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A workshop titled Beyond the Symptom: The Biology of Fatigue was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.

The awareness of individuals’ biological status is critical for creating interactive and adaptive environments that can actively assist the users to achieve optimal outcomes. Accordingly, specialized human–machine interfaces—equipped with bioperception and interpretation capabilities—are required. To this end, we devised a multimodal cryptographic bio-human–machine interface (CB-HMI), which seamlessly translates the user’s touch-based entries into encrypted biochemical, biophysical, and biometric indices. As its central component, the CB-HMI features thin hydrogel-coated chemical sensors and inference algorithms to noninvasively and inconspicuously acquire biochemical indices such as circulating molecules that partition onto the skin (here, ethanol and acetaminophen). Additionally, the CB-HMI hosts physical sensors and associated algorithms to simultaneously acquire the user’s heart rate, blood oxygen level, and fingerprint minutiae pattern. Supported by human subject studies, we demonstrated the CB-HMI’s capability in terms of acquiring physiologically relevant readouts of target bioindices, as well as user-identifying and biometrically encrypting/decrypting these indices in situ (leveraging the fingerprint feature). By upgrading the common surrounding objects with the CB-HMI, we created interactive solutions for driving safety and medication use. Specifically, we demonstrated a vehicle-activation system and a medication-dispensing system, where the integrated CB-HMI uniquely enabled user bioauthentication (on the basis of the user’s biological state and identity) prior to rendering the intended services. Harnessing the levels of bioperception achieved by the CB-HMI and other intelligent HMIs, we can equip our surroundings with a comprehensive and deep awareness of individuals’ psychophysiological state and needs.

Purpose: Negative attitudes towards peers with disabilities can lead to undesirable behaviour and reduced social participation of students with disabilities. The present study aimed to investigate the effectiveness of a Paralympic sports class on the attitudes towards peers with disabilities and perceptions of human rights of Korean high school students without disabilities. Method: Participants were 168 freshmen high school students without disabilities. Participants were randomly divided into two groups. The intervention group participated in a Paralympic sports class and the control group in a general physical education class. The Attitude towards Peer with Disabilities Scale (APDS) and Human Rights Sensitivity Scale (HRSS) were measured three times -- pre-intervention, post-intervention, and after a 9-month follow-up period. Results: APDS and HRSS scores significantly increased following intervention and maintained after 12 months. No changes were observed in the control group. Conclusions: The attitudes of high school students towards peers with disabilities and their human rights sensitivity improved and this improvement was maintained for 9 month s after completing a Paralympic sports class. Such classes could provide benefits for the psychosocial development of high school students without disabilities.

To achieve the mission of personalized medicine, centering on delivering the right drug to the right patient at the right dose, therapeutic drug monitoring solutions are necessary. In that regard, wearable biosensing technologies, capable of tracking drug pharmacokinetics in noninvasively retrievable biofluids (e.g., sweat), play a critical role, because they can be deployed at a large scale to monitor the individuals' drug transcourse profiles (semi)continuously and longitudinally. To this end, voltammetry-based sensing modalities are suitable, as in principle they can detect and quantify electroactive drugs on the basis of the target's redox signature. However, the target's redox signature in complex biofluid matrices can be confounded by the immediate biofouling effects and distorted/buried by the interfering voltammetric responses of endogenous electroactive species. Here, we devise a wearable voltammetric sensor development strategy-centering on engineering the molecule-surface interactions-to simultaneously mitigate biofouling and create an "undistorted potential window" within which the target drug's voltammetric response is dominant and interference is eliminated. To inform its clinical utility, our strategy was adopted to track the temporal profile of circulating acetaminophen (a widely used analgesic and antipyretic) in saliva and sweat, using a surface-modified boron-doped diamond sensing interface (cross-validated with laboratory-based assays, R 2 ∼ 0.94). Through integration of the engineered sensing interface within a custom-developed smartwatch, and augmentation with a dedicated analytical framework (for redox peak extraction), we realized a wearable solution to seamlessly render drug readouts with minute-level temporal resolution. Leveraging this solution, we demonstrated the pharmacokinetic correlation and significance of sweat readings.

