Unique Responses Research Articles

A single protein to multiple peptides: Investigation of protein-peptide correlations using targeted alpha-2-macroglobulin analysis

Recent advances in proteomics technologies have enabled the analysis of thousands of proteins in a high-throughput manner. Mass spectrometry (MS) based proteomics uses a peptide-centric approach where biological samples undergo specific proteolytic digestion and then only unique peptides are used for protein identification and quantification. Considering the fact that a single protein may have multiple unique peptides and a number of different forms, it becomes essential to understand dynamic protein-peptide relationships to ensure robust and reliable peptide-centric protein analysis. In this study, we investigated the correlation between protein concentration and corresponding unique peptide responses under a conventional proteolytic digestion condition. Protein-peptide correlation, digestion efficiency, matrix-effect, and concentration-effect were evaluated. Twelve unique peptides of alpha-2-macroglobulin (A2MG) were monitored using a targeted MS approach to acquire insights into protein-peptide dynamics. Although the peptide responses were reproducible between replicates, protein-peptide correlation was moderate in protein standards and low in complex matrices. The results suggest that reproducible peptide signal could be misleading in clinical studies and a peptide selection could dramatically change the outcome at protein level. This is the first study investigating quantitative protein-peptide correlations in biological samples using all unique peptides representing the same protein and opens a discussion on peptide-based proteomics.

Efficacy of oseltamivir treatment in influenza virus-infected obese mice.

Obesity has been epidemiologically and empirically linked with more severe diseases upon influenza infection. To ameliorate severe disease, treatment with antivirals, such as the neuraminidase inhibitor oseltamivir, is suggested to begin within days of infection especially in high-risk hosts. However, this treatment can be poorly effective and may generate resistance variants within the treated host. Here, we hypothesized that obesity would reduce oseltamivir treatment effectiveness in the genetically obese mouse model. We demonstrated that oseltamivir treatment does not improve viral clearance in obese mice. While no traditional variants associated with oseltamivir resistance emerged, we did note that drug treatment failed to quench the viral population and did lead to phenotypic drug resistance in vitro. Together, these studies suggest that the unique pathogenesis and immune responses in obese mice could have implications for pharmaceutical interventions and the within-host dynamics of the influenza virus population. IMPORTANCE Influenza virus infections, while typically resolving within days to weeks, can turn critical, especially in high-risk populations. Prompt antiviral administration is crucial to mitigating these severe sequalae, yet concerns remain if antiviral treatment is effective in hosts with obesity. Here, we show that oseltamivir does not improve viral clearance in genetically obese or type I interferon receptor-deficient mice. This suggests a blunted immune response may impair oseltamivir efficacy and render a host more susceptible to severe disease. This study furthers our understanding of oseltamivir treatment dynamics both systemically and in the lungs of obese mice, as well as the consequences of oseltamivir treatment for the within-host emergence of drug-resistant variants.

Evaluating the effects of episodic and semantic memory induction procedures on divergent thinking in younger and older adults.

Evidence suggesting that episodic specificity induction improves divergent thinking performance in younger and older adults has been taken as indicative of the role of declarative memory processes in creativity. A series of studies were carried out to verify the specificity of such findings by investigating the effects of several novel episodic and semantic memory induction procedures on a widely employed measure of divergent creative thinking (the Alternate Uses Task), in comparison to a control induction and a no-induction baseline in both younger and older adults. There was no clear evidence for a specific role played by the induction of episodic or semantic memory processes in facilitating creative thinking across the three experiments, and the effects of the induction procedures (episodic, semantic and control) on divergent thinking were not comparable across age groups. On the other hand, higher levels of creativity were generally associated with older adults (60-80 years). In Experiments 2 and 3, older adults generated a greater number of responses (fluency), more unique responses (average originality, peak originality, creativity ratings) and more varied responses (flexibility) than younger adults (18-30 years). The findings are discussed in relation to the specificity of declarative memory operations and their impact on creative thinking, especially within the context of healthy ageing.

