A minimal colloid model of solution crystallization nucleates crystals classically.

A fundamental assumption of the classical theories of crystal nucleation is that the individual molecules from the "old" phase associate to an emerging nucleus individually and sequentially. Numerous recent studies of crystal nucleation in solution have revealed nonclassical pathways, whereby crystal nuclei are hosted and fed by amorphous clusters pre-formed in the solution. A sizable knowledge gap has persisted, however, in the definition of the molecular-level parameters that direct a solute towards classical or nonclassical nucleation. Here we construct a suspension of colloid particles of hydrodynamic diameter 1.1 µm and monitor their individual motions towards a quasi-two-dimensional crystal by scanning confocal microscopy. We combine electrostatic repulsion and polymer-induced attraction to obtain a simple isotropic pair interaction potential with a single attractive minimum of tunable depth between 1.2kBT and 2.7kBT. We find that even the smallest aggregates that form in this system structure as hexagonal two-dimensional crystals and grow and maturate by the association and exchange of single particles from the solution, signature behaviors during classical nucleation. The particles in the suspension equilibrate with those in the clusters and the volume fractions of suspensions at equilibrium correspond to straightforward thermodynamic predictions based on depth of the interparticle attraction. These results demonstrate that classical nucleation is selected by particles interacting with a minimal potential and present a benchmark for future modifications of the molecular interactions that may induce nonclassical nucleation.

Matrix Dynamics and Their Crucial Role in Non-radiative Decay during Thermally Activated Delayed Fluorescence.

We investigated the interplay of matrix dynamics with the molecular dynamics of a thermally activated delayed fluorescence (TADF) emitter, NAI-DMAC, to identify factors that influence the photophysical processes leading to TADF. The matrix dynamics surrounding NAI-DMAC molecules were varied continuously from the liquid to the solid state by depositing toluene solutions containing poly(methyl methacrylate) (PMMA) and NAI-DMAC onto optical substrates. We monitored changes of the NAI-DMAC emission as the liquid films dried to form solid PMMA films using temperature- and time-resolved photoluminescence spectroscopy. We observed that, in low-viscosity solutions, the proportion of delayed fluorescence from NAI-DMAC was much smaller than that of prompt fluorescence, indicating that negligible TADF occurred in the low-viscosity environment. However, as the viscosity of the environment diverged at the final stages of dry-down to form solid PMMA films, the delayed fluorescence component of NAI-DMAC emission was extended to longer time scales and increased in amplitude relative to prompt emission as the temperature increased─signatures that TADF occurred in the solid state as expected. Our findings reveal the influence that matrix dynamics have on the competition between conformational motion needed to access emissive states and undergo TADF versus larger amplitude structural fluctuations that lead to non-radiative decay. Insights from these studies will inform ongoing work to understand and predict how host matrices used in organic light-emitting devices can be designed to maximize the radiative properties of TADF emitters by allowing molecular motion needed to undergo TADF while restricting larger amplitude motion leading to non-radiative decay.

Preparation and processing of dried blood spots for microRNA sequencing.

Dried blood spots (DBS) are biological samples commonly collected from newborns and in geographic areas distanced from laboratory settings for the purposes of disease testing and identification. MicroRNAs (miRNAs)-small non-coding RNAs that regulate gene activity at the post-transcriptional level-are emerging as critical markers and mediators of disease, including cancer, infectious diseases, and mental disorders. This protocol describes optimized procedural steps for utilizing DBS as a reliable source of biological material for obtaining peripheral miRNA expression profiles. We outline key practices, such as the method of DBS rehydration that maximizes RNA extraction yield, and the use of degenerate oligonucleotide adapters to mitigate ligase-dependent biases that are associated with small RNA sequencing. The standardization of miRNA readout from DBS offers numerous benefits: cost-effectiveness in sample collection and processing, enhanced reliability and consistency of miRNA profiling, and minimal invasiveness that facilitates repeated testing and retention of participants. The use of DBS-based miRNA sequencing is a promising method to investigate disease mechanisms and to advance personalized medicine.

Interplay of molecular dynamics and radiative decay of a TADF emitter in a glass-forming liquid.