When it comes to simulate or calculate an optoelectronic tweezer (OET) response for a microparticle suspended in a given medium, a precise electrical conductivity (later referred to as conductivity) value for the microparticle is critical. However, there are not well-established measurements or well-referenced values for microparticle conductivities in the OET realm. Thus, we report a method based on measuring the escape velocity of a microparticle with a standard OET system to calculate its conductivity. A widely used 6 μm polystyrene bead (PSB) is used for the study. The conductivity values are found to be invariant around 2×10-3 S/m across multiple different aqueous media, which helps clarify the ambiguity in the usage of PSB conductivity. Our convenient approach could principally be applied for the measurement of multiple unknown OET-relevant material properties of microparticle-medium systems with various OET responses, which can be beneficial to carry out more accurate characterization in relevant fields. [ABSTRACT FROM AUTHOR]

Perspiration-based wearable biosensors facilitate continuous monitoring of individuals' health states with real-time and molecular-level insight. The inherent inaccessibility of sweat in sedentary individuals in large volume (≥10 µL) for on-demand and in situ analysis has limited our ability to capitalize on this noninvasive and rich source of information. A wearable and miniaturized iontophoresis interface is an excellent solution to overcome this barrier. The iontophoresis process involves delivery of stimulating agonists to the sweat glands with the aid of an electrical current. The challenge remains in devising an iontophoresis interface that can extract sufficient amount of sweat for robust sensing, without electrode corrosion and burning/causing discomfort in subjects. Here, we overcame this challenge through realizing an electrochemically enhanced iontophoresis interface, integrated in a wearable sweat analysis platform. This interface can be programmed to induce sweat with various secretion profiles for real-time analysis, a capability which can be exploited to advance our knowledge of the sweat gland physiology and the secretion process. To demonstrate the clinical value of our platform, human subject studies were performed in the context of the cystic fibrosis diagnosis and preliminary investigation of the blood/sweat glucose correlation. With our platform, we detected the elevated sweat electrolyte content of cystic fibrosis patients compared with that of healthy control subjects. Furthermore, our results indicate that oral glucose consumption in the fasting state is followed by increased glucose levels in both sweat and blood. Our solution opens the possibility for a broad range of noninvasive diagnostic and general population health monitoring applications.

Isolation and characterization of rare cells and molecules from a heterogeneous population is of critical importance in diagnosis of common lethal diseases such as malaria, tuberculosis, HIV, and cancer. For the developing world, point-of-care (POC) diagnostics design must account for limited funds, modest public health infrastructure, and low power availability. To address these challenges, here we integrate microfluidics, electronics, and inkjet printing to build an ultra-low-cost, rapid, and miniaturized lab-on-a-chip (LOC) platform. This platform can perform label-free and rapid single-cell capture, efficient cellular manipulation, rare-cell isolation, selective analytical separation of biological species, sorting, concentration, positioning, enumeration, and characterization. The miniaturized format allows for small sample and reagent volumes. By keeping the electronics separate from microfluidic chips, the former can be reused and device lifetime is extended. Perhaps most notably, the device manufacturing is significantly less expensive, time-consuming, and complex than traditional LOC platforms, requiring only an inkjet printer rather than skilled personnel and clean-room facilities. Production only takes 20 min (vs. up to weeks) and $0.01-an unprecedented cost in clinical diagnostics. The platform works based on intrinsic physical characteristics of biomolecules (e.g., size and polarizability). We demonstrate biomedical applications and verify cell viability in our platform, whose multiplexing and integration of numerous steps and external analyses enhance its application in the clinic, including by nonspecialists. Through its massive cost reduction and usability we anticipate that our platform will enable greater access to diagnostic facilities in developed countries as well as POC diagnostics in resource-poor and developing countries.

Objectives: Self-description research on athletes with intellectual disabilities (ID) is under investigated. The specific aims in this paper are (a) to identify the differences in physical self-concept and body image by Unified Sports experiences, and (b) to investigate predictors of physical self-concept. Methods: Participants included 89 Special Olympics athletes who had Unified Sports experiences (USE, n = 43) and those without USE (n = 46). Demographic, anthropometric, self-description data were collected during the questionnaire interview and physical examination. Analyses included descriptive and regression modeling to determine differences in the psychological attributes by USE and best subsets of predictors of each physical self-concept construct. Results: The findings suggest that the participation of USE facilitated greater sport competence and there is no single predictor across the six physical self-concept constructs. Conclusion: The findings provide evidence that sports participation may have positive impacts on physical self-concept toward athletes with ID.

Active forgetting is an essential component of the memory management system of the brain.sup.1. Forgetting can be permanent, in which prior memory is lost completely, or transient, in which memory exists in a temporary state of impaired retrieval. Temporary blocks on memory seem to be universal, and can disrupt an individual's plans, social interactions and ability to make rapid, flexible and appropriate choices. However, the neurobiological mechanisms that cause transient forgetting are unknown. Here we identify a single dopamine neuron in Drosophila that mediates the memory suppression that results in transient forgetting. Artificially activating this neuron did not abolish the expression of long-term memory. Instead, it briefly suppressed memory retrieval, with the memory becoming accessible again over time. The dopamine neuron modulates memory retrieval by stimulating a unique dopamine receptor that is expressed in a restricted physical compartment of the axons of mushroom body neurons. This mechanism for transient forgetting is triggered by the presentation of interfering stimuli immediately before retrieval. A dopamine neuron that underpins transient forgetting in Drosophila is activated by the presentation of interfering stimuli immediately before memory retrieval, modulating this retrieval by stimulating a dopamine receptor in mushroom body neurons., Author(s): John Martin Sabandal [sup.1] , Jacob A. Berry [sup.1] , Ronald L. Davis [sup.1] Author Affiliations: (1) Department of Neuroscience, Scripps Research Institute Florida, Jupiter, USA Main Memory formation, [...]

The brain is designed not only with molecules and cellular processes that help to form memories but also with molecules and cellular processes that suppress the formation and retention of memory. The latter processes are critical for an efficient memory management system, given the vast amount of information that each person experiences in their daily activities and that most of this information becomes irrelevant with time. Thus, efficiency dictates that the brain should have processes for selecting the most critical information for storage and suppressing the irrelevant or forgetting it later should it escape the initial filters. Such memory suppressor molecules and processes are revealed by genetic or pharmacologic insults that lead to enhanced memory expression. We review here the predominant memory suppressor molecules and processes that have recently been discovered. They are diverse, as expected, because the brain is complex and employs many different strategies and mechanisms to form memories. They include the gene-repressive actions of small noncoding RNAs, repressors of protein synthesis, cAMP-mediated gene expression pathways, inter- and intracellular signaling pathways for normal forgetting, and others. A deep understanding of memory suppressor molecules and processes is necessary to fully comprehend how the brain forms, stabilizes, and retrieves memories and to reveal how brain disorders disrupt memory. [ABSTRACT FROM AUTHOR]

Homeostasis of ionized calcium in biofluids is critical for human biological functions and organ systems. Measurement of ionized calcium for clinical applications is not easily accessible due to its strict procedures and dependence on pH. pH balance in body fluids greatly affects metabolic reactions and biological transport systems. Here, we demonstrate a wearable electrochemical device for continuous monitoring of ionized calcium and pH of body fluids using a disposable and flexible array of Ca(2+) and pH sensors that interfaces with a flexible printed circuit board. This platform enables real-time quantitative analysis of these sensing elements in body fluids such as sweat, urine, and tears. Accuracy of Ca(2+) concentration and pH measured by the wearable sensors is validated through inductively coupled plasma-mass spectrometry technique and a commercial pH meter, respectively. Our results show that the wearable sensors have high repeatability and selectivity to the target ions. Real-time on-body assessment of sweat is also performed, and our results indicate that calcium concentration increases with decreasing pH. This platform can be used in noninvasive continuous analysis of ionized calcium and pH in body fluids for disease diagnosis such as primary hyperparathyroidism and kidney stones.

