HC). Patients were classified as pSD, aSD, or NSS based on clinical, serological, and histological assessment. Histopathological analysis and mRNA expression analysis of genes associated with ERS and UPR (PERK, XBP1, ATF-6, ATF-4, CANX, CALR, CHOP, and BIP) were performed on the samples. Differences between groups (pSD, aSD, NSS, and HC) were assessed. The influence of chloroquine (CQ) on the ER was also investigated.ResultsTwenty-eight SD patients showed increased expression of PERK (p = 0.0117) and XBP1 (p = 0.0346), and reduced expression of ATF-6 (p = 0.0003) and CHOP (p = 0.0003), compared to the HC group. Increased expression of BIP (p < 0.0001), PERK (p = 0.0003), CALR (p < 0.0001), and CANX (p = 0.0111) was also observed in the SD group compared to the NSS group (n = 16). Patients receiving CQ (n = 16) showed a significant increase in ATF-6 (p = 0.0317) compared to patients not taking the medication (n = 29).ConclusionsAltogether, the results suggest a greater activation of the ERS and UPR genes in patients with SD, especially in the pSD group. Antimalarial drugs, like CQ, used to treat RAD, may affect the ER function in exocrine glands.

Vocal and Facial Behavior During Affect Production in Autism Spectrum Disorder.

We investigate the extent to which automated audiovisual metrics extracted during an affect production task show statistically significant differences between a cohort of children diagnosed with autism spectrum disorder (ASD) and typically developing controls. Forty children with ASD and 21 neurotypical controls interacted with a multimodal conversational platform with a virtual agent, Tina, who guided them through tasks prompting facial and vocal communication of four emotions-happy, angry, sad, and afraid-under conditions of high and low verbal and social cognitive task demands. Individuals with ASD exhibited greater standard deviation of the fundamental frequency of the voice with the minima and maxima of the pitch contour occurring at an earlier time point as compared to controls. The intensity and voice quality of emotional speech were also different between the two cohorts in certain conditions. Additionally, facial metrics capturing the acceleration of the lower lip, lip width, eye opening, and vertical displacement of the eyebrows were also important markers to distinguish between children with ASD and neurotypical controls. Both facial and speech metrics performed well above chance in group classification accuracy. Speech acoustic and facial metrics associated with affect production were effective in distinguishing between children with ASD and neurotypical controls. https://doi.org/10.23641/asha.28027796.

Area Studies in Russia and the Challenges of the Polycentric World

The article is dedicated to the state of contemporary Russian area studies and their research field in the conditions of high demand for comprehensive and multifaceted approach. The author deliberates on the problem of new normality in connection with the phenomenon of partial deglobalisation. He analyses the interplay between the politics of geopolitisation of relations among leading powers and the institution of nation-state. Also, the topics of foreign interference, resilience and deep state are dwelt upon. Besides, the research looks into an issue of primary and secondary nature of the political and the economical in international relations. The significant part of the work covers the role of civilisations in area studies. The author supports the thesis that civilisational studies occupy a place between area and global studies. At the same time, he questions the validity of the application of civilisational approach to the daily politics in light of its ambivalences and numerous assumptions. Typologically, the notion of border, or multi-composite, civilisation is discussed. The article pays a significant attention to the discourse of juxtaposition of European and Russian civilisations and also raises the problems of conceptual substance of state-civilisation and criteria of historical development. The conclusion is drawn that civilisations’ spaces will continue to be porous and changeable and exposed both to augmentation and fragmentation.

Leaf Aquaporin Expression in Grafted Plants and the Influence of Genotypes and Scion/Rootstock Combinations on Stomatal Behavior in Grapevines Under Water Deficit.

This study investigates the impact of water stress on grapevines, specifically examining the role of rootstocks and aquaporins. Two experiments on potted plants were conducted in central Chile during the summer, under conditions of high water demand, involving various rootstock genotypes and combinations of Cabernet Sauvignon (CS) grafted onto rootstocks. Significant differences were observed among plants in terms of stem water potential, stomatal conductance, and growth rate. Notably, the CS/CS combination consistently displayed the slowest growth rate, regardless of the irrigation treatment. The study also analyzed the expression levels of plasma membrane intrinsic protein (PIP) and tonoplast intrinsic protein (TIP) aquaporins in the leaves of grafted plants. Specifically, VvPIP2;2 aquaporins showed reduced expression after 14 days without irrigation, whereas VvTIP1;1 and VvTIP2;1 expression levels correlated positively with gs responses in grafted plants, suggesting their role in modulating water content in leaves under water stress. TIP aquaporins likely play a significant role in the differential responses of CS plants towards near-isohydric or anisohydric behavior. The CS/CS combination exhibited near-isohydric behavior, correlating with lower TIP aquaporin expression, while the combination of CS onto 1103P and 101-14 showed higher expression, indicating anisohydric behavior. The findings suggest that grafted plants are more resilient to water stress, supporting the idea that rootstocks can mitigate the effects of water stress on the scion.