We investigate the role of molecular dynamics in the luminescent properties of a prototypical thermally activated delayed fluorescence (TADF) emitter, NAI-DMAC, in solution using a combination of temperature dependent time-resolved photoluminescence and absorption spectroscopies. We use a glass forming liquid, 2-methylfuran, to introduce an abrupt change in the temperature dependent diffusion dynamics of the solvent and examine the influence this has on the emission intensity of NAI-DMAC molecules. Comparison of experiment with first principles molecular dynamics simulations reveals that the emission intensity of NAI-DMAC molecules follows the temperature-dependent self-diffusion dynamics of the solvent. A marked reduction of emission intensity is observed as the temperature decreases toward the glass transition because the rate at which NAI-DMAC molecules can access emissive molecular conformations is greatly reduced. Below the glass transition, the diffusion dynamics of the solvent changes more slowly with temperature, which causes the emission intensity to decrease more slowly as well. The combination of experiment and computation suggests a pathway by which TADF emitters may transiently access a distribution of conformational states and avoid the need for an average conformation that strikes a balance between lower singlet-triplet energy splittings versus higher emission probabilities.

Applying the task-technology fit model to construct the prototype of a medical staff scheduling system.

BACKGROUND: Medical staff scheduling problems are complex and involve numerous constraints. OBJECTIVE: This research uses the task-technology fit (TTF) model to measure the technology characteristics of information technology (IT) systems as a reference for constructing a prototype for a medical staff scheduling system to identify function requirements and design human interfaces. METHOD: After the evaluation of the proposed scheduling system, this research excludes compatibility from the 13 technology characteristics and adds two technology characteristics for consideration: customization and scalability. RESULTS: Based on the revised technology characteristics of the TTF model, this research develops flexible scheduling functions to satisfy daily manpower requirements and allow predetermined schedules and day-off reservations for a hospital's radiological technologists. Characterized by flexibility, customization, and scalability, the system can accommodate several algorithms to generate a better schedule that satisfies hard and soft constraints. Furthermore, the scheduler can choose the required hard and soft constraints from all constraints. The prototype of the scheduling system will be easily extended to add or modify constraints in the case of requirement or regulation changes. CONCLUSION: The results of this study provide a prototype for system developers to design a customized staff scheduling system for each medical unit.

Using Simulation Optimization to Solve Patient Appointment Scheduling and Examination Room Assignment Problems for Patients Undergoing Ultrasound Examination.

This study investigates patient appointment scheduling and examination room assignment problems involving patients who undergo ultrasound examination with considerations of multiple examination rooms, multiple types of patients, multiple body parts to be examined, and special restrictions. Following are the recommended time intervals based on the findings of three scenarios in this study: In Scenario 1, the time interval recommended for patients' arrival at the radiology department on the day of the examination is 18 min. In Scenario 2, it is best to assign patients to examination rooms based on weighted cumulative examination points. In Scenario 3, we recommend that three outpatients come to the radiology department every 18 min to undergo ultrasound examinations; the number of inpatients and emergency patients arriving for ultrasound examination is consistent with the original time interval distribution. Simulation optimization may provide solutions to the problems of appointment scheduling and examination room assignment problems to balance the workload of radiological technologists, maintain high equipment utilization rates, and reduce waiting times for patients undergoing ultrasound examination.

Evaluating Methylation of the Oxytocin Receptor Gene and the Oxytocin Intergenic Region.

Oxytocin and its paralogue, vasopressin, are widely studied biomarkers in relation to pregnancy and birth, maternal and social behavior, and mental health. Epigenetics is a biological mechanism that mediates the link between environmental influences and behavioral patterns. In a candidate gene approach, we describe here a DNA methylation assay of two regions within the oxytocin system, using human buccal cells and next-generation sequencing. Two nanograms of DNA were sufficient to assess the DNA methylation status of 28 CpG sites (22 corresponding to the oxytocin receptor and 6 corresponding to the vasopressin/oxytocin intergenic region). This method proved to be non-invasive for the participants, and reproducible; its validity remains to be confirmed alongside other biomarkers of gene function.

Oxytocin receptor expression and epigenetic regulation in the anterior cingulate cortex of individuals with a history of severe childhood abuse.

