The value of prospective metabolomic susceptibility endotypes: broad applicability for infectious diseases.

BACKGROUND: As new infectious diseases (ID) emerge and others continue to mutate, there remains an imminent threat, especially for vulnerable individuals. Yet no generalizable framework exists to identify the at-risk group prior to infection. Metabolomics has the advantage of capturing the existing physiologic state, unobserved via current clinical measures. Furthermore, metabolomics profiling during acute disease can be influenced by confounding factors such as indications, medical treatments, and lifestyles. METHODS: We employed metabolomic profiling to cluster infection-free individuals and assessed their relationship with COVID severity and influenza incidence/recurrence. FINDINGS: We identified a metabolomic susceptibility endotype that was strongly associated with both severe COVID (ORICUadmission = 6.7, p-value = 1.2 × 10-08, ORmortality = 4.7, p-value = 1.6 × 10-04) and influenza (ORincidence = 2.9; p-values = 2.2 × 10-4, ßrecurrence = 1.03; p-value = 5.1 × 10-3). We observed similar severity associations when recapitulating this susceptibility endotype using metabolomics from individuals during and after acute COVID infection. We demonstrate the value of using metabolomic endotyping to identify a metabolically susceptible group for two-and potentially more-IDs that are driven by increases in specific amino acids, including microbial-related metabolites such as tryptophan, bile acids, histidine, polyamine, phenylalanine, and tyrosine metabolism, as well as carbohydrates involved in glycolysis. INTERPRETATIONS: These metabolites may be identified prior to infection to enable protective measures for these individuals. FUNDING: The Longitudinal EMR and Omics COVID-19 Cohort (LEOCC) and metabolomic profiling were supported by the National Heart, Lung, and Blood Institute and the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health.

Probing the Activation Mechanisms of Agonist DPI-287 to Delta-Opioid Receptor and Novel Agonists Using Ensemble-Based Virtual Screening with Molecular Dynamics Simulations.

Pain drugs targeting mu-opioid receptors face major addiction problems that have caused an epidemic. The delta-opioid receptor (DOR) has shown to not cause addictive effects when bound to an agonist. While the active conformation of the DOR in complex with agonist DPI-287 has been recently solved, there are still no FDA-approved agonists targeting it, providing the opportunity for structure-based virtual screening. In this study, the conformational plasticity of the DOR was probed using molecular dynamics (MD) simulations, identifying two representative conformations from clustering analysis. The two MD conformations as well as the crystal conformation of DOR were used to screen novel compounds from the ZINC database (17 million compounds), in which 69 drugs were picked as potential compounds based on their docking scores. Notably, 37 out of the 69 compounds were obtained from the simulated conformations. The binding stability of the 69 compounds was further investigated using MD simulations. Based on the MM-GBSA binding energy and the predicted drug properties, eight compounds were chosen as the most favorable, six of which were from the simulated conformations. Using a dynamic network model, the communication between the crystal agonist and the top eight molecules with the receptor was analyzed to confirm if these novel compounds share a similar activation mechanism to the crystal ligand. Encouragingly, docking of these eight compounds to the other two opioid receptors (kappa and mu) suggests their good selectivity toward DOR.

To probe the activation mechanism of the Delta opioid receptor by an agonist ADL5859 started from inactive conformation using molecular dynamic simulations.

The δ-opioid receptor (DOR) is a critical pharmaceutical target for pain management. Although the high-resolution crystal structures of the DOR with both agonist and antagonist have recently been solved, the activation mechanism remains to be elusive. In this study, a DOR agonist ADL5859 was docked to the inactive DOR and multiple microsecond molecular dynamic (MD) simulations were conducted to probe the activation mechanism. While the receptor with the crystal ligand (i.e. antagonist naltrindole) maintained the inactive conformation in all three independent simulations, the receptor with ADL5859 was adopting toward the active conformation in three out of six independent simulations. Major conformational differences were located on transmembrane (TM) 5 and 6, as well as intracellular loop 3. Compared to naltrindole, ADL5859 exhibited high conformational flexibility and strong interaction with the transmission switch. The putative key residues (W274, D95, V267, L139, V263, M142, T260, R146, R258 and others) involving in the activation pathway were identified through the conventional molecular switch analysis and a pairwise distance analysis, which provides a short list for experimental mutagenesis study. These insights will facilitate further development of therapeutic agents targeting the DOR.Communicated by Ramaswamy H. Sarma.