The Propagation of Congestion on Transportation Networks Analyzed by the Percolation Process

Percolation theory has been widely employed in network systems as an effective tool to analyze phase transitions from functional to nonfunctional states. In this paper, we analyze the propagation of congestion on transportation networks and its influence on origin–destination (OD) pairs using the percolation process. This approach allows us to identify the most critical links within the network that, when disrupted due to congestion, significantly impact overall network performance. Understanding the role of these critical links is essential for developing strategies to mitigate congestion effects and enhance network resilience. Building on this analysis, we propose two methods to adjust the capacities of these critical links. First, we introduce a greedy method that incrementally adjusts the capacities based on their individual impact on network connectivity and traffic flow. Second, we employ a Particle Swarm Optimization (PSO) method to strategically increase the capacities of certain critical links, considering the network as a whole. These capacity adjustments are designed to enhance the network’s resilience by ensuring it remains functional even under conditions of high demand and congestion. By preventing the propagation of congestion through strategic capacity enhancements, the transportation network can maintain connectivity between OD pairs, reduce travel times, and improve overall efficiency. Our approach provides a systematic method for improving the robustness of transportation networks against congestion propagation. The results demonstrate that both the greedy method and the PSO method effectively enhance network performance, with the PSO method showing superior results in optimizing capacity allocations. This research is crucial for maintaining efficient and reliable mobility in urban areas, where congestion is a persistent challenge, and offers valuable insights for transportation planners and policymakers aiming to design more resilient transportation infrastructures.

Artificially Intelligent Vehicle-to-Grid Energy Management: A Semantic-Aware Framework Balancing Grid Demands and User Autonomy

As the adoption of electric vehicles increases, the challenge of managing bidirectional energy flow while ensuring grid stability and respecting user preferences becomes increasingly critical. This paper aims to develop an intelligent framework for vehicle-to-grid (V2G) energy management that balances grid demands with user autonomy. The research presents VESTA (vehicle energy sharing through artificial intelligence), featuring the semantic-aware vehicle access control (SEVAC) model for efficient and intelligent energy sharing. The methodology involves developing a comparative analysis framework, designing the SEVAC model, and implementing a proof-of-concept simulation. VESTA integrates advanced technologies, including artificial intelligence, blockchain, and edge computing, to provide a comprehensive solution for V2G management. SEVAC employs semantic awareness to prioritise critical vehicles, such as those used by emergency services, without compromising user autonomy. The proof-of-concept simulation demonstrates VESTA’s capability to handle complex V2G scenarios, showing a 15% improvement in energy distribution efficiency and a 20% reduction in response time compared to traditional systems under high grid demand conditions. The results highlight VESTA’s ability to balance grid demands with vehicle availability and user preferences, maintaining transparency and security through blockchain technology. Future work will focus on large-scale pilot studies, improving AI reliability, and developing robust privacy-preserving techniques.

Measuring the Effects of Cognitive Capacity on Sentence Comprehension: Evidence From Elementary School-Age Children.

Our aim was to (a) develop a sentence comprehension measure that distinguished between cognitive capacity and syntactic knowledge in school-age children and (b) examine the relationship between comprehension performance and cognitive variables (working memory capacity and retrieval from long-term memory). We developed and administered a picture selection sentence comprehension task to 122 school-age children representing varied cognitive abilities. We evaluated comprehension accuracy and response time in two syntactically identical conditions but with different cognitive demands incorporated in picture foils-one with low demand using superfluous adjectives and another with high demand using contrastive adjectives. Children also completed tasks measuring working memory capacity and long-term memory retrieval. Comprehension accuracy was significantly lower, and response times were longer in the high-cognitive demand condition compared to the low-demand condition. Errors frequently involved incorrect attribute selection in the high-demand condition that included contrastive adjectives in picture foils, while reversal errors prevailed in the low-demand condition, which included superfluous adjectives. Accuracy correlated positively with the memory variables. Hierarchical regression analysis showed that after adjusting for comprehension in the low-cognitive demand condition (38.60% variance), memory variables accounted for 4.50% additional variance in the high-demand condition with only working memory capacity as the unique predictor. The significant role of working memory capacity in comprehending sentences with high cognitive demand indicated the recruitment of active attention and verbal rehearsal. Data support the newly developed measure's potential for assessing cognitive skills integral to sentence comprehension in school-age children. https://doi.org/10.23641/asha.26767063.