The improvements in our ability to sequence and genotype DNA have opened up numerous avenues in the understanding of human biology and medicine with various applications, especially in medical diagnostics. But the realization of a label free, real time, high-throughput and low cost biosensing platforms to detect molecular interactions with a high level of sensitivity has been yet stunted due to two factors: one, slow binding kinetics caused by the lack of probe molecules on the sensors and two, limited mass transport due to the planar structure (two-dimensional) of the current biosensors. Here we present a novel three-dimensional (3D), highly sensitive, real-time, inexpensive and label-free nanotip array as a rapid and direct platform to sequence-specific DNA screening. Our nanotip sensors are designed to have a nano sized thin film as their sensing area (~ 20 nm), sandwiched between two sensing electrodes. The tip is then conjugated to a DNA oligonucleotide complementary to the sequence of interest, which is electrochemically detected in real-time via impedance changes upon the formation of a double-stranded helix at the sensor interface. This 3D configuration is specifically designed to improve the biomolecular hit rate and the detection speed. We demonstrate that our nanotip array effectively detects oligonucleotides in a sequence-specific and highly sensitive manner, yielding concentration-dependent impedance change measurements with a target concentration as low as 10 pM and discrimination against even a single mismatch. Notably, our nanotip sensors achieve this accurate, sensitive detection without relying on signal indicators or enhancing molecules like fluorophores. It can also easily be scaled for highly multiplxed detection with up to 5000 sensors/square centimeter, and integrated into microfluidic devices. The versatile, rapid, and sensitive performance of the nanotip array makes it an excellent candidate for point-of-care diagnostics, and high-throughput DNA analysis applications.

MicroRNAs have been associated with many different biological functions, but little is known about their roles in conditioned behavior. We demonstrate that Drosophila miR-980 is a memory suppressor gene functioning in multiple regions of the adult brain. Memory acquisition and stability were both increased by miR-980 inhibition. Whole cell recordings and functional imaging experiments indicated that miR-980 regulates neuronal excitability. We identified the autism susceptibility gene, A2bp1, as an mRNA target for miR-980. A2bp1 levels varied inversely with miR-980 expression; memory performance was directly related to A2bp1 levels. In addition, A2bp1 knockdown reversed the memory gains produced by miR-980 inhibition, consistent with A2bp1 being a downstream target of miR-980 responsible for the memory phenotypes. Our results indicate that miR-980 represses A2bp1 expression to tune the excitable state of neurons, and the overall state of excitability translates to memory impairment or improvement.

Wearable sensor technologies are essential to the realization of personalized medicine through continuously monitoring an individual's state of health. Sampling human sweat, which is rich in physiological information, could enable non-invasive monitoring. Previously reported sweat-based and other non-invasive biosensors either can only monitor a single analyte at a time or lack on-site signal processing circuitry and sensor calibration mechanisms for accurate analysis of the physiological state. Given the complexity of sweat secretion, simultaneous and multiplexed screening of target biomarkers is critical and requires full system integration to ensure the accuracy of measurements. Here we present a mechanically flexible and fully integrated (that is, no external analysis is needed) sensor array for multiplexed in situ perspiration analysis, which simultaneously and selectively measures sweat metabolites (such as glucose and lactate) and electrolytes (such as sodium and potassium ions), as well as the skin temperature (to calibrate the response of the sensors). Our work bridges the technological gap between signal transduction, conditioning (amplification and filtering), processing and wireless transmission in wearable biosensors by merging plastic-based sensors that interface with the skin with silicon integrated circuits consolidated on a flexible circuit board for complex signal processing. This application could not have been realized using either of these technologies alone owing to their respective inherent limitations. The wearable system is used to measure the detailed sweat profile of human subjects engaged in prolonged indoor and outdoor physical activities, and to make a real-time assessment of the physiological state of the subjects. This platform enables a wide range of personalized diagnostic and physiological monitoring applications.