Persistent yet vulnerable: resurvey of an Abies ecotone reveals few differences but vulnerability to climate change.

Climate change is shifting forest tree species distributions across elevational and latitudinal gradients, and these changes are often pronounced at ecotones where species meet their climatic bounds and are replaced by other species. Using an extensive ecotone composed of lower-montane white fir (Abies concolor var. lowiana) and upper-montane red fir (Abies magnifica var. magnifica) in the central Sierra Nevada range of California, USA, we (1) examined how the demographics of the ecotone have responded to recent climate using a field observational study and a historical dataset, (2) quantified climate drivers across species life stages using contemporary demographic data, and (3) tested the potential impacts of future climate on species-specific seedling survival and growth in a fully factorial growth chamber experiment that varied temperature, growing season length, and water availability. A re-examination of the ecotone midpoint after 35 yr suggested a reduction in A. concolor sapling and tree densities and a rise in A. magnifica proportional dominance between surveys. Seedling abundances across the ecotone indicated that A. magnifica tends to dominate the regeneration layer and currently forms an important component of the seedling community at elevations below those where A. magnifica saplings or trees begin to co-dominate stands. Observational and experimental assessments suggest that temperature and precipitation serve as important drivers, differentiating A. concolor vs. A. magnifica distributions, and are primary stressors at the seedling stage. Seedlings of both species were adversely affected by experimental climate treatments, although A. concolor exhibited greater survival and a more conservative growth strategy under extreme climatic stress than A. magnifica. Projections indicate that historical climate conditions will rise by an amount greater than the ecotone's current elevational extent by the end of the 21st century. Differential drivers of species abundances suggest that the projected climate will expand conditions that promote A. concolor abundance and impede A. magnifica abundance across the ecotone; however, disturbance activity and microclimatic conditions will also influence regeneration and overstory tree dynamics. Our study demonstrates the importance of quantifying species-specific responses to climate and indicates that widespread regeneration failure may be one possible consequence in which species exhibit strong sensitivity to projected climate conditions.

Context-dependent effects of whole-genome duplication during mammary tumor recurrence.

Whole-genome duplication (WGD) generates polyploid cells possessing more than two copies of the genome and is among the most common genetic abnormalities in cancer. The frequency of WGD increases in advanced and metastatic tumors, and WGD is associated with poor prognosis in diverse tumor types, suggesting a functional role for polyploidy in tumor progression. Experimental evidence suggests that polyploidy has both tumor-promoting and suppressing effects, but how polyploidy regulates tumor progression remains unclear. Using a genetically engineered mouse model of Her2-driven breast cancer, we explored the prevalence and consequences of whole-genome duplication during tumor growth and recurrence. While primary tumors in this model are invariably diploid, nearly 40% of recurrent tumors undergo WGD. WGD in recurrent tumors was associated with increased chromosomal instability, decreased proliferation and increased survival in stress conditions. The effects of WGD on tumor growth were dependent on tumor stage. Surprisingly, in recurrent tumor cells WGD slowed tumor formation, growth rate and opposed the process of recurrence, while WGD promoted the growth of primary tumors. These findings highlight the importance of identifying conditions that promote the growth of polyploid tumors, including the cooperating genetic mutations that allow cells to overcome the barriers to WGD tumor cell growth and proliferation.

Activation Mechanism of Corticotrophin Releasing Factor Receptor Type 1 Elucidated Using Molecular Dynamics Simulations.

The corticotropin-releasing factor receptor type 1 (CRF1R), a member of class B G-protein-coupled receptors (GPCRs), is a good drug target for treating depression, anxiety, and other stress-related neurodisorders. However, there is no approved drug targeting the CRF1R to date, partly due to inadequate structural information and its elusive activation mechanism. Here, by use of the crystal structures of its transmembrane domain (TMD) and the N-terminal extracellular domain (ECD) as a template, a full-length homology model of CRF1R was built and its complexes with peptide agonist urocortin 1 or small molecule antagonist CP-376395 were subjected to all-atom molecular dynamics simulations. We observed well preserved helical contents in the TMD through simulations, while the transmembrane (TM) helices showed clear rearrangements. The TM rearrangement is especially pronounced for the TM6 in the agonist-bound CRF1R system. The observed conformational changes are likely due to breakage of interhelical/inter-regional hydrogen bonds in the TMD. Dynamical network analysis identifies communities with high connections to TM6. Simulations reveal three key residues, Y3566.53, Q3847.49, and L3957.60, which corroborate experimental mutagenesis data, implying the important roles in the receptor activation. The observed large-scale conformational changes are related to CRF1R activation by agonist binding, providing guidance for ligand design.