Childhood abuse significantly increases the lifetime risk of negative mental health outcomes. The oxytocinergic system, which plays a role in complex social and emotional behaviors, has been shown to be sensitive to early-life experiences. While previous studies have investigated the relationship between early-life adversity and oxytocin, they did so with peripheral samples. We, therefore, aimed to characterize the relationship between early-life adversity and oxytocin receptor (OXTR) expression in the brain, using post-mortem human samples, as well as a rodent model of naturally occurring variation in early-life environment. Focusing on the dorsal anterior cingulate cortex, we compared OXTR expression and epigenetic regulation between MDD suicides with (N = 26) and without history of childhood abuse (N = 24), as well as psychiatrically healthy controls (N = 23). We also compared Oxtr expression in the cingulate cortex of adult rats raised by dams displaying high (N = 13) and low levels (N = 12) of licking and grooming (LG) behavior. Overall, our results indicate that childhood abuse associates with an upregulation of OXTR expression, and that similarly, this relationship is also observed in the cingulate cortex of adult rats raised by low-LG dams. Additionally, we found an effect of rs53576 genotype on expression, showing that carriers of the A variant also show upregulated OXTR expression. The effects of early-life adversity and rs53576 genotype on OXTR expression are, however, not explained by differences in DNA methylation within and around the MT region of the OXTR gene.

Stochastic Epigenetic Mutations Influence Parkinson's Disease Risk, Progression, and Mortality.

BACKGROUND: Stochastic epigenetic mutations (SEM) reflect a deviation from normal site-specific methylation patterns. Epigenetic mutation load (EML) captures the accumulation of SEMs across an individual's genome and may reflect dysfunction of the epigenetic maintenance system in response to epigenetic challenges. OBJECTIVE: We investigate whether EML is associated with PD risk and time to events (i.e., death and motor symptom decline). METHODS: We employed logistic regression and Cox proportional hazards regression to assess the association between EML and several outcomes. Our analyses are based on 568 PD patients and 238 controls from the Parkinson's disease, Environment and Genes (PEG) study, for whom blood-based methylation data was available. RESULTS: We found an association for PD onset and EML in all genes (OR = 1.90; 95%CI 1.52-2.37) and PD-related genes (OR = 1.87; 95%CI 1.50-2.32). EML was also associated with time to a minimum score of 35 points on the motor UPDRS exam (OR = 1.28; 95%CI 1.06-1.56) and time to death (OR = 1.29, 95%CI 1.11-1.49). An analysis of PD related genes only revealed five intragenic hotspots of high SEM density associated with PD risk. CONCLUSION: Our findings suggest an enrichment of methylation dysregulation in PD patients in general and specifically in five PD related genes. EML may also be associated with time to death and motor symptom progression in PD patients.

Rare glomus tumor formation following trauma to the first digit.

INTRODUCTION: Glomus tumors are rare and few cases are reported in the literature. They typically occur in females on the digits of the hands. CASE PRESENTATION: We report a case of a 30 year-old woman who presented with a mass that developed on the distal tip of her right thumb after traumatic injury. Magnetic resonance imaging (MRI) was conducted and mass resection was performed. Histopathology confirmed that the mass was a glomus tumor. CLINICAL DISCUSSION: Clinical presentations of glomus tumors are typically non-specific, mainly consisting of a small mass with chronic pain, with a lengthy time to diagnosis and potentially improper management. MRI is the preferred diagnostic step, followed by curative surgical excision and pathological confirmation. CONCLUSION: Glomus tumors can cause significant discomfort for patients, and clinicians should be aware of the rare diagnosis when treating painful masses on the extremities, as surgical excision is often curative.

Integrative DNA Methylation and Gene Expression Analysis in the Prefrontal Cortex of Mexicans Who Died by Suicide.