DNA sequencing by imaging in an electron microscope is an approach that holds promise to deliver long reads with low error rates and without the need for amplification. Earlier work using transmission electron microscopes, which use high electron energies on the order of 100 keV, has shown that low contrast and radiation damage necessitates the use of heavy atom labeling of individual nucleotides, which increases the read error rates. Other prior work using scattering electrons with much lower energy has shown to suppress beam damage on DNA. Here we explore possibilities to increase contrast by employing two methods, X-ray photoelectron and Auger electron spectroscopy. Using bulk DNA samples with monomers of each base, both methods are shown to provide contrast mechanisms that can distinguish individual nucleotides without labels. Both spectroscopic techniques can be readily implemented in a low energy electron microscope, which may enable label-free DNA sequencing by direct imaging.

Recent advances in biosensing technologies present great potential for medical diagnostics, thus improving clinical decisions. However, creating a label-free general sensing platform capable of detecting multiple biotargets in various clinical specimens over a wide dynamic range, without lengthy sample-processing steps, remains a considerable challenge. In practice, these barriers prevent broad applications in clinics and at patients' homes. Here, we demonstrate the nanoplasmonic electrical field-enhanced resonating device (NE(2)RD), which addresses all these impediments on a single platform. The NE(2)RD employs an immunodetection assay to capture biotargets, and precisely measures spectral color changes by their wavelength and extinction intensity shifts in nanoparticles without prior sample labeling or preprocessing. We present through multiple examples, a label-free, quantitative, portable, multitarget platform by rapidly detecting various protein biomarkers, drugs, protein allergens, bacteria, eukaryotic cells, and distinct viruses. The linear dynamic range of NE(2)RD is five orders of magnitude broader than ELISA, with a sensitivity down to 400 fg/mL This range and sensitivity are achieved by self-assembling gold nanoparticles to generate hot spots on a 3D-oriented substrate for ultrasensitive measurements. We demonstrate that this precise platform handles multiple clinical samples such as whole blood, serum, and saliva without sample preprocessing under diverse conditions of temperature, pH, and ionic strength. The NE(2)RD's broad dynamic range, detection limit, and portability integrated with a disposable fluidic chip have broad applications, potentially enabling the transition toward precision medicine at the point-of-care or primary care settings and at patients' homes.

The evolutionarily conserved Elongator Complex associates with RNA polymerase II for transcriptional elongation. Elp3 is the catalytic subunit, contains histone acetyltransferase activity, and is associated with neurodegeneration in humans. Elp1 is a scaffolding subunit and when mutated causes familial dysautonomia. Here, we show that "elp3" and "elp1" are required for aversive long-term olfactory memory in "Drosophila." RNAi knockdown of "elp3" in adult mushroom bodies impairs long-term memory (LTM) without affecting earlier forms of memory. RNAi knockdown with coexpression of "elp3" cDNA reverses the impairment. Similarly, RNAi knockdown of "elp1" impairs LTM and coexpression of "elp1" cDNA reverses this phenotype. The LTM deficit in "elp3" and "elp1" knockdown flies is accompanied by the abolishment of a LTM trace, which is registered as increased calcium influx in response to the CS+ odor in the a-branch of mushroom body neurons. Coexpression of "elp1" or "elp3" cDNA rescues the memory trace in parallel with LTM. These data show that the Elongator complex is required in adult mushroom body neurons for long-term behavioral memory and the associated long-term memory trace.