Repeatability and reproducibility of the color contrast technique for fingermark age estimation applications.

This research complements previous studies in which color contrast between ridges and furrows of latent fingermarks was investigated as a potential aging parameter. In this case, the robustness of the technique has been tested by including five female and five male donors who deposited sebaceous-rich latent fingermarks onto ceramic tile and polystyrene plastic as well as flat and rolled inked fingerprints on commercially available ten-print cards. Fresh latent fingermarks were visualized with either carbon black or titanium dioxide powder (TiO2 ) and inked fingerprints were imprinted in succession without re-charging ink. The mean intensity (MI) and intensity amplitude (IA) metrics of the color histogram were collected from each image for statistical analyses. The goals were to detect any differences within and between the analysts' own interpretation of the protocol as well as examine how color contrast may be influenced by donor, substrate, biological sex, powder type, and the quantity of ink deposited. Results show that the color contrast metrics (MI and IA) are repeatable and reproducible and not affected significantly by donor, sex, deposition pressure, or distortion. However, the metrics were sufficiently sensitive to distinguish substrate and powder types and to detect different quantities of ink. The statistical analyses confirm and expand upon previous observations regarding the reliability of MI and IA as metrics that could eventually be used to estimate the age of a latent fingermark. At the same time, it was revealed that the technique needs further improvement and standardization by including a universal "white color standard" to conduct image comparisons.

Evaluation of latent fingermark color contrast as aging parameter under different environmental conditions: A preliminary study.

This research expands previous studies in which color contrast between ridges and furrows of powder-enhanced latent fingermarks was explored as a possible aging parameter. The main goal is to test the sensitivity of the technique across a predetermined set of factors. In this case, experiment factors have included two donors who deposited sebaceous- and eccrine-rich fingermarks onto ceramic tile and polystyrene plastic. These were developed with either black carbon or titanium dioxide powder (TiO2 ) over eight time periods (0-72 days) and aged under three light conditions (direct light, shade, and darkness). The mean intensity (MI) and intensity amplitude (IA) metrics of color were collected from each image for statistical analyses. Results show that color contrast is affected significantly by substrate, secretion, and powder types, with an interaction effect between the substrate and powder type on both MI and IA metrics. The degree of light exposure did not have a noticeable impact on distinguishing aging patterns of fingermarks by neither powder methods. Different aging patterns were detected between sebaceous-rich and their eccrine-rich counterparts for all light conditions using regression analysis. All eccrine-rich fingermarks exhibited little (or minimal) change in IA over time, whereas sebaceous-rich samples showed varied patterns, from significant decreases to slight increases. These findings confirm and expand previous observations on the potential use of MI and IA as metrics to study latent fingermark degradation patterns that could eventually be used to estimate the age of a fingermark.

The Relationship Among Multiple Sclerosis-Related Symptoms, Sleep Quality, and Sleep Hygiene Behaviors.

AIMS AND OBJECTIVES: The aim of this study was to examine the relationships among multiple sclerosis (MS)-related symptoms, sleep hygiene behaviors, and sleep quality in adults with MS who self-report fatigue. BACKGROUND: Fatigue is a frequent, prevalent symptom among adults with MS. Few studies have examined the relationship among fatigue and other symptoms with sleep quality and sleep behaviors. DESIGN: This is a descriptive correlational study. METHODS: A convenience sample of 39 adults with MS were recruited for the study. Instruments used included the revised MS Related Symptom Scale and the Pittsburgh Sleep Quality Index. Correlations examined the relationships among fatigue and other MS symptoms with sleep quality and sleep hygiene behaviors. RESULTS: The frequency of several symptoms correlated with poor sleep quality, and fatigue frequency was higher in those who used electronic devices and practiced poor sleep hygiene behaviors. NURSING IMPLICATIONS: Nurses should incorporate interventions for symptoms that impact sleep quality. These findings suggest that sleep hygiene education should be a part of routine clinical care. CONCLUSION: Adults with MS experience the burden of many symptoms that impact sleep quality. Interventions that include education to improve symptoms, sleep hygiene behaviors, and sleep quality are needed.