BACKGROUND: Suicide represents a major health concern, especially in developing countries. While many demographic risk factors have been proposed, the underlying molecular pathology of suicide remains poorly understood. A body of evidence suggests that aberrant DNA methylation and expression is involved. In this study, we examined DNA methylation profiles and concordant gene expression changes in the prefrontal cortex of Mexicans who died by suicide. METHODS: In collaboration with the coroner's office in Mexico City, brain samples of males who died by suicide (n = 35) and age-matched sudden death controls (n = 13) were collected. DNA and RNA were extracted from prefrontal cortex tissue and analyzed with the Infinium Methylation480k and the HumanHT-12 v4 Expression Beadchips, respectively. RESULTS: We report evidence of altered DNA methylation profiles at 4430 genomic regions together with 622 genes characterized by differential expression in cases vs controls. Seventy genes were found to have concordant methylation and expression changes. Metacore-enriched analysis identified 10 genes with biological relevance to psychiatric phenotypes and suicide (ADCY9, CRH, NFATC4, ABCC8, HMGA1, KAT2A, EPHA2, TRRAP, CD22, and CBLN1) and highlighted the association that ADCY9 has with various pathways, including signal transduction regulated by the cAMP-responsive element modulator, neurophysiological process regulated by the corticotrophin-releasing hormone, and synaptic plasticity. We therefore went on to validate the observed hypomethylation of ADCY9 in cases vs control through targeted bisulfite sequencing. CONCLUSION: Our study represents the first, to our knowledge, analysis of DNA methylation and gene expression associated with suicide in a Mexican population using postmortem brain, providing novel insights for convergent molecular alterations associated with suicide.

Isomer-specific kinetics of the C+ + H2O reaction at the temperature of interstellar clouds.

The reaction C+ + H2O → HCO+/HOC+ + H is one of the most important astrophysical sources of HOC+ ions, considered a marker for interstellar molecular clouds exposed to intense ultraviolet or x-ray radiation. Despite much study, there is no consensus on rate constants for formation of the formyl ion isomers in this reaction. This is largely due to difficulties in laboratory study of ion-molecule reactions under relevant conditions. Here, we use a novel experimental platform combining a cryogenic buffer-gas beam with an integrated, laser-cooled ion trap and high-resolution time-of-flight mass spectrometer to probe this reaction at the temperature of cold interstellar clouds. We report a reaction rate constant of k = 7.7(6) × 10-9 cm3 s-1 and a branching ratio of formation η = HOC+/HCO+ = 2.1(4). Theoretical calculations suggest that this branching ratio is due to the predominant formation of HOC+ followed by isomerization of products with internal energy over the isomerization barrier.

Non-CG methylation and multiple histone profiles associate child abuse with immune and small GTPase dysregulation.

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we describe molecular cross-talk among multiple mechanisms of genomic regulation, including 6 histone marks and DNA methylation, and the transcriptome, in subjects with a history of ELA and controls. In the healthy brain tissue, we first uncover interactions between different histone marks and non-CG methylation in the CAC context. Additionally, we find that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states. Combining these multiple data indicates that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. Overall, this work provides insights into genomic brain regulation as a function of early-life experience.

Cocaine-related DNA methylation in caudate neurons alters 3D chromatin structure of the IRXA gene cluster.

Epigenetic mechanisms, like those involving DNA methylation, are thought to mediate the relationship between chronic cocaine dependence and molecular changes in addiction-related neurocircuitry, but have been understudied in human brain. We initially used reduced representation bisulfite sequencing (RRBS) to generate a methylome-wide profile of cocaine dependence in human post-mortem caudate tissue. We focused on the Iroquois Homeobox A (IRXA) gene cluster, where hypomethylation in exon 3 of IRX2 in neuronal nuclei was associated with cocaine dependence. We replicated this finding in an independent cohort and found similar results in the dorsal striatum from cocaine self-administering mice. Using epigenome editing and 3C assays, we demonstrated a causal relationship between methylation within the IRX2 gene body, CTCF protein binding, three-dimensional (3D) chromatin interaction, and gene expression. Together, these findings suggest that cocaine-related hypomethylation of IRX2 contributes to the development and maintenance of cocaine dependence through alterations in 3D chromatin structure in the caudate nucleus.

Differential ESR1 Promoter Methylation in the Peripheral Blood-Findings from the Women 40+ Healthy Aging Study.

Background Estrogen receptor α (ERα) contributes to maintaining biological processes preserving health during aging. DNA methylation changes of ERα gene (ESR1) were established as playing a direct role in the regulation of ERα levels. In this study, we hypothesized decreased DNA methylation of ESR1 associated with postmenopause, lower estradiol (E2) levels, and increased age among healthy middle-aged and older women. Methods We assessed DNA methylation of ESR1 promoter region from dried blood spots (DBSs) and E2 from saliva samples in 130 healthy women aged 40-73 years. Results We found that postmenopause and lower E2 levels were associated with lower DNA methylation of a distal regulatory region, but not with DNA methylation of proximal promoters. Conclusion Our results indicate that decreased methylation of ESR1 cytosine-phosphate-guanine island (CpGI) shore may be associated with conditions of lower E2 in older healthy women.