Peripheral T-cell lymphoma-not otherwise specified, angioimmunoblastic T-cell lymphoma and anaplastic large cell lymphoma: Are the outcomes any different in Hispanics?

e18773 Background: Peripheral T cell lymphoma – not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) are unusual non-Hodgkin lymphomas with miscellaneous clinical characteristics which share the same treatment regimen (Blood PMID28115372 Cancer Treat ResPMID30596215 Blood PMID28115369). Gene expression profiling has facilitated their diagnosis; but much remains to be learned about risk factors, biological and clinical implications (Oncologist PMID16880242). This is the first national population-based analysis evaluating ethnic differences for Hispanics (HI) diagnosed with PTCL-NOS, AITL and ALCLin the US. Methods: Data were analyzed on PTCL-NOS, AITL and ALCL patients in the US reported to the Surveillance, Epidemiology, and End Results (SEER) database between 2000-2018. Demographic, clinical and survival patterns were analyzed. Kaplan-Meier and Cox regression analyses were used when appropriate. Multivariate analysis and propensity score matching were performed with adjustment for age, stage and B-symptoms. Results: 12,749 patients were diagnosed with PTCL-NOS, AITL and ALCL (1,666 cases were HI = 798 PTCL-NOS, 316 AITL and 552 ALCL). Male predominated for HI and Non-HI (NH) in the 3 malignancies. HI were diagnosed at a younger median age than NH, PTCL-NOS 60 years(y) vs 65y, AITL 65y vs 69y, and ALCL 45y vs 55y, respectively [p <0.001]. White race predominated for both. When diagnosed with PTCL-NOS or AITL, HI were more likely diagnosed from 2015-2018 but those with ALCL were identified from 2000-2004. For the 3 malignancies limited information regarding B symptoms was available. Most of the cases of HI and NH were diagnosed at advanced stages in all subtypes. Overall, for both the tendency was towards not receiving radiation. HI vs NH diagnosed with PTLC-NOS had median survival of 1.2 vs 1.3y; AITL was 2.2 vs 1.7y and ALCL 6.0 vs 9.3y. Survival probability for 2, 5 and 10y were comparable among HI and NH for all malignancies and no difference in OS was noted. On multivariate analysis, patients who were older than 80y and between 60-80 y, had worse OS compared to those <60y. For all subtypes, those who were diagnosed at stage III/IV had worse OS than those at early stage I/II. Conclusions: Similar OS for HI and NH diagnosed with PTCL-NOS, AITL and ALCL. Nonetheless, diagnosis at younger age and early stage play a significant role to better survival. Although HI were more subjected to early age at diagnosis and less likely to be at a stage I/II, no impact in survival was evidenced, which suggests that unique responses may counteract within this race. It is captivating that no gradual increase in diagnosis was noted despite the continuous development of genetic testing and improved diagnostic tools, which highlights that socioeconomical variables may have been influencing its access.

Consumers’ Attitude Toward Electric Vehicles in India : Mapping Psychological Antecedents and Consequences

Purpose : Deteriorating air quality, rising carbon footprint, and increasing fuel prices have called for India’s automobile industry to gear up for acute transformation. The current study, drawing parallel lines from SOR theory, investigated how the attitude toward EVs was affected by three psychological antecedents—utilitarian shopping value, conspicuous consumption, and lifestyle. Further, the study examined how this attitude impacted the intention of Indian consumers to purchase an EV and their ecological behavior. Design/Methodology/Approach : The study included 382 Indian consumers of EVs who constituted the sample population. A structured questionnaire was created to gather information from this sample. The SEM (structural equation modeling) approach was applied to draw conclusions from the data. Findings : The results indicated that out of three antecedents, only utilitarian shopping value had no significant relationship with attitude toward EVs. Also, the attitude was found to be positively related to purchase intention and ecological behavior. Implications : Manufacturers and marketers of EVs must include lifestyle and conspicuous aspects in their offerings. Moreover, they should work on enhancing the utilitarian value of EVs. Never should a person feel that he/she is paying more than he/she is getting. Special note for conspicuous consumers who are shedding huge resources to make a statement among peers. Originality Value : The current study was one of the prime ones to draw the impact of lifestyle, conspicuousness, and utilitarian values on attitudes toward EVs. Moreover, the current study provided a one-of-a-kind modified model of SOR theory by including unique stimuli and responses.