Purpose: This study explored the effect of whole-body vibration (WBV) using accelerations of 2.56 "g" to 7.68 "g" on lower-body detraining. Methods: All participants (N = 20) were trained using a lower-body resistance-training program for 30 min twice per week from Week 0 to Week 6. At the end of the program, they were randomly assigned to a control group that performed no further training or a WBV group that performed a progressive static WBV program. Data for the 5-repetition-maximum (5RM) squat and extensors and flexors of the knee and ankle were collected at Weeks 0, 6, 8, 10, and 12 for all participants. Results: Two-way (condition vs. time) analysis of variance revealed that although the WBV group maintained strength in the 5RM from Week 6 through Week 8 and the control group had a lower 5RM in Week 8 from Week 6, no differences in the 5RM squat existed between the groups at Week 8. Two-way factorial multivariate analysis of variance revealed no differences between the groups at any of the time for torque of knee flexion, dorsiflexion, or plantar flexion. Conclusion: Static WBV of 2.56 "g" to 7.68 "g" did not attenuate detraining of the flexors and extensors of the knee and ankle.

UnlabelledThe genomes of sulfate-reducing bacteria remain poorly characterized, largely due to a paucity of experimental data and genetic tools. To meet this challenge, we generated an archived library of 15,477 mapped transposon insertion mutants in the sulfate-reducing bacterium Desulfovibrio alaskensis G20. To demonstrate the utility of the individual mutants, we profiled gene expression in mutants of six regulatory genes and used these data, together with 1,313 high-confidence transcription start sites identified by tiling microarrays and transcriptome sequencing (5' RNA-Seq), to update the regulons of Fur and Rex and to confirm the predicted regulons of LysX, PhnF, PerR, and Dde_3000, a histidine kinase. In addition to enabling single mutant investigations, the D. alaskensis G20 transposon mutants also contain DNA bar codes, which enables the pooling and analysis of mutant fitness for thousands of strains simultaneously. Using two pools of mutants that represent insertions in 2,369 unique protein-coding genes, we demonstrate that the hypothetical gene Dde_3007 is required for methionine biosynthesis. Using comparative genomics, we propose that Dde_3007 performs a missing step in methionine biosynthesis by transferring a sulfur group to O-phosphohomoserine to form homocysteine. Additionally, we show that the entire choline utilization cluster is important for fitness in choline sulfate medium, which confirms that a functional microcompartment is required for choline oxidation. Finally, we demonstrate that Dde_3291, a MerR-like transcription factor, is a choline-dependent activator of the choline utilization cluster. Taken together, our data set and genetic resources provide a foundation for systems-level investigation of a poorly studied group of bacteria of environmental and industrial importance.ImportanceSulfate-reducing bacteria contribute to global nutrient cycles and are a nuisance for the petroleum industry. Despite their environmental and industrial significance, the genomes of sulfate-reducing bacteria remain poorly characterized. Here, we describe a genetic approach to fill gaps in our knowledge of sulfate-reducing bacteria. We generated a large collection of archived, transposon mutants in Desulfovibrio alaskensis G20 and used the phenotypes of these mutant strains to infer the function of genes involved in gene regulation, methionine biosynthesis, and choline utilization. Our findings and mutant resources will enable systematic investigations into gene function, energy generation, stress response, and metabolism for this important group of bacteria.

Sensory and cognitive performance decline with age. Neural dysfunction caused by nerve death in senile dementia and neurodegenerative disease has been intensively studied; however, functional changes in neural circuits during the normal aging process are not well understood. Caspases are key regulators of cell death, a hallmark of age-related neurodegeneration. Using a genetic probe for caspase-3-like activity (DEVDase activity), we have mapped age-dependent neuronal changes in the adult brain throughout the lifespan of Drosophila. Spatio-temporally restricted caspase activation was observed in the antennal lobe and ellipsoid body, brain structures required for olfaction and visual place memory, respectively. We also found that caspase was activated in an age-dependent manner in specific subsets of Drosophila olfactory receptor neurons (ORNs), Or42b and Or92a neurons. These neurons are essential for mediating innate attraction to food-related odors. Furthermore, age-induced impairments of neural transmission and attraction behavior could be reversed by specific inhibition of caspase in these ORNs, indicating that caspase activation in Or42b and Or92a neurons is responsible for altering animal behavior during normal aging.