Octahedral spinel electrocatalysts for alkaline fuel cells.

Designing high-performance nonprecious electrocatalysts to replace Pt for the oxygen reduction reaction (ORR) has been a key challenge for advancing fuel cell technologies. Here, we report a systematic study of 15 different AB2O4/C spinel nanoparticles with well-controlled octahedral morphology. The 3 most active ORR electrocatalysts were MnCo2O4/C, CoMn2O4/C, and CoFe2O4/C. CoMn2O4/C exhibited a half-wave potential of 0.89 V in 1 M KOH, equal to the benchmark activity of Pt/C, which was ascribed to charge transfer between Co and Mn, as evidenced by X-ray absorption spectroscopy. Scanning transmission electron microscopy (STEM) provided atomic-scale, spatially resolved images, and high-energy-resolution electron-loss near-edge structure (ELNES) enabled fingerprinting the local chemical environment around the active sites. The most active MnCo2O4/C was shown to have a unique Co-Mn core-shell structure. ELNES spectra indicate that the Co in the core is predominantly Co2.7+ while in the shell, it is mainly Co2+ Broader Mn ELNES spectra indicate less-ordered nearest oxygen neighbors. Co in the shell occupies mainly tetrahedral sites, which are likely candidates as the active sites for the ORR. Such microscopic-level investigation probes the heterogeneous electronic structure at the single-nanoparticle level, and may provide a more rational basis for the design of electrocatalysts for alkaline fuel cells.

Integrated genome-wide methylation and expression analyses reveal functional predictors of response to antidepressants.

Major depressive disorder (MDD) is primarily treated with antidepressants, yet many patients fail to respond adequately, and identifying antidepressant response biomarkers is thus of clinical significance. Some hypothesis-driven investigations of epigenetic markers for treatment response have been previously made, but genome-wide approaches remain unexplored. Healthy participants (n = 112) and MDD patients (n = 211) between 18-60 years old were recruited for an 8-week trial of escitalopram treatment. Responders and non-responders were identified using differential Montgomery-Åsberg Depression Rating Scale scores before and after treatment. Genome-wide DNA methylation and gene expression analyses were assessed using the Infinium MethylationEPIC Beadchip and HumanHT-12 v4 Expression Beadchip, respectively, on pre-treatment peripheral blood DNA and RNA samples. Differentially methylated positions (DMPs) located in regions of differentially expressed genes between responders (n = 82) and non-responders (n = 95) were identified, and technically validated using a targeted sequencing approach. Three DMPs located in the genes CHN2 (cg23687322, p = 0.00043 and cg06926818, p = 0.0014) and JAK2 (cg08339825, p = 0.00021) were the most significantly associated with mRNA expression changes and subsequently validated. Replication was then conducted with non-responders (n = 76) and responders (n = 71) in an external cohort that underwent a similar antidepressant trial. One CHN2 site (cg06926818; p = 0.03) was successfully replicated. Our findings indicate that differential methylation at CpG sites upstream of the CHN2 and JAK2 TSS regions are possible peripheral predictors of antidepressant treatment response. Future studies can provide further insight on robustness of our candidate biomarkers, and greater characterization of functional components.

Correction: A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay.

The original version of this Article contained an error in the spelling of the author Siddharth Banka, which was incorrectly given as Siddhart Banka. This has now been corrected in both the PDF and HTML versions of the Article.

Isotope-selective chemistry in the Be+(2S1/2) + HOD → BeOD+/BeOH+ + H/D reaction.

Low temperature reactions between laser-cooled Be+(2S1/2) ions and partially deuterated water (HOD) molecules have been investigated using an ion trap and interpreted with zero-point corrected quasi-classical trajectory calculations on a highly accurate global potential energy surface for the ground electronic state. Both product channels have been observed for the first time, and the branching to BeOD+ + H is found to be 0.58 ± 0.14. The experimental observation is reproduced by both quasi-classical trajectory and statistical calculations. Theoretical analyses reveal that the branching to the two product channels is largely due to the availability of open states in each channel.

A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay.

PURPOSE: Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes. METHODS: Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed. RESULTS: All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants. CONCLUSIONS: We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy.