Pub Date : 2024-08-28DOI: 10.1093/pnasnexus/pgae370
Saman Khazaei, Rose T Faghih
The skin conductance (SC) and eye tracking data are two potential arousal-related psychophysiological signals that can serve as the interoceptive unconditioned response (UR) to aversive stimuli (e.g., electric shocks). The current research investigates the sensitivity of these signals in detecting mild electric shock by decoding the hidden arousal and interoceptive awareness (IA) states. While well-established frameworks exist to decode the arousal state from the SC signal, there is a lack of a systematic approach that decodes the IA state from pupillometry and eye gaze measurements. We extract the physiological-based features from eye tracking data to recover the IA-related neural activity. Employing a Bayesian filtering framework, we decode the IA state in fear conditioning and extinction experiments where mild electric shock is used. We independently decode the underlying arousal state using binary and marked point process (MPP) observations derived from concurrently collected SC data. 8 of 11 subjects present a significantly (p-value < 0.001) higher IA state in trials that were always accompanied by electric shock (CS + US+) compared to trials that were never accompanied by electric shock (CS−). According to the decoded SC-based arousal state, only 5 (binary observation) and 4 (MPP observation) subjects present a significantly higher arousal state in CS + US+ trials than CS− trials. In conclusion, the decoded hidden brain state from eye tracking data better agrees with the presented mild stimuli. Tracking IA state from eye tracking data can lead to the development of contactless monitors for neuropsychiatric and neurodegenerative disorders.
皮肤电导（SC）和眼球追踪数据是两种潜在的唤醒相关心理生理信号，可作为对厌恶刺激（如电击）的感知间非条件反应（UR）。目前的研究通过解码隐藏的唤醒和感知间意识（IA）状态，调查了这些信号在检测轻微电击时的灵敏度。虽然已有成熟的框架可从 SC 信号中解码唤醒状态，但还缺乏一种系统的方法可从瞳孔测量和眼球注视测量中解码 IA 状态。我们从眼动数据中提取了基于生理的特征，以恢复与 IA 相关的神经活动。采用贝叶斯过滤框架，我们解码了使用轻微电击的恐惧条件反射和消退实验中的 IA 状态。我们使用从同时收集的 SC 数据中得到的二进制和标记点过程（MPP）观察结果独立解码了潜在的唤醒状态。与从未伴有电击的试验（CS-）相比，在始终伴有电击的试验（CS + US+）中，11 名受试者中有 8 人的 IA 状态明显更高（p 值为 0.001）。根据解码的基于 SC 的唤醒状态，只有 5 名（二元观察）和 4 名（MPP 观察）受试者在 CS + US+ 试验中的唤醒状态明显高于 CS- 试验。总之，从眼动跟踪数据中解码出的隐藏大脑状态与呈现的轻微刺激更吻合。通过眼动跟踪数据追踪内隐状态，可以开发出治疗神经精神疾病和神经退行性疾病的非接触式监测器。
{"title":"Eye tracking is more sensitive than skin conductance response in detecting mild environmental stimuli","authors":"Saman Khazaei, Rose T Faghih","doi":"10.1093/pnasnexus/pgae370","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae370","url":null,"abstract":"The skin conductance (SC) and eye tracking data are two potential arousal-related psychophysiological signals that can serve as the interoceptive unconditioned response (UR) to aversive stimuli (e.g., electric shocks). The current research investigates the sensitivity of these signals in detecting mild electric shock by decoding the hidden arousal and interoceptive awareness (IA) states. While well-established frameworks exist to decode the arousal state from the SC signal, there is a lack of a systematic approach that decodes the IA state from pupillometry and eye gaze measurements. We extract the physiological-based features from eye tracking data to recover the IA-related neural activity. Employing a Bayesian filtering framework, we decode the IA state in fear conditioning and extinction experiments where mild electric shock is used. We independently decode the underlying arousal state using binary and marked point process (MPP) observations derived from concurrently collected SC data. 8 of 11 subjects present a significantly (p-value &lt; 0.001) higher IA state in trials that were always accompanied by electric shock (CS + US+) compared to trials that were never accompanied by electric shock (CS−). According to the decoded SC-based arousal state, only 5 (binary observation) and 4 (MPP observation) subjects present a significantly higher arousal state in CS + US+ trials than CS− trials. In conclusion, the decoded hidden brain state from eye tracking data better agrees with the presented mild stimuli. Tracking IA state from eye tracking data can lead to the development of contactless monitors for neuropsychiatric and neurodegenerative disorders.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1093/pnasnexus/pgae367
Michael Phillips, Murugappan Muthukumar, Kingshuk Ghosh