Long-term follow-up results of ipilimumab and nivolumab for the treatment of mismatch repair deficient locally advanced rectal cancer.

e15652 Background: Mismatch repair deficient (dMMR) colorectal cancers have unique biology and responses to therapy. In the advanced setting, first line immunotherapy has superior activity compared to chemotherapy. Recent studies have demonstrated improved responses with neoadjuvant anti-PD1 therapy for dMMR locally advanced rectal cancer (LARC). In this study, we review our experience with the combination of ipilimumab (ipi) and nivolumab (nivo) for the treatment of dMMR LARC. Methods: Patients (pts) with dMMR LARC treated with ipi/nivo at the University of Wisconsin Carbone Center were identified under an IRB-approved protocol. Baseline demographics, molecular testing, treatment history, clinical imaging, and pathological evaluations were collected and summarized. Pts were followed with serial imaging (CT/MRI), endoscopic evaluations, and ctDNA MRD assays. Results: Fours pts (median age: 63 [range: 59-68]; 50% female) with dMMR LARC treated with ipi/nivo were identified. 3 pts had T4 tumors and were node positive. 1 patient had a mutation in MSH6, 1 patient had 2 mutations in MSH2, another had loss of MLH1/PMS2 on IHC, and the last patient had loss of MSH2/MSH6 on IHC. None of the patients have known germline variants. 2 patients were treated initially with FOLFOX chemotherapy and had progressive disease prior to conversion to ipi/nivo. Median follow-up is 25.5 months [range: 9-42] and 1 pt continues on nivo treatment. Pts were treated with 1-4 infusions of ipi and 2-24 months of nivolumab. All patients achieved a complete clinical/pathologic response and remain without evidence of disease recurrence. None of the pts required additional surgery or radiation therapy for cancer recurrence/progression. 3 of the 4 patients developed grade 3/4 immune-related adverse events, including 2 patients with adrenal insufficiency and 1 patient with immune hepatitis. 1 pt developed a fibrotic stricture at the site of the prior cancer requiring resection. Conclusions: dMMR LARC is a unique subtype of rectal cancer sensitive to combination immunotherapy with high potential for complete responses and organ preservation. The use of ipi/nivo in this cohort of pts resulted in complete pathogenic responses for all that remain durable over an extended period of time, though with increased immune-related adverse events compared to anti-PD1 therapies alone. This regimen is currently being studied further in prospective studies.

Energy stress modulation of AMPK/FoxO3 signaling inhibits mitochondria-associated ferroptosis

Cancer cells and ischemic diseases exhibit unique metabolic responses and adaptations to energy stress. Forkhead box O 3a (FoxO3a) is a transcription factor that plays an important role in cell metabolism, mitochondrial dysfunction and oxidative stress response. Although the AMP-activated protein kinase (AMPK)/FoxO3a signaling pathway plays a pivotal role in maintaining energy homeostasis under conditions of energy stress, the role of AMPK/FoxO3a signaling in mitochondria-associated ferroptosis has not yet been fully elucidated. We show that glucose starvation induced AMPK/FoxO3a activation and inhibited ferroptosis induced by erastin. Inhibition of AMPK or loss of FoxO3a in cancer cells under the glucose starvation condition can sensitize these cells to ferroptosis. Glucose deprivation inhibited mitochondria-related gene expression, reduced mitochondrial DNA(mtDNA) copy number, decreased expression of mitochondrial proteins and lowered the levels of respiratory complexes by inducing FoxO3a. Loss of FoxO3a promoted mitochondrial membrane potential hyperpolarization, oxygen consumption, lipid peroxide accumulation and abolished the protective effects of energy stress on ferroptosis in vitro. In addition, we identified a FDA-approved antipsychotic agent, the potent FoxO3a agonist trifluoperazine, which largely reduced ferroptosis-associated cerebral ischemia-reperfusion (CIR) injuries in rats through AMPK/FoxO3a/HIF-1α signaling and mitochondria-dependent mechanisms. We found that FoxO3a binds to the promoters of SLC7A11 and reduces CIR-mediated glutamate excitotoxicity through inhibiting the expression of SLC7A11. Collectively, these results suggest that energy stress modulation of AMPK/FoxO3a signaling regulates mitochondrial activity and alters the ferroptosis response. The regulation of FoxO3a by AMPK may play a crucial role in mitochondrial gene expression that controls energy balance and confers resistance to mitochondria-associated ferroptosis and CIR injuries.

Transcriptome profiling uncovers the involvement of CmXyn1, a glycosyl hydrolase 11, in Cochliobolus miyabeanus pathogenicity

Necrotrophic pathogen Cochliobolus miyabeanus (C. miyabeanus) causes rice brown leaf spot disease and drastically affects the yield and quality of rice grains. However, the molecular mechanism of rice-C. miyabeanus remains poorly understood due to the limited research conducted on this pathosystem. To elucidate the molecular mechanism of rice-C. miyabeanus, a transcriptome analysis was conducted from in vitro and in planta grown C. miyabeanus. This analysis led to the identification of a total of 24,060 genes of which 426 in vitro and 57 in planta expressed genes were predicted to encode for secretory proteins. As these 57 genes were specifically expressed in planta and were predicted to be secretory in nature, these were consider as putative effectors, highlighting their possible roles in the fungal pathogenicity. Notably, among these putative effectors, CmXyn1 which encodes a glycosyl hydrolase 11 displayed the highest expression level under in planta conditions and was thus selected for further functional characterization. Interestingly, the extracellular expression of CmXyn1 transiently induced cell death in Nicotiana benthamiana leaves, while intracellular expression was comparatively lesser effective. In addition, transcriptome analysis on rice leaves during C. miyabeanus infection and comparing it to the rice leaf transcriptome data obtained during hemibiotrophic pathogen Magnaporthe oryzae infection led to the discovery of 18 receptors/receptor-like kinases that were commonly expressed in response to both pathogens, indicating their key roles in rice defense response. Taken together, our findings provide new insights into rice-C. miyabeanus interaction as well as the unique and common defense responses of rice against hemibiotroph and necrotroph model systems.

Early-life experience reorganizes neuromodulatory regulation of stage-specific behavioral responses and individuality dimensions during development.

Early-life experiences may promote stereotyped behavioral alterations that are dynamic across development time, but also behavioral responses that are variable among individuals, even when initially exposed to the same stimulus. Here, by utilizing longitudinal monitoring of Caenorhabditis elegans individuals throughout development we show that behavioral effects of early-life starvation are exposed during early and late developmental stages and buffered during intermediate stages of development. We further found that both dopamine and serotonin shape the discontinuous behavioral responses by opposite and temporally segregated functions across development time. While dopamine buffers behavioral responses during intermediate developmental stages, serotonin promotes behavioral sensitivity to stress during early and late stages. Interestingly, unsupervised analysis of individual biases across development uncovered multiple individuality dimensions that coexist within stressed and unstressed populations and further identified experience-dependent effects on variation within specific individuality dimensions. These results provide insight into the complex temporal regulation of behavioral plasticity across developmental timescales, structuring shared and unique individual responses to early-life experiences.

From Social Psychological Perspective to the Factors Influencing Suicide Among Minors

Despite the growing clamour for psychosocial knowledge and the measures held by the state to protect the mental health of minors, there are still minors whose negative emotions simply cannot be attended to. In this paper, in order to understand and respond to underage suicide, it is needed to think about the three main causes that influence underage suicide rates in terms of two sociological theories: family conflict, academic pressure and teacher-student conflict. Mead's proposal that human consciousness influences human behaviour can explain the impact of family conflict, academic pressure and teacher-student conflict on underage suicide rates; underage suicide rates are socially social, cultural and historical contexts in which constructivism arose, influenced and shaped by the three main causes of underage suicide. With an understanding of the root causes of the underage suicide rate, it is possible to consider and implement unique responses to combat the rise in the underage suicide rate. The consciousness of Chinese minors is socially generated and influenced by the historical inheritance brought about by social constructivism. It is also believed that the age of 15-18 is the age when minors are desperate to study and that the pressure from studying eventually becomes. The pressure from studying eventually becomes a conflict between parents and teachers and students, and minors develop a negative psychological consciousness that is eventually acted upon.

Electrical Stimulation of Temporal and Limbic Circuitry Produces Distinct Responses in Human Ventral Temporal Cortex.

The human ventral temporal cortex (VTC) is highly connected to integrate visual perceptual inputs with feedback from cognitive and emotional networks. In this study, we used electrical brain stimulation to understand how different inputs from multiple brain regions drive unique electrophysiological responses in the VTC. We recorded intracranial EEG data in 5 patients (3 female) implanted with intracranial electrodes for epilepsy surgery evaluation. Pairs of electrodes were stimulated with single-pulse electrical stimulation, and corticocortical evoked potential responses were measured at electrodes in the collateral sulcus and lateral occipitotemporal sulcus of the VTC. Using a novel unsupervised machine learning method, we uncovered 2-4 distinct response shapes, termed basis profile curves (BPCs), at each measurement electrode in the 11-500 ms after stimulation interval. Corticocortical evoked potentials of unique shape and high amplitude were elicited following stimulation of several regions and classified into a set of four consensus BPCs across subjects. One of the consensus BPCs was primarily elicited by stimulation of the hippocampus; another by stimulation of the amygdala; a third by stimulation of lateral cortical sites, such as the middle temporal gyrus; and the final one by stimulation of multiple distributed sites. Stimulation also produced sustained high-frequency power decreases and low-frequency power increases that spanned multiple BPC categories. Characterizing distinct shapes in stimulation responses provides a novel description of connectivity to the VTC and reveals significant differences in input from cortical and limbic structures.SIGNIFICANCE STATEMENT Disentangling the numerous input influences on highly connected areas in the brain is a critical step toward understanding how brain networks work together to coordinate human behavior. Single-pulse electrical stimulation is an effective tool to accomplish this goal because the shapes and amplitudes of signals recorded from electrodes are informative of the synaptic physiology of the stimulation-driven inputs. We focused on targets in the ventral temporal cortex, an area strongly implicated in visual object perception. By using a data-driven clustering algorithm, we identified anatomic regions with distinct input connectivity profiles to the ventral temporal cortex. Examining high-frequency power changes revealed possible modulation of excitability at the recording site induced by electrical stimulation of connected regions.