Reproductive tract infection is a major initiator of preterm birth (PTB). The objective of this prospective cohort study of 88 participants was to determine whether PTB correlates with the vaginal microbiome during pregnancy. Total DNA was purified from posterior vaginal fornix swabs during gestation. The 16S ribosomal RNA gene was amplified using polymerase chain reaction primers, followed by chain-termination sequencing. Bacteria were identified by comparing contig consensus sequences with the Ribosomal Database Project. Dichotomous responses were summarized via proportions and continuous variables via means ± standard deviation. Mean Shannon Diversity index differed by Welch t test (P = .00016) between caucasians with PTB and term gestation. Species diversity was greatest among African Americans (P = .0045). Change in microbiome/Lactobacillus content and presence of putative novel/noxious bacteria did not correlate with PTB. We conclude that uncultured vaginal bacteria play an important role in PTB and race/ethnicity and sampling location are important determinants of the vaginal microbiome.

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) presents substantial challenges in patient care due to its intricate multisystem nature, comorbidities, and global prevalence. The heterogeneity among patient populations, coupled with the absence of FDA-approved diagnostics and therapeutics, further complicates research into disease etiology and patient managment. Integrating longitudinal multi-omics data with clinical, health, textual, pharmaceutical, and nutraceutical data offers a promising avenue to address these complexities, aiding in the identification of underlying causes and providing insights into effective therapeutics and diagnostic strategies. Methods: This study focused on an exceptionally severe ME/CFS patient with hypermobility spectrum disorder (HSD) during a period of marginal symptom improvements. Longitudinal cytokine profiling was conducted alongside the collection of extensive multi-modal health data to explore the dynamic nature of symptoms, severity, triggers, and modifying factors. Additionally, an updated severity assessment platform and two applications, ME-CFSTrackerApp and LexiTime, were introduced to facilitate real-time symptom tracking and enhance patient-physician/researcher communication, and evaluate response to medical intervention. Results: Longitudinal cytokine profiling revealed the significance of Th2-type cytokines and highlighted synergistic activities between mast cells and eosinophils, skewing Th1 toward Th2 immune responses in ME/CFS pathogenesis, particularly in cognitive impairment and sensorial intolerance. This suggests a potentially shared underlying mechanism with major ME/CFS comorbidities such as HSD, Mast cell activation syndrome, postural orthostatic tachycardia syndrome (POTS), and small fiber neuropathy. Additionally, the data identified potential roles of BCL6 and TP53 pathways in ME/CFS etiology and emphasized the importance of investigating adverse reactions to medication and supplements and drug interactions in ME/CFS severity and progression. Discussion: Our study advocates for the integration of longitudinal multi-omics with multi-modal health data and artificial intelligence (AI) techniques to better understand ME/CFS and its major comorbidities. These findings highlight the significance of dysregulated Th2-type cytokines in patient stratification and precision medicine strategies. Additionally, our results suggest exploring the use of low-dose drugs with partial agonist activity as a potential avenue for ME/CFS treatment. This comprehensive approach emphasizes the importance of adopting a patient-centered care approach to improve ME/CFS healthcare management, disease severity assessment, and personalized medicine. Overall, these findings contribute to our understanding of ME/CFS and offer avenues for future research and clinical practice. [ABSTRACT FROM AUTHOR]

Using Black Shoals as a theoretical guide, we explore how intentional emergence (IE) can help erode the colonial and capitalist underpinnings of leadership education. Informed by Black Shoals and IE, we offer three pedagogical recommendations we frame as decolonial interventions—dissolving the center, weaving the margins, and collective imagining. Attending to these, and other, interventions stand to disrupt the normative structures and cultures of leadership learning, catalyze new relations and relationships, and engendering new possibilities for leadership development and social change. [ABSTRACT FROM AUTHOR]