Conformations and dynamics of an intrinsically disordered protein (IDP) depend on its composition of charged and uncharged amino acids, and their specific placement in the protein sequence. In general, the charge (positive or negative) on an amino acid residue in the protein is not a fixed quantity. Each of the ionizable groups can exist in an equilibrated distribution of fully ionized state (monopole) and an ion-pair (dipole) state formed between the ionizing group and its counterion from the background electrolyte solution. The dipole formation (counterion condensation) depends on the protein conformation, which in turn depends on the distribution of charges and dipoles on the molecule. Consequently, effective charges of ionizable groups in the IDP backbone may differ from their chemical charges in isolation — a phenomenon termed charge-regulation. Accounting for the inevitable dipolar interactions, that have so far been ignored, and using a self-consistent procedure, we present a theory of charge-regulation as a function of sequence, temperature and ionic strength. The theory quantitatively agrees with both charge reduction and salt dependent conformation data of Prothymosin-alpha, and makes several testable predictions. We predict charged groups are less ionized in sequences where opposite charges are well mixed compared to sequences where they are strongly segregated. Emergence of dipolar interactions from charge-regulation allows spontaneous coexistence of two phases having different conformations and charge states, sensitively depending on the charge patterning. These findings highlight sequence dependent charge-regulation and its potential exploitation by biological regulators such as phosphorylation and mutations in controlling protein conformation and function.
{"title":"Beyond monopole electrostatics in regulating conformations of intrinsically disordered proteins","authors":"Michael Phillips, Murugappan Muthukumar, Kingshuk Ghosh","doi":"10.1093/pnasnexus/pgae367","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae367","url":null,"abstract":"Conformations and dynamics of an intrinsically disordered protein (IDP) depend on its composition of charged and uncharged amino acids, and their specific placement in the protein sequence. In general, the charge (positive or negative) on an amino acid residue in the protein is not a fixed quantity. Each of the ionizable groups can exist in an equilibrated distribution of fully ionized state (monopole) and an ion-pair (dipole) state formed between the ionizing group and its counterion from the background electrolyte solution. The dipole formation (counterion condensation) depends on the protein conformation, which in turn depends on the distribution of charges and dipoles on the molecule. Consequently, effective charges of ionizable groups in the IDP backbone may differ from their chemical charges in isolation — a phenomenon termed charge-regulation. Accounting for the inevitable dipolar interactions, that have so far been ignored, and using a self-consistent procedure, we present a theory of charge-regulation as a function of sequence, temperature and ionic strength. The theory quantitatively agrees with both charge reduction and salt dependent conformation data of Prothymosin-alpha, and makes several testable predictions. We predict charged groups are less ionized in sequences where opposite charges are well mixed compared to sequences where they are strongly segregated. Emergence of dipolar interactions from charge-regulation allows spontaneous coexistence of two phases having different conformations and charge states, sensitively depending on the charge patterning. These findings highlight sequence dependent charge-regulation and its potential exploitation by biological regulators such as phosphorylation and mutations in controlling protein conformation and function.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1093/pnasnexus/pgae339
Yanxia Wang, Yanjuan Sun, Xinyan Liu, Fan Dong
The highly selective conversion of carbon dioxide into value-added products is extremely valuable. However, even with the aid of in situ characterization techniques, it remains challenging to directly correlate extensive spectral data carrying microscopic information with macroscopic performance. Herein, we adopted advanced machine learning (ML) approaches to establish an accurate and interpretable relationship between vibrational spectral signals and catalytic performances to uncover hidden physical insights. Focusing on photocatalytic CO2 reduction, our model is shown to effectively and accurately predict the CO production activity and selectivity based solely on the infrared (IR) spectral signals, the generalizability of which is additionally demonstrated with a new Bi5O7I photocatalytic system. More importantly, further model analysis has revealed a novel strategy to steer CO selectivity, the physical sanity of which is verified by a detailed reaction mechanism analysis. This work demonstrates the tremendous potential of machine-learned spectroscopy to efficiently identify reaction control factors, which can further lay the foundation for targeted optimization and reverse design.