Workload and Need for Recovery in the Academy: The Moderating Role of Student Demands and Meaningful Work Perceptions

ABSTRACTResearch has often focused on which teaching‐related stressors might undermine teachers' effectiveness, with spillover effects on students' performance. This connection makes studies on teacher well‐being crucial, as well as the search for variables that can act as a buffer for unavoidable job stressors. The present study investigates whether the relationship between academic workload and the need for recovery varies based on student demands and meaningful work perceptions. Hence, a moderated moderation model was tested on 236 Italian university teachers. The results show that the effect of academic workload on the need for recovery is higher in conditions of high student demands. Meaningful work plays a protective role, mitigating the effect of academic workload in both high and low student demands conditions. These findings suggest the promotion of protective elements that can trigger a virtuous process such that teachers' well‐being improves effectiveness, which, in turn, improves students' learning experience.

Appendage regeneration requires IMPDH2 and creates a sensitized environment for enzyme filament formation.

Regeneration of lost tissue requires biosynthesis of metabolites needed for cell proliferation and growth. Among these are the critical purine nucleotides ATP and GTP. The abundance and balance of these purines is regulated by inosine monophosphate dehydrogenase 2 (IMPDH2), which catalyzes the committing step of GTP synthesis. IMPDH2 assembles into filaments that resist allosteric inhibition under conditions of high GTP demand. Here we asked whether IMPDH2 is required in the highly proliferative context of regeneration, and whether its assembly into filaments takes place in regenerating tissue. We find that inhibition of IMPDH2 leads to impaired tail regeneration and reduced cell proliferation in the tadpole Xenopus tropicalis. We find that both endogenous and fluorescent fusions of IMPDH2 robustly assemble into filaments throughout the tadpole tail, and that the regenerating tail creates a sensitized condition for filament formation. These findings clarify the role of purine biosynthesis in regeneration and reveal that IMPDH2 enzyme filament formation is a biologically relevant mechanism of regulation in vertebrate regeneration.

Adenosine signalling to astrocytes coordinates brain metabolism and function

Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient and oxygen supply1,2. Astrocytes, the ubiquitous glial neighbours of neurons, govern brain glucose uptake and metabolism3,4, but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood5,6. Here we show, using experimental in vitro and in vivo animal models, that neuronal activity-dependent metabolic activation of astrocytes is mediated by neuromodulator adenosine acting on astrocytic A2B receptors. Stimulation of A2B receptors recruits the canonical cyclic adenosine 3′,5′-monophosphate–protein kinase A signalling pathway, leading to rapid activation of astrocyte glucose metabolism and the release of lactate, which supplements the extracellular pool of readily available energy substrates. Experimental mouse models involving conditional deletion of the gene encoding A2B receptors in astrocytes showed that adenosine-mediated metabolic signalling is essential for maintaining synaptic function, especially under conditions of high energy demand or reduced energy supply. Knockdown of A2B receptor expression in astrocytes led to a major reprogramming of brain energy metabolism, prevented synaptic plasticity in the hippocampus, severely impaired recognition memory and disrupted sleep. These data identify the adenosine A2B receptor as an astrocytic sensor of neuronal activity and show that cAMP signalling in astrocytes tunes brain energy metabolism to support its fundamental functions such as sleep and memory.

Physiological and agronomic response of young ‘Verna’ lemon trees to the application of partial root irrigation compared to conventional deficit irrigation under conditions of high evaporative demand

Physiological and agronomic response of young ‘Verna’ lemon trees to the application of partial root irrigation compared to conventional deficit irrigation under conditions of high evaporative demand

Registered report: Age-preserved semantic memory and the CRUNCH effect manifested as differential semantic control networks: An fMRI study.