Accommodation Decision Making for Postsecondary Students With Learning Disabilities: Individually Tailored or One Size Fits All?

Clinicians uniformly recommend accommodations for college students with learning disabilities; however, we know very little about which accommodations they select and the validity of their recommendations. We examined the assessment documentation of a large sample of community college students receiving academic accommodations for learning disabilities to determine (a) which accommodations their clinicians recommended and (b) whether clinicians' recommendations were supported by objective data gathered during the assessment process. In addition to test and instructional accommodations, many clinicians recommended that students with learning disabilities should have different educational expectations, standards, and methods of evaluation (i.e., grading) than their nondisabled classmates. Many of their recommendations for accommodations were not supported by objective evidence from students' history, diagnosis, test data, and current functioning. Furthermore, clinicians often recommended accommodations that were not specific to the student's diagnosis or area of disability. Our findings highlight the need for individually selected accommodations matched to students' needs and academic contexts.

First aid for the laminitic foot: therapeutic and mechanical support.

The goals of mechanical treatment during the acute phase of laminitis are to preserve the lamellar interface by reducing the forces that are compromising its integrity and to make the horse more comfortable. Early decision making is important in managing acute laminitis. This article helps the practitioner to identify some of the commonly used and accepted methods of protecting the laminitic foot. The materials available and the theories behind their use are also described. The laminitic foot needs to be understood before determining methods for its support. Most treatment options involve shifting the weight-bearing forces from compromised areas of the foot (ie, the lamellar interface) to areas more capable of supporting the patient's weight, remembering that the sum of the forces should remain the same. The many treatment options available allow for flexibility and effective management and permit each modality to be combined in infinite ways for hoof support. The goal of therapy is to support the foot and stop the progression of the disease to the chronic phase.

Why elementary teachers might be inadequately prepared to teach reading.

Several national reports have suggested the usefulness of systematic, explicit, synthetic phonics instruction based on English word structure along with wide reading of quality literature for supporting development in early reading instruction. Other studies have indicated, however, that many in-service teachers are not knowledgeable in the basic concepts of the English language. They may be well versed in children's literature but not know how to address the basic building blocks of language and reading. The authors hypothesized that one of the reasons for this situation is that many instructors responsible for training future elementary teachers are not familiar with the concepts of the linguistic features of English language. This hypothesis was tested by administering a survey of language concepts to 78 instructors. The results showed that even though teacher educators were familiar with syllabic knowledge, they performed poorly on concepts relating to morphemes and phonemes. In a second study, 40 instructors were interviewed about best practices in teaching components and subskills of reading. Eighty percent of instructors defined phonological awareness as letter-sound correspondence. They also did not mention synthetic phonics as a desirable method to use for beginning reading instruction, particularly for students at risk for reading difficulties. In conclusion, providing professional development experiences related to language concepts to instructors could provide them the necessary knowledge of language concepts related to early literacy instruction, which they could then integrate into their preservice reading courses.

Do textbooks used in university reading education courses conform to the instructional recommendations of the national reading panel?

Two reasons may be responsible for the poor grasp of the linguistic concepts related to literacy acquisition by preservice and in-service teachers: a lack of attention given to such concepts by teacher educators (college faculty members) and a lack of relevant information provided in the textbooks used in college courses. In an earlier study, the authors found that many teacher educators involved in the training of preservice and in-service teachers were not well acquainted with these concepts. In this study, the authors examined the extent to which textbooks used in reading education courses contain the information about the five components of literacy instruction (phonemic awareness, phonics, fluency, vocabulary, and text comprehension) recommended by the National Reading Panel. Such scrutiny shows that many textbooks do not adequately cover these five components and the related instructional procedures for teaching them. In addition to the paucity of information about teaching the five components, some textbooks present inaccurate information.