Dr. Google's Advice on First Aid: Evaluation of the Search Engine's Question-Answering System Responses to Queries Seeking Help in Health Emergencies.

The ever-growing penetration of internet and mobile technologies into society suggests that people will increasingly use web searches to seek health-related information, including advice on first aid in medical emergencies. When a bystander is incompetent in first aid and has no immediate support from Emergency Medical Services (EMS), as it happens in low-resource settings or in disasters, instructions found online could be the sole driver for administering first aid before arrival of professional help. The aim of this study was to evaluate quality of advice on first aid generated by a web search engine's question-answering system (QAS) in response to search queries concerning provision of help in common health emergencies. In December 2022-January 2023, an English-language search was carried out in Google with ten queries based on the keyword combinations (what to do OR how to help) AND (bleeding OR chest pain OR choking OR not breathing OR seizure). The search engine's QAS responses (up to 11 per search query) were evaluated for compliance with the International Federation of Red Cross First Aid Guidelines 2020 using the pre-developed checklists. Out of 98 QAS items generated by Google, 67.3% (n = 66) were excluded, mainly because the QAS answers did not address original queries. Eligible unique QAS responses (n = 27) showed poor coverage of the guideline-compliant instructions on first aid. Mean percentage of QAS responses providing a first aid instruction with complete adherence to the guidelines varied from 0.0 for choking to 19.5 for seizure. Only three (11.1%) QAS responses contained an explicit instruction to access EMS, while 66.7% (n = 18) included directions either contradictory to the guidelines and potentially harmful (eg, use of home remedies in chest pain) or inapplicable for an untrained person (eg, use of tourniquet in bleeding). Although the search engine's QAS responds to user's inquiries concerning assistance in health emergencies, the QAS-generated answers, as a rule, omit potentially life-saving evidence-based instructions on first aid and oftentimes give advices noncompliant with current guidelines or inadequate for untrained people, and thus create risks for causing harm to a victim.

One-Pot Three Component Synthesis of Quinazolin-4(3H)-One Derivatives: Investigation of Photophysical Properties and FRET Application toward Protein Lysozyme

A one-pot, three-component reaction between isatoic anhydride, 1,3-diketones, and amines/arylhydrazines catalyzed by a combination of molecular I2 and Et3N in open-air affords a series of quinazolin-4(3H)-one derivatives in good yield. The protocol offers an operationally simple, facile, and cost-effective pathway utilizing easily accessible reagents under mild reaction conditions with significant substrate scope. The results of steady state and time-resolved absorption and emission spectroscopy indicate the potential of quinazolin-4(3H)-one derivatives as a fluorescence probe. They exhibit unique photophysical responses in different solvent environments. In addition, they can also act as FRET acceptors during interaction with protein lysozyme. Preliminary biological studies indicate that quinazolin-4(3H)-ones are cell permeable and can be used as a fluorescent probe for bio-imaging of human cervical cancer (HeLa) cells.

Fault-tolerant reversible logic gate-based RO-PUF design

Physically Unclonable Function (PUF) is an emerging modern approach to the security concerns of the physical systems which require the protection of sensitive data. PUF generates unique, reliable, and secure responses which can be utilized for cryptographic applications. In this paper, a fault-tolerant reversible logic gate-based RO PUF is proposed. We utilized a fault-tolerant reversible logic Double Feynman Gate in place of conventional inverters to design the ring oscillators (RO). The proposed RO PUF designs implemented and evaluated on the Basys-3 Artix-7 FPGA board. The PUF parameters such as uniqueness, reliability, and uniformity were analyzed based on the experimental results. The empirical results show that the proposed RO PUF has uniqueness and reliability of 0.49 and 85.95%, respectively. The inter-chip and intra-chip uniqueness for the proposed design is 23% and 25.5%, respectively higher than the conventional RO PUF design. This fault-tolerant reversible logic gate-based RO PUF design shows better uniqueness, reliability, and uniformity than other considered PUF designs.

A method for multiplexed and volumetric-based magnetic particle spectroscopy bioassay: mathematical study

Magnetic particle spectroscopy (MPS) is an emerging biosensing technique that detects target analytes by exploiting the dynamic magnetic responses of magnetic nanoparticles (MNPs). Due to the ease of synthesis and surface chemical functionalization of MNPs, MPS-based bioassays have gained popularity around the globe. One limiting factor for MPS-based assay is the ability to detect multiple analytes simultaneously in a single run, namely, multiplexed bioassay. Several groups have reported the realization of multiplexed bioassays on surface-based MPS platforms by spatially separating reaction areas by using the unique magnetic responses of different MNPs. In this work, we systematically study the magnetization curves (M-H curves) of different types of MNPs and their relationship to the dynamic magnetic responses when subjected to AC magnetic driving fields. Due to the different structures, sizes, and magnetic properties of each kind of MNP, the resulting harmonics are unique. Thus, concurrent quantification (also called ‘colorization’) of each type of MNP in a mixture is possible by solving the harmonic matrix function. Our results show that the uniqueness of M-H response curves of selected types of MNP and the signal-to-noise ratio of the system can affect the accuracy of multiplexed, volumetric-based MPS bioassays. The reported method assumes that each type of MNPs nanoparticles does not interact, and that the magnetic response of the mixture is a linear combination of the responses of each kind of MNP. This assumption may not hold for very dense systems where inter-particle interactions become significant and may require more complex models.

Detecting unique analyte-specific radio frequency spectral responses in liquid solutions -- implications for non-invasive physiologic monitoring

With rising healthcare costs and the rapid increase in remote physiologic monitoring and care delivery, there is increasing need for economical, accurate and non-invasive continuous measures of blood analytes. Based on radio-frequency identification (RFID), we have developed a novel electromagnetic platform technology (the Bio-RFID platform) to non-invasively penetrate inanimate surfaces, capture data from individual radio frequencies, and convert those data into physiologically meaningful information and insights. Here we describe ground-breaking proof-of-principle studies using Bio-RFID to accurately measure various concentrations of analytes in deionized water. The in vitro Bio-RFID platform consists of an acrylic cuvette in the shape of a 4 inch x 4 inch x 8 inch rectangular prism mounted on the Bio-RFID sensor. This apparatus is in turn mounted on a balance that allows the determination of the mass of the analyte being scanned to within 0.1g. The hardware scans through several thousand radio frequencies and sends the data to proprietary software running on a laptop computer. The software displays a spectral scan known as the Bio-RFID signature of the analyte and computes a similarity metric to compare different signatures.We tested the hypothesis that the Bio-RFID platform is able to precisely and non-invasively measure and identify a variety of analytes in vitro. For this assessment, varying solutions of 1) water in isopropyl alcohol; 2) salt in water; and 3) commercial bleach in water were tested, using a randomized double-blind trial design, as proxies for biochemical solutions in general. The Bio-RFID technology was able to detect concentrations of 2000 parts per million (ppm), with evidence suggesting the ability to detect considerably smaller concentration differences. The novel application of a Bio-RFID electromagnetic platform technology accurately detects, measures, and quantifies specific molecules in liquid. While these findings have in vitro commercial applications, these proof-of-principle studies provide strong support for the application of Bio-RFID technology for non-invasive bio-monitoring of physiologically and medically relevant analytes, such as alcohol and glucose, in the human body. These studies were funded by a grant from Know Labs to Mayo Clinic. PB and JHA are employed by Know Labs. VKS and Mayo Clinic acknowledge a financial interest in Know Labs. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dietary potassium restriction reprograms the distal tubule causing adverse metabolic consequences