Semantic memory representations are generally well maintained in aging, whereas semantic control is thought to be more affected. To explain this phenomenon, this study tested the predictions of the Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH), focusing on task demands in aging as a possible framework. The CRUNCH effect would manifest itself in semantic tasks through a compensatory increase in neural activation in semantic control network regions but only up to a certain threshold of task demands. This study compares 39 younger (20-35 years old) with 39 older participants (60-75 years old) in a triad-based semantic judgment task performed in an fMRI scanner while manipulating task demand levels (low versus high) through semantic distance. In line with the CRUNCH predictions, differences in neurofunctional activation and behavioral performance (accuracy and response times) were expected in younger versus older participants in the low- versus high-demand conditions, which should be manifested in semantic control Regions of Interest (ROIs). Our older participants had intact behavioral performance, as proposed in the literature for semantic memory tasks (maintained accuracy and slower response times (RTs)). Age-invariant behavioral performance in the older group compared to the younger one is necessary to test the CRUNCH predictions. The older adults were also characterized by high cognitive reserve, as our neuropsychological tests showed. Our behavioral results confirmed that our task successfully manipulated task demands: error rates, RTs and perceived difficulty increased with increasing task demands in both age groups. We did not find an interaction between age group and task demand, or a statistically significant difference in activation between the low- and high-demand conditions for either RTs or accuracy. As for brain activation, we did not find the expected age group by task demand interaction, or a significant main effect of task demand. Overall, our results are compatible with some neural activation in the semantic network and the semantic control network, largely in frontotemporoparietal regions. ROI analyses demonstrated significant effects (but no interactions) of task demand in the left and right inferior frontal gyrus, the left posterior middle temporal gyrus, the posterior inferior temporal gyrus and the prefrontal gyrus. Overall, our test did not confirm the CRUNCH predictions.

Security Performance Analysis of Full-Duplex UAV Assisted Relay System Based on SWIPT Technology

In this paper, a new methodology is developed for modeling and analyzing a full-duplex UAV-assisted relay system to facilitate solving the problems of UAV energy constraints and the vulnerability of UAVs to eavesdropping in the air. Combining simultaneous wireless information and power transfer (SWIPT) technology, we model the downlink UAV eavesdropping channel and propose a secure transmission protocol for a full-duplex UAV-assisted relay system. Using this transmission protocol, we analyze and derive the connectivity and security of the entire communication link, including connection probability and lower bounds on secrecy outage probability. A key intermediate step in our analysis is to derive the signal-to-digital noise ratio of the destination and eavesdropping nodes of the full-duplex UAV relay link. The analyses show that the power allocation factor λ is a trade-off between system connectivity and security, while greater eavesdropping interference needs to be sacrificed for an equal magnitude of security performance improvement under high security demand conditions.

Predictive Modeling of Groundwater Recharge under Climate Change Scenarios in the Northern Area of Saudi Arabia

Water scarcity is considered a major problem in dry regions, such as the northern areas of Saudi Arabia and especially the city of Hail. Water resources in this region come mainly from groundwater aquifers, which are currently suffering from high demand and severe climatic conditions. Forecasting water consumption as accurately as possible may contribute to a high level of sustainability of water resources. This study investigated different Machine Learning (ML) algorithms, namely Support Vector Machine (SVM), Random Forest (RF), Linear Regression (LR), and Gradient Boosting (GB), to efficiently predict water consumption in such areas. These models were evaluated using a set of performance measures, including Mean Squared Error (MSE), R-squared (R2), Mean Absolute Error (MAE), Explained Variance Score (EVS), Mean Absolute Percentage Error (MAPE), and Median Absolute Error (MedAE). Two datasets, water consumption and weather data, were collected from different sources to examine the performance of the ML algorithms. The novelty of this study lies in the integration of both weather and water consumption data. After examining the most effective features, the two datasets were merged and the proposed algorithms were applied. The RF algorithm outperformed the other models, indicating its robustness in capturing water usage behavior in dry areas such as Hail City. The results of this study can be used by local authorities in decision-making, water consumption analysis, new project construction, and consumer behavior regarding water usage habits in the region.

Edible antimicrobial yeast-based coating with basil essential oil for enhanced food safety

Foodborne pathogen contamination is recognized as a critical public health burden. The application of conventional antimicrobial strategies is significantly restricted in the food industry due to concerns over potential impacts on food quality and human health safety. Herein, this study developed a scalable methodology for encapsulating basil essential oil (BO) into yeast cell wall particles (YCWPs), creating edible antimicrobial coating suspensions for effective pathogen control on real food matrices. Thermal stability and long-term durability of the antimicrobial BO were enhanced after being encapsulated into the YCWPs, which served as a protective barrier, reducing the evaporation of small molecules in the BO mixture. In addition, benefiting from the specific affinity between the YCWP microcarriers and pathogens, the encapsulated BO with a high local concentration around the pathogens could avoid the unexpected consumption caused by organic pollutants encountered in the food system. The obtained BO@YCWPs demonstrated promising antimicrobial efficiency, even under high chemical oxygen demand (COD) conditions, achieving approximately 6 log CFU reductions of S. aureus and E. coli within 30 and 15 min, respectively. Moreover, the antimicrobial BO@YCWPs were suspended in an aqueous solution and then spray-coated onto the fresh basil leaves, significantly inhibiting the proliferation of various microorganisms and demonstrating the great potential application of the BO@YCWPs in ensuring food safety.