将二氧化碳高选择性地转化为高附加值产品具有极高的价值。然而，即使有了原位表征技术的帮助，要将携带微观信息的大量光谱数据与宏观性能直接关联起来仍然具有挑战性。在此，我们采用了先进的机器学习（ML）方法，在振动光谱信号和催化性能之间建立了准确且可解释的关系，从而揭示了隐藏的物理原理。以光催化二氧化碳还原为重点，我们的模型仅根据红外光谱信号就能有效、准确地预测二氧化碳的生成活性和选择性。更重要的是，进一步的模型分析揭示了一种引导 CO 选择性的新策略，详细的反应机理分析验证了这种策略的物理合理性。这项工作展示了机器学习光谱学在有效识别反应控制因素方面的巨大潜力，可进一步为有针对性的优化和逆向设计奠定基础。
{"title":"Predicting and understanding photocatalytic CO2 reduction reaction with IR spectroscopy-based interpretable machine learning framework","authors":"Yanxia Wang, Yanjuan Sun, Xinyan Liu, Fan Dong","doi":"10.1093/pnasnexus/pgae339","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae339","url":null,"abstract":"The highly selective conversion of carbon dioxide into value-added products is extremely valuable. However, even with the aid of in situ characterization techniques, it remains challenging to directly correlate extensive spectral data carrying microscopic information with macroscopic performance. Herein, we adopted advanced machine learning (ML) approaches to establish an accurate and interpretable relationship between vibrational spectral signals and catalytic performances to uncover hidden physical insights. Focusing on photocatalytic CO2 reduction, our model is shown to effectively and accurately predict the CO production activity and selectivity based solely on the infrared (IR) spectral signals, the generalizability of which is additionally demonstrated with a new Bi5O7I photocatalytic system. More importantly, further model analysis has revealed a novel strategy to steer CO selectivity, the physical sanity of which is verified by a detailed reaction mechanism analysis. This work demonstrates the tremendous potential of machine-learned spectroscopy to efficiently identify reaction control factors, which can further lay the foundation for targeted optimization and reverse design.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1093/pnasnexus/pgae365
Xiaohu Ge, Muyao Ruan, Xiaoxuan Peng, Yong Xiao, Yang Yang
To reduce the energy consumption of logic gates in digital circuits, the size of transistors approaches the mesoscopic scale, e.g., sub-7 nanometers (nm). However, existing energy consumption analysis methods exhibit various deviation for logic gates when the non-equilibrium information processing of mesoscopic scale transistors with ultra-low voltages is analyzed. Based on the stochastic thermodynamics theory, an information energy ratio method is proposed for the energy consumption estimation of XOR gates composed of mesoscopic scale transistors. The proposed method provides a new insight to quantify the transformation between the information capacity and energy consumption for XOR gates and extending to other logic gates. Utilizing the proposed analysis method, the supply voltage of the parity check circuit can be optimized by numerical simulations without expensive and complex practical measurements. The information energy ratio is the first analytical method to quantify the energy and information transformation of logic gates at the mesoscopic scale.
{"title":"An energy and information analysis method of logic gates based on stochastic thermodynamics","authors":"Xiaohu Ge, Muyao Ruan, Xiaoxuan Peng, Yong Xiao, Yang Yang","doi":"10.1093/pnasnexus/pgae365","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae365","url":null,"abstract":"To reduce the energy consumption of logic gates in digital circuits, the size of transistors approaches the mesoscopic scale, e.g., sub-7 nanometers (nm). However, existing energy consumption analysis methods exhibit various deviation for logic gates when the non-equilibrium information processing of mesoscopic scale transistors with ultra-low voltages is analyzed. Based on the stochastic thermodynamics theory, an information energy ratio method is proposed for the energy consumption estimation of XOR gates composed of mesoscopic scale transistors. The proposed method provides a new insight to quantify the transformation between the information capacity and energy consumption for XOR gates and extending to other logic gates. Utilizing the proposed analysis method, the supply voltage of the parity check circuit can be optimized by numerical simulations without expensive and complex practical measurements. The information energy ratio is the first analytical method to quantify the energy and information transformation of logic gates at the mesoscopic scale.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-24DOI: 10.1093/pnasnexus/pgae366
Jooyoung Im, J Carlos Santamarina
Waste containment and isolation strategies often utilize bentonite as a buffer material due to its swelling capacity, sealing efficiency, low permeability and limited diffusive transport. However, previous experimental studies of ionic diffusion through bentonite have shown discrepancies with binary diffusion assumptions. Meticulous experiments and complementary analyses reveal that the migration of preexisting ions in the medium enables the differential flux of diffusing anions and cations, while maintaining local electro-neutrality in all cases. The separation between the cationic and anionic fronts is electrically tied to the motion of the preexisting ions, and reflects the interplay between valence, concentration, and self-diffusion coefficients of the ions involved. Imposing binary diffusion conditions forces the faster anions to diffuse at the same rate as cations. Therefore, effective barriers to mitigate both cation and anion transport should have low surface charge and low excess salts to minimize the preexisting ionic concentration.