Low potassium (K) intake has adverse health effects, including hypertension, osteoporosis, and nephrolithiasis. Dietary K restriction rapidly activates a K switch in the distal nephron to maintain homeostasis by reducing K excretion and activating the sodium chloride cotransporter (NCC). The distal convoluted tubule (DCT) is morphologically and functionally divided into DCT1 and DCT2, with each segment specialized for a different function. Here, we define the differences between DCT1 and DCT2 transcriptionally, examine their unique responses to potassium restriction, and detrimental physiological responses in mice.The K restriction effects were examined at 3 time points, overnight (acute), 4 days (short-term), and 4 weeks (chronic). Electrophysiology was used to assess effects of acute K deprivation on basolateral K channel (Kir4.1/5.1) activity. To determine effects of K restriction for 4 days, the DCT-targeted single-nucleus RNA-sequencing (snRNAseq) approach was applied. Female NCC-Cre-INTACT (PMID: 26087164) mice were provided either normal (NK) or K deficient (KD) diet for 4 days (short-term) and kidneys were snap-frozen for targeted snRNAseq (10X Chromium, NovaSeq) (3 mice per diet, 10,000 nuclei per mouse). Effects of chronic K-restriction were assessed by serum electrolytes, tissue clearing, and western blot.Acute K restriction stimulated basolateral K channel activity in DCT1, but not in DCT2, indicating that DCT1 and DCT2 respond differently. Although both DCT1 and DCT2 express NCC, snRNAseq data showed that DCT1 and DCT2 have distinct transcriptional signatures, with DCT1 expressing genes involved in magnesium reabsorption, and DCT2 expressing genes involved in calcium reabsorption and electrogenic sodium channel (ENaC). Four days of K restriction switched the DCT from a K-wasting state to K-sparing state, shown by reduction of gENaC ( Scnn1g) and Kallikrein ( Klk1) expression. Furthermore, K restriction decreased the expression of the calcium-handling genes Slc8a1, Calb and Vdr. When prolonged, K restriction led to increases in NCC, reduction in ENaC cleavage, and elongation of the DCT. It also led to calcium wasting (plasma iCa in NK, 1.38 ± 0.03, n=7; KD, 1.24 ± 0.01 mM, n=6) and reduction in calbindin D-28k protein.Our results suggest that DCT1 and DCT2 both express NCC, but have distinct transcriptomic signatures with unique roles in magnesium and calcium transport, respectively. Dietary K restriction reprograms DCT2 cells to be more like DCT1 cells, thereby maintaining K balance but contributing to calcium wasting as a complication. NIH DK51496, NIH DK054983, VA 1I01BX002228, LeDucq Fondation This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Conceptualizing Indigenous strengths-based health and wellness research using group concept mapping

BackgroundIn recent years public health research has shifted to more strengths or asset-based approaches to health research but there is little understanding of what this concept means to Indigenous researchers. Therefore our purpose was to define an Indigenous strengths-based approach to health and well-being research.MethodsUsing Group Concept Mapping, Indigenous health researchers (N = 27) participated in three-phases. Phase 1: Participants provided 218 unique responses to the focus prompt “Indigenous Strengths-Based Health and Wellness Research…” Redundancies and irrelevant statements were removed using content analysis, resulting in a final set of 94 statements. Phase 2: Participants sorted statements into groupings and named these groupings. Participants rated each statement based on importance using a 4-point scale. Hierarchical cluster analysis was used to create clusters based on how statements were grouped by participants. Phase 3: Two virtual meetings were held to share and invite researchers to collaboratively interpret results. ResultsA six-cluster map representing the meaning of Indigenous strengths-based health and wellness research was created. Results of mean rating analysis showed all six clusters were rated on average as moderately important.ConclusionsThe definition of Indigenous strengths-based health research, created through collaboration with leading AI/AN health researchers, centers Indigenous knowledges and cultures while shifting the research narrative from one of illness to one of flourishing and relationality. This framework offers actionable steps to researchers, public health practitioners, funders, and institutions to promote relational, strengths-based research that has the potential to promote Indigenous health and wellness at individual, family, community, and population levels.

Characterization of Childhood Neurodegeneration and Associated Ataxia in UBTF-Related Disorder (P12-9.011)