Prediction of the weighted-mean soil water diffusivity in supporting the falling rate stage of evaporation

Daily soil evaporation from drying soil can be described as isothermal linear diffusion process, resulting in a simple equation for estimating soil evaporation rate. However, determining soil water diffusivity and subsequently the crucial parameter of weighted-mean diffusivity, essential for estimating soil evaporation rate, is challenging and time-consuming. In this paper, the soil water diffusivity was re-evaluated by considering the effect of film flow, a phenomenon often overlooked but recently argued by Wang et al. (2019, https://doi.org/10.1029/2019WR025003) as the dominant process in the falling rate stage of evaporation. Theoretical derivation reveals a universal relationship between soil water diffusivity and matric potential, independent of soil types. Additionally, soil water diffusivity can be expressed in the form of an exponential function, a form commonly assumed empirically in the literature. Testing with various datasets suggests that the theoretically derived soil water diffusivity generally agrees closely with observations for matric potentials less than about −1 m, wherein the diffusivity accounting for capillary flow shows significant underestimation. Furthermore, a simple function is derived for estimating the weighted-mean diffusivity, enabling a direct estimation of soil evaporation rates in the falling rate stage. Testing with various data sets of different soil types and ambient conditions generally demonstrates close agreements between the estimated soil evaporation rates and observations, indicating that the developed method provides a robust estimation of the weighted-mean soil water diffusivity. When the initial matric potential of the linear diffusion process of drying is higher than about −1 m, which usually occurs under very high atmospheric demand conditions or for very coarse-textured soils, however, the effects of capillary flow were found to be important and need consideration. The effects of vapor diffusion were also discussed and found to have a negligible impact on the estimation of weighted-mean soil water diffusivity.

Cooperation Dynamic through Individualistic Indirect Reciprocity Mechanism in a Multi-Dynamic Model

This research proposes a new variant of Nowak and Sigmund’s indirect reciprocity model focused on agents’ individualism, which means that an agent strengthens its profile to the extent to which it makes a profit; this is using agent-based modeling. In addition, our model includes environmentally related conditions such as visibility and cooperative demand and internal poses such as obstinacy. The simulation results show that cooperators appear in a more significant proportion with conditions of low reputation visibility and high cooperative demand. Still, severe defectors take advantage of this situation and exceed the cooperators’ ratio. Some events show a heterogeneous society only with conditions of high obstinacy and cooperative demand. In general, the simulations show diverse scenarios, including centralized, polarized, and mixed societies. Simulation results show no healthy cooperation in indirect reciprocity due to individualism.

Integrated Functions of Cardiac Energetics, Mechanics, and Purine Nucleotide Metabolism.

Purine nucleotides play central roles in energy metabolism in the heart. Most fundamentally, the free energy of hydrolysis of the adenine nucleotide adenosine triphosphate (ATP) provides the thermodynamic driving force for numerous cellular processes including the actin-myosin crossbridge cycle. Perturbations to ATP supply and/or demand in the myocardium lead to changes in the homeostatic balance between purine nucleotide synthesis, degradation, and salvage, potentially affecting myocardial energetics and, consequently, myocardial mechanics. Indeed, both acute myocardial ischemia and decompensatory remodeling of the myocardium in heart failure are associated with depletion of myocardial adenine nucleotides and with impaired myocardial mechanical function. Yet there remain gaps in the understanding of mechanistic links between adenine nucleotide degradation and contractile dysfunction in heart disease. The scope of this article is to: (i) review current knowledge of the pathways of purine nucleotide depletion and salvage in acute ischemia and in chronic heart disease; (ii) review hypothesized mechanisms linking myocardial mechanics and energetics with myocardial adenine nucleotide regulation; and (iii) highlight potential targets for treating myocardial metabolic and mechanical dysfunction associated with these pathways. It is hypothesized that an imbalance in the degradation, salvage, and synthesis of adenine nucleotides leads to a net loss of adenine nucleotides in both acute ischemia and under chronic high-demand conditions associated with the development of heart failure. This reduction in adenine nucleotide levels results in reduced myocardial ATP and increased myocardial inorganic phosphate. Both of these changes have the potential to directly impact tension development and mechanical work at the cellular level. © 2024 American Physiological Society. Compr Physiol 14:5345-5369, 2024.

Independent activation of CREB3L2 by glucose fills a regulatory gap in mouse β-cells by co-ordinating insulin biosynthesis with secretory granule formation

ObjectiveAlthough individual steps have been characterized, there is little understanding of the overall process whereby glucose co-ordinates the biosynthesis of insulin with its export out of the endoplasmic reticulum (ER) and incorporation into insulin secretory granules (ISGs). Here we investigate a role for the transcription factor CREB3L2 in this context. MethodsMIN6 cells and mouse islets were analysed by immunoblotting after treatment with glucose, fatty acids, thapsigargin and various inhibitors. Knockdown of CREB3L2 was achieved using si or sh constructs by transfection, or viral delivery. In vivo metabolic phenotyping was conducted after deletion of CREB3L2 in β-cells of adult mice using Ins1-CreER+. Islets were isolated for RNAseq and assays of glucose-stimulated insulin secretion (GSIS). Trafficking was monitored in islet monolayers using a GFP-tagged proinsulin construct that allows for synchronised release from the ER. ResultsWith a Km ≈3.5 mM, glucose rapidly (T1/2 0.9 h) increased full length (FL) CREB3L2 followed by a slower rise (T1/2 2.5 h) in its transcriptionally-active cleavage product, P60 CREB3L2. Glucose stimulation repressed the ER stress marker, CHOP, and this was partially reverted by knockdown of CREB3L2. Activation of CREB3L2 by glucose was not due to ER stress, however, but a combination of O-GlcNAcylation, which impaired proteasomal degradation of FL-CREB3L2, and mTORC1 stimulation, which enhanced its conversion to P60. cAMP generation also activated CREB3L2, but independently of glucose. Deletion of CREB3L2 inhibited GSIS ex vivo and, following a high-fat diet (HFD), impaired glucose tolerance and insulin secretion in vivo. RNAseq revealed that CREB3L2 regulated genes controlling trafficking to-and-from the Golgi, as well as a broader cohort associated with β-cell compensation during a HFD. Although post-Golgi trafficking appeared intact, knockdown of CREB3L2 impaired the generation of both nascent ISGs and proinsulin condensates in the Golgi, implying a defect in ER export of proinsulin and/or its processing in the Golgi. ConclusionThe stimulation of CREB3L2 by glucose defines a novel, rapid and direct mechanism for co-ordinating the synthesis, packaging and storage of insulin, thereby minimizing ER overload and optimizing β-cell function under conditions of high secretory demand. Upregulation of CREB3L2 also potentially contributes to the benefits of GLP1 agonism and might in itself constitute a novel means of treating β-cell failure.

The dependence of maximum oxygen uptake and utilization (V̇O2 max) on hemoglobin-oxygen affinity and altitude.

Oxygen transport from the lungs to peripheral tissue is dependent on the affinity of hemoglobin for oxygen. Recent experimental data have suggested that the maximum human capacity for oxygen uptake and utilization (V̇O2 max) at sea level and altitude (~3000 m) is sensitive to alterations in hemoglobin-oxygen affinity. However, the effect of such alterations on V̇O2 max at extreme altitudes remains largely unknown due to the rarity of mutations affecting hemoglobin-oxygen affinity. This work uses a mathematical model that couples pulmonary oxygen uptake with systemic oxygen utilization under conditions of high metabolic demand to investigate the effect of hemoglobin-oxygen affinity on V̇O2 max as a function of altitude. The model includes the effects of both diffusive and convective limitations on oxygen transport. Pulmonary oxygen uptake is calculated using a spatially-distributed model that accounts for the effects of hematocrit and hemoglobin-oxygen affinity. Systemic oxygen utilization is calculated assuming Michaelis-Menten kinetics. The pulmonary and systemic model components are solved iteratively to compute predicted arterial and venous oxygen levels. Values of V̇O2 max are predicted for several values of hemoglobin-oxygen affinity and hemoglobin concentration based on data from humans with hemoglobin mutations. The model predicts that increased hemoglobin-oxygen affinity leads to increased V̇O2 max at altitudes above ~4500 m.