{"title":"Understanding the limits of binary diffusion for enhanced clay barrier design","authors":"Jooyoung Im, J Carlos Santamarina","doi":"10.1093/pnasnexus/pgae366","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae366","url":null,"abstract":"Waste containment and isolation strategies often utilize bentonite as a buffer material due to its swelling capacity, sealing efficiency, low permeability and limited diffusive transport. However, previous experimental studies of ionic diffusion through bentonite have shown discrepancies with binary diffusion assumptions. Meticulous experiments and complementary analyses reveal that the migration of preexisting ions in the medium enables the differential flux of diffusing anions and cations, while maintaining local electro-neutrality in all cases. The separation between the cationic and anionic fronts is electrically tied to the motion of the preexisting ions, and reflects the interplay between valence, concentration, and self-diffusion coefficients of the ions involved. Imposing binary diffusion conditions forces the faster anions to diffuse at the same rate as cations. Therefore, effective barriers to mitigate both cation and anion transport should have low surface charge and low excess salts to minimize the preexisting ionic concentration.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-24DOI: 10.1093/pnasnexus/pgae368
Hadi Askari, Anshuman Chhabra, Bernhard Clemm von Hohenberg, Michael Heseltine, Magdalena Wojcieszak
Polarization, misinformation, declining trust, and wavering support for democratic norms are pressing threats to the U.S. Exposure to verified and balanced news may make citizens more resilient to these threats. This project examines how to enhance users’ exposure to and engagement with verified and ideologically balanced news in an ecologically valid setting. We rely on a two-week long field experiment on 28,457 Twitter users. We created 28 bots utilizing GPT-2 that replied to users tweeting about sports, entertainment, or lifestyle with a contextual reply containing a URL to the topic-relevant section of a verified and ideologically balanced news organization and an encouragement to follow its Twitter account. To test differential effects by gender of the bots, the treated users were randomly assigned to receive responses by bots presented as female or male. We examine whether our intervention enhances the following of news media organizations, sharing and liking of news content (determined by our extensive list of news media outlets), tweeting about politics, and liking of political content (determined using our fine-tuned RoBERTa NLP transformer-based model). Although the treated users followed more news accounts and the users in the female bot treatment liked more news content than the control, these results were small in magnitude and confined to the already politically interested users, as indicated by their pre-treatment tweeting about politics. In addition, the effects on liking and posting political content were uniformly null. These findings have implications for social media and news organizations and offer directions for pro-social computational interventions on platforms.
{"title":"Incentivizing news consumption on social media platforms using large language models and realistic bot accounts","authors":"Hadi Askari, Anshuman Chhabra, Bernhard Clemm von Hohenberg, Michael Heseltine, Magdalena Wojcieszak","doi":"10.1093/pnasnexus/pgae368","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae368","url":null,"abstract":"Polarization, misinformation, declining trust, and wavering support for democratic norms are pressing threats to the U.S. Exposure to verified and balanced news may make citizens more resilient to these threats. This project examines how to enhance users’ exposure to and engagement with verified and ideologically balanced news in an ecologically valid setting. We rely on a two-week long field experiment on 28,457 Twitter users. We created 28 bots utilizing GPT-2 that replied to users tweeting about sports, entertainment, or lifestyle with a contextual reply containing a URL to the topic-relevant section of a verified and ideologically balanced news organization and an encouragement to follow its Twitter account. To test differential effects by gender of the bots, the treated users were randomly assigned to receive responses by bots presented as female or male. We examine whether our intervention enhances the following of news media organizations, sharing and liking of news content (determined by our extensive list of news media outlets), tweeting about politics, and liking of political content (determined using our fine-tuned RoBERTa NLP transformer-based model). Although the treated users followed more news accounts and the users in the female bot treatment liked more news content than the control, these results were small in magnitude and confined to the already politically interested users, as indicated by their pre-treatment tweeting about politics. In addition, the effects on liking and posting political content were uniformly null. These findings have implications for social media and news organizations and offer directions for pro-social computational interventions on platforms.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-24DOI: 10.1093/pnasnexus/pgae369
Rasmus Aamand, Peter M Rasmussen, Katrine Schilling Andersen, Stine de Paoli, Eddie Weitzberg, Michael Christiansen, Torben E Lund, Leif Østergaard
APOE-ε4 is a genetic risk factor for Alzheimer’s Disease (AD). AD is associated with reduced cerebral blood flow (CBF) and with microvascular changes that limit the transport of oxygen from blood into brain tissue: reduced microvascular cerebral blood volume and high relative transit time heterogeneity (RTH). Healthy APOE-ε4 carriers reveal brain regions with elevated CBF compared to carriers of the common ε3 allele. Such asymptomatic hyperemia may reflect microvascular dysfunction: a vascular disease entity characterized by suboptimal tissue oxygen uptake, rather than limited blood flow per se. Here, we used perfusion MRI to show that elevated regional CBF is accompanied by reduced CBV in healthy APOE-ε4 carriers (carriers) aged 30-70 compared to similarly aged APOE-ε3 carriers (non-carriers). Younger carriers have elevated hippocampal RTH and more extreme RTH values throughout both white matter (WM) and cortical gray matter (GM) compared to non-carriers. Older carriers have reduced WM CBF and more extreme GM RTH values than non-carriers. Across all groups, lower WM and hippocampal RTH correlate with higher educational attainment, which is associated with lower AD risk. Three days of dietary nitrate supplementation increased carriers’ WM CBF but caused older carriers to score worse on two of six aggregate neuropsychological scores. The intervention improved late recall in younger carriers and in non-carriers. The APOE-ε4 gene is associated with microvascular changes that may impair tissue oxygen extraction. We speculate that vascular risk factor control is particularly important for APOE-ε4 carriers’ healthy aging.
{"title":"Cerebral microvascular changes in healthy carriers of the APOE-ε4 Alzheimer’s disease risk gene","authors":"Rasmus Aamand, Peter M Rasmussen, Katrine Schilling Andersen, Stine de Paoli, Eddie Weitzberg, Michael Christiansen, Torben E Lund, Leif Østergaard","doi":"10.1093/pnasnexus/pgae369","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae369","url":null,"abstract":"APOE-ε4 is a genetic risk factor for Alzheimer’s Disease (AD). AD is associated with reduced cerebral blood flow (CBF) and with microvascular changes that limit the transport of oxygen from blood into brain tissue: reduced microvascular cerebral blood volume and high relative transit time heterogeneity (RTH). Healthy APOE-ε4 carriers reveal brain regions with elevated CBF compared to carriers of the common ε3 allele. Such asymptomatic hyperemia may reflect microvascular dysfunction: a vascular disease entity characterized by suboptimal tissue oxygen uptake, rather than limited blood flow per se. Here, we used perfusion MRI to show that elevated regional CBF is accompanied by reduced CBV in healthy APOE-ε4 carriers (carriers) aged 30-70 compared to similarly aged APOE-ε3 carriers (non-carriers). Younger carriers have elevated hippocampal RTH and more extreme RTH values throughout both white matter (WM) and cortical gray matter (GM) compared to non-carriers. Older carriers have reduced WM CBF and more extreme GM RTH values than non-carriers. Across all groups, lower WM and hippocampal RTH correlate with higher educational attainment, which is associated with lower AD risk. Three days of dietary nitrate supplementation increased carriers’ WM CBF but caused older carriers to score worse on two of six aggregate neuropsychological scores. The intervention improved late recall in younger carriers and in non-carriers. The APOE-ε4 gene is associated with microvascular changes that may impair tissue oxygen extraction. We speculate that vascular risk factor control is particularly important for APOE-ε4 carriers’ healthy aging.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-24DOI: 10.1093/pnasnexus/pgae349
Fritz Markwardt, Eike Christian Schön, Michaela Raycheva, Aparna Malisetty, Sanaria Hawro Yakoob, Malte Berthold, Günther Schmalzing
The human P2X7R (hP2X7R) is a homotrimeric cell surface receptor gated by extracellular ATP4- with two transmembrane helices per subunit, TM1 and TM2. A ring of three S342 residues, one from each pore-forming TM2 helix, located halfway across the membrane bilayer, functions to close and open the gate in the apo and ATP4- bound open states, respectively. The hP2X7R is selective for small inorganic cations, but can also conduct larger organic cations such as Tris+. Here, we show by voltage-clamp electrophysiology in Xenopus laevis oocytes that mutation of S342 residues to positively charged lysines decreases the selectivity for Na+ over Tris+, but maintains cation selectivity. Deep in the membrane, laterally below the S342 ring are nine acidic residues arranged as an isosceles triangle consisting of residues E14, D352, and D356 on each side, which do not move significantly during gating. When the E14K mutation is combined with lysine substitutions of D352 and/or D356, cation selectivity is lost and permeation of the small anion Cl- is allowed. Lysine substitutions of S342 together with D352 or E14 plus D356 in the acidic triangle convert the hP2X7R mutant to a fully Cl--selective ATP4--gated receptor. We conclude that the ion selectivity of wild-type hP2X7R is determined by two sequential filters in one single pathway: (1) a primary size filter, S342, in the membrane center and (2) three cation filters lateral to the channel axis, one per subunit interface, consisting of a total of nine acidic residues at the cytoplasmic interface.
{"title":"Two serial filters control P2X7 cation selectivity, Ser342 in the central pore and lateral acidic residues at the cytoplasmic interface","authors":"Fritz Markwardt, Eike Christian Schön, Michaela Raycheva, Aparna Malisetty, Sanaria Hawro Yakoob, Malte Berthold, Günther Schmalzing","doi":"10.1093/pnasnexus/pgae349","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae349","url":null,"abstract":"The human P2X7R (hP2X7R) is a homotrimeric cell surface receptor gated by extracellular ATP4- with two transmembrane helices per subunit, TM1 and TM2. A ring of three S342 residues, one from each pore-forming TM2 helix, located halfway across the membrane bilayer, functions to close and open the gate in the apo and ATP4- bound open states, respectively. The hP2X7R is selective for small inorganic cations, but can also conduct larger organic cations such as Tris+. Here, we show by voltage-clamp electrophysiology in Xenopus laevis oocytes that mutation of S342 residues to positively charged lysines decreases the selectivity for Na+ over Tris+, but maintains cation selectivity. Deep in the membrane, laterally below the S342 ring are nine acidic residues arranged as an isosceles triangle consisting of residues E14, D352, and D356 on each side, which do not move significantly during gating. When the E14K mutation is combined with lysine substitutions of D352 and/or D356, cation selectivity is lost and permeation of the small anion Cl- is allowed. Lysine substitutions of S342 together with D352 or E14 plus D356 in the acidic triangle convert the hP2X7R mutant to a fully Cl--selective ATP4--gated receptor. We conclude that the ion selectivity of wild-type hP2X7R is determined by two sequential filters in one single pathway: (1) a primary size filter, S342, in the membrane center and (2) three cation filters lateral to the channel axis, one per subunit interface, consisting of a total of nine acidic residues at the cytoplasmic interface.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-23DOI: 10.1093/pnasnexus/pgae363
Sharath Kumar Channarayappa, Sankalp Kumar, N S Vidhyadhiraja, Sumiran Pujari, M P Saravanan, Amal Sebastian, Eun Sang Choi, Shalinee Chikara, Dolly Nambi, Athira Suresh, Siddhartha Lal, D Jaiswal-Nagar
The ground state of a one-dimensional spin-½ uniform antiferromagnetic Heisenberg chain (AfHc) is a Tomonaga-Luttinger liquid which is quantum-critical with respect to applied magnetic fields upto a saturation field μ0 Hs beyond which it transforms to a fully polarised state. Wilson ratio has been predicted to be a good indicator for demarcating these phases [Phys. Rev. B 96, 220401 (2017)]. From detailed temperature and magnetic field dependent magnetisation, magnetic susceptibility and specific heat measurements in a metalorganic complex and comparisons with field theory and quantum transfer matrix method calculations, the complex was found to be a very good realisation of a spin-½ AfHc. Wilson ratio obtained from experimentally obtained magnetic susceptibility and magnetic contribution of specific heat values was used to map the magnetic phase diagram of the uniform spin-½ AfHc over large regions of phase space demarcating Tomonaga-Luttinger liquid, saturation field quantum critical, and fully polarised states. Luttinger parameter and spinon velocity were found to match very well with the values predicted from conformal field theory.
{"title":"Tomonaga-Luttinger liquid and quantum criticality in spin-½ antiferromagnetic Heisenberg chain C14H18CuN4O10 via Wilson ratio","authors":"Sharath Kumar Channarayappa, Sankalp Kumar, N S Vidhyadhiraja, Sumiran Pujari, M P Saravanan, Amal Sebastian, Eun Sang Choi, Shalinee Chikara, Dolly Nambi, Athira Suresh, Siddhartha Lal, D Jaiswal-Nagar","doi":"10.1093/pnasnexus/pgae363","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae363","url":null,"abstract":"The ground state of a one-dimensional spin-½ uniform antiferromagnetic Heisenberg chain (AfHc) is a Tomonaga-Luttinger liquid which is quantum-critical with respect to applied magnetic fields upto a saturation field μ0 Hs beyond which it transforms to a fully polarised state. Wilson ratio has been predicted to be a good indicator for demarcating these phases [Phys. Rev. B 96, 220401 (2017)]. From detailed temperature and magnetic field dependent magnetisation, magnetic susceptibility and specific heat measurements in a metalorganic complex and comparisons with field theory and quantum transfer matrix method calculations, the complex was found to be a very good realisation of a spin-½ AfHc. Wilson ratio obtained from experimentally obtained magnetic susceptibility and magnetic contribution of specific heat values was used to map the magnetic phase diagram of the uniform spin-½ AfHc over large regions of phase space demarcating Tomonaga-Luttinger liquid, saturation field quantum critical, and fully polarised states. Luttinger parameter and spinon velocity were found to match very well with the values predicted from conformal field theory.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-23DOI: 10.1093/pnasnexus/pgae364
Chad M Topaz, Berenize Garcia Nueva, Patrick Izidro de Souza, Jesse Schumann, Leah Shvedova, Xizhen Cai, Shaoyang Ning
Superfund is a federal program established in 1980 to manage the cleanup of hazardous waste sites across the United States. Given the health and economic costs borne by people living near these sites, any demographic disparities within the Superfund program are issues of environmental justice. We investigate whether racial demographics local to a Superfund site are associated with its cleanup status, and if so, how. Our work addresses gaps in the literature by using detailed geospatial processing, comprehensive data, and a more complete set of racial/ethnic categorizations. We study 1,688 Superfund sites across the country. Under a wide variety of modeling scenarios, we consistently find that the proportion of the nearby population that is Asian is negatively associated with the probability of a Superfund site being cleaned up. This association has remained unidentified until now, possibly because earlier research on Superfund sites did not distinguish Asian populations as a separate group. Our result underscores the need for specific measurement and inclusion of diverse populations in environmental studies.
{"title":"Race and Superfund site remediation","authors":"Chad M Topaz, Berenize Garcia Nueva, Patrick Izidro de Souza, Jesse Schumann, Leah Shvedova, Xizhen Cai, Shaoyang Ning","doi":"10.1093/pnasnexus/pgae364","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae364","url":null,"abstract":"Superfund is a federal program established in 1980 to manage the cleanup of hazardous waste sites across the United States. Given the health and economic costs borne by people living near these sites, any demographic disparities within the Superfund program are issues of environmental justice. We investigate whether racial demographics local to a Superfund site are associated with its cleanup status, and if so, how. Our work addresses gaps in the literature by using detailed geospatial processing, comprehensive data, and a more complete set of racial/ethnic categorizations. We study 1,688 Superfund sites across the country. Under a wide variety of modeling scenarios, we consistently find that the proportion of the nearby population that is Asian is negatively associated with the probability of a Superfund site being cleaned up. This association has remained unidentified until now, possibly because earlier research on Superfund sites did not distinguish Asian populations as a separate group. Our result underscores the need for specific measurement and inclusion of diverse populations in environmental studies.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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