<h3>Objective:</h3> To clarify the natural history of neurodegeneration related to a heterozygous missense de novo mutation in the upstream binding transcription factor (<i>UBTF</i>) gene and to understand the movement patterns extracted from continuous wrist and ankle accelerometer data. <h3>Background:</h3> <i>UBTF</i>-related childhood-onset neurodegeneration is characterized by a period of typical or mildly delayed development followed by regression. Affected individuals frequently experience movement disorders, including ataxia. <h3>Design/Methods:</h3> An online REDCap survey of families of patients with a pathogenic variant in <i>UBTF</i> was conducted. Between March 2021 and February 2022, 52 surveys were started. Duplicate and incomplete responses were excluded. Ten unique responses were fully submitted, and these were included for analysis. Patients with <i>UBTF</i>-related disorder evaluated in a neurogenetics clinic were enrolled for data collection using wearable wrist and ankle accelerometers. Longitudinal data during typical daily activities was collected remotely for continuous one-week periods. These findings were compared to similar data collected from patients with Ataxia-Telangiectasia (A-T) and control subjects. Motor activity was compared with clinical severity using the Brief Ataxia Rating Scale (BARS). <h3>Results:</h3> Median age of the survey subjects was 12.5 years (range 5–20 years), with symptom onset at a median of 2.5 years. All participants reported motor regression (median 3.75 years at onset), with 90% reporting ataxia. Motor activity data was collected from 5 participants (median age 12 years, range 8–12 years), with 3 time points included for one participant (2 with wrist data only) and 1 time point for the other 4 participants. Data from both sensors had high test-retest reliability. Motor activity showed similarities to A-T over controls across multiple measures and correlated with BARS scores. <h3>Conclusions:</h3> Ataxia is frequent in <i>UBTF-</i>related disorder. Motor activity data collected via wrist and ankle accelerometers is a highly reliable measure correlated to disease severity with results resembling other hereditary ataxias, indicating potential use as a motor biomarker. <b>Disclosure:</b> Dr. Nagy has nothing to disclose. Ms. Gupta has nothing to disclose. Ms. Molay has nothing to disclose. Miss De la Rosa Abreu has nothing to disclose. Catherine Becker has nothing to disclose. Dr. Gupta has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Biogen. The institution of Dr. Gupta has received research support from Biogen. An immediate family member of Dr. Eichler has received personal compensation for serving as an employee of UpToDate. Dr. Eichler has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for SwanBio Therapeutics. Dr. Eichler has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam. Dr. Eichler has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Origin Biosciences. Dr. Eichler has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Orchard Therapeutics. Dr. Eichler has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Autobahn Therapeutics. Dr. Eichler has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bluebird Bio. Dr. Eichler has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for UpToDate. Dr. Eichler has received stock or an ownership interest from SwanBio Therapeutics. The institution of Dr. Eichler has received research support from Bluebird Bio. The institution of Dr. Eichler has received research support from Minoryx Therpeutics. The institution of Dr. Eichler has received research support from Sio Therapeutics. Dr. Eichler has received intellectual property interests from a discovery or technology relating to health care.

A Night at the Neurocinema: Evaluating the Educational Impact of a Neurology-Centric Film Series on a Medical Student Cohort (P3-2.002)

<h3>Objective:</h3> This study evaluated impact of a monthly “Neurology Movie Night” film program on student knowledge and interest in neurological disorders. <h3>Background:</h3> Neurophobia is the fear of neurology reported among medical students who find it complex and intimidating. The high incidence of neurophobia warrants research into novel methods of neurological education especially in stress-free and informal settings. The term “Neurocinema” has been used to described the portrayal of neurological disorders in movies; its educational value for medical students has not yet been significantly investigated. <h3>Design/Methods:</h3> This was an IRB approved, single-center prospective cohort study inviting voluntary participation of medical students across all years of training. Once per month, participants were asked to virtually view a select movie portraying neurological disease(s). Viewers completed an anonymous survey assessing their perceived knowledge and interest in the subject. Quantitative variables were reported in percentage with change in student perception being assessed on Likert scale. <h3>Results:</h3> Total 17 unique responses were collected. 12/17 (70%) students were in pre-clinical years. 8/17 (47%) students reported an increase in interest and 9/17 (53%) reported increase in perceived knowledge pertaining to the specific disorder after watching the movie. There was no decline in interest or knowledge reported. Majority of students (15/17) had at least some baseline interest in neurology, but about 23% reported an increase in level of interest after completion of activity. 29% of respondents reported additional self-directed reading on topics portrayed in the movies. <h3>Conclusions:</h3> Neurocinema can be a strategy to combat neurophobia and increase medical student engagement in neurology. Based on our results, groups most responsive include students who have a baseline interest in neurology, and those who are in their pre-clinical years. Therefore, an activity such as “Neurology Movie Night” can be a tool to further increase student interest in neurology via local Student Interest Group in Neurology (SIGN) chapters. <b>Disclosure:</b> Mr. Schmitt has nothing to disclose. Dr. Bryden has nothing to disclose. Dr. Das has nothing to disclose. Dr. Lakhotia has nothing to disclose.