Combined modelling of mRNA decay dynamics and single-molecule imaging in the Drosophila embryo uncovers a role for P-bodies in 5' to 3' degradation.

Regulation of mRNA degradation is critical for a diverse array of cellular processes and developmental cell fate decisions. Many methods for determining mRNA half-lives rely on transcriptional inhibition or metabolic labelling. Here, we use a non-invasive method for estimating half-lives for hundreds of mRNAs in the early Drosophila embryo. This approach uses the intronic and exonic reads from a total RNA-seq time series and Gaussian process regression to model the dynamics of premature and mature mRNAs. We show how regulation of mRNA stability is used to establish a range of mature mRNA dynamics during embryogenesis, despite shared transcription profiles. Using single-molecule imaging, we provide evidence that, for the mRNAs tested, there is a correlation between short half-life and mRNA association with P-bodies. Moreover, we detect an enrichment of mRNA 3' ends in P-bodies in the early embryo, consistent with 5' to 3' degradation occurring in P-bodies for at least a subset of mRNAs. We discuss our findings in relation to recently published data suggesting that the primary function of P-bodies in other biological contexts is mRNA storage.

Can accurate demographic information about people who use prescription medications nonmedically be derived from Twitter?

Traditional substance use (SU) surveillance methods, such as surveys, incur substantial lags. Due to the continuously evolving trends in SU, insights obtained via such methods are often outdated. Social media-based sources have been proposed for obtaining timely insights, but methods leveraging such data cannot typically provide fine-grained statistics about subpopulations, unlike traditional approaches. We address this gap by developing methods for automatically characterizing a large Twitter nonmedical prescription medication use (NPMU) cohort (n = 288,562) in terms of age-group, race, and gender. Our natural language processing and machine learning methods for automated cohort characterization achieved 0.88 precision (95% CI:0.84 to 0.92) for age-group, 0.90 (95% CI: 0.85 to 0.95) for race, and 94% accuracy (95% CI: 92 to 97) for gender, when evaluated against manually annotated gold-standard data. We compared automatically derived statistics for NPMU of tranquilizers, stimulants, and opioids from Twitter with statistics reported in the National Survey on Drug Use and Health (NSDUH) and the National Emergency Department Sample (NEDS). Distributions automatically estimated from Twitter were mostly consistent with the NSDUH [Spearman r: race: 0.98 (P < 0.005); age-group: 0.67 (P < 0.005); gender: 0.66 (P = 0.27)] and NEDS, with 34/65 (52.3%) of the Twitter-based estimates lying within 95% CIs of estimates from the traditional sources. Explainable differences (e.g., overrepresentation of younger people) were found for age-group-related statistics. Our study demonstrates that accurate subpopulation-specific estimates about SU, particularly NPMU, may be automatically derived from Twitter to obtain earlier insights about targeted subpopulations compared to traditional surveillance approaches.

Colorimetric Detection of Sulfur Mustard with 4-(p-Nitrobenzyl)pyridine and Its Derivatives.

In this study, we present a simple, highly sensitive, and selective colorimetric method for detecting sulfur mustard (SM) and its simulants. This method relies on a nucleophilic substitution reaction between derivatives of 4-(p-nitrobenzyl)pyridine (NBP) and SM and subsequent treatment with an external base, resulting in a visible response. This reaction exhibits an impressively low detection threshold by the naked eye, as low as 10 ppm at room temperature. In contrast to the conventional use of NBP for detecting other alkylating agents, such as nitrogen mustard, our approach eliminates the need for prolonged heating or intricate extraction processes. Both computational and experimental investigations underscore the significance of water within our detection medium as it stabilizes crucial episulfonium cation intermediates. Furthermore, we demonstrate the practical applicability of this sensor by incorporating it onto cellulose and silica surfaces, which may provide guidance for the design and development of solid-state SM detectors.

National Institute on Drug Abuse Clinical Trials Network Meeting Report: Managing Patients Exposed to Xylazine-Adulterated Opioids in Emergency, Hospital and Addiction Care Settings.

Used as a veterinary sedative and not approved for human use, xylazine has been increasingly linked with opioid overdose deaths in the United States. A growing number of people have been exposed to xylazine in the illicit opioid supply (especially fentanyl) or in other drugs, particularly in some areas of the Northeast. Xylazine is an α-2 adrenergic agonist that decreases sympathetic nervous system activity. When combined with fentanyl or heroin, it is purported to extend the duration of the opioid's sedative effect and to cause dependence and an associated withdrawal syndrome; however, data to support these concerns are limited. Despite the escalating frequency of detection of xylazine in people with nonfatal and fatal opioid overdose, direct links to these outcomes have not been identified. Because the strongest causal link is to fentanyl coexposure, ventilatory support and naloxone remain the cornerstones of overdose management. Xylazine is also associated with severe tissue injury, including skin ulcers and tissue loss, but little is known about the underlying mechanisms. Nonetheless, strategies for prevention and treatment are emerging. The significance and clinical effects of xylazine as an adulterant is focused on 4 domains that merit further evaluation: fentanyl-xylazine overdose, xylazine dependence and withdrawal, xylazine-associated dermal manifestations, and xylazine surveillance and detection in clinical and nonclinical settings. This report reflects the Proceedings of the National Institute on Drug Abuse Center for the Clinical Trials Network convening of clinical and scientific experts, federal staff, and other stakeholders to describe emerging best practices for treating people exposed to xylazine-adulterated opioids. Participants identified scientific gaps and opportunities for research to inform clinical practice in emergency departments, hospitals, and addiction medicine settings.

Emergency Department Screening and Interventions for Adolescents With Substance Use: A Narrative Review.

BACKGROUND: Adolescent substance use is a growing public health concern, particularly given rising mortality rates from drug overdose deaths. The emergency department (ED) provides a unique opportunity to screen adolescents for substance use and provide brief interventions and linkage to care. OBJECTIVE OF THE REVIEW: This article provides a narrative review of the current evidence for ED screening and brief interventions for adolescents with substance use and identifies important opportunities, challenges, and areas for future research. DISCUSSION: There are several validated substance use screening and assessment tools for use with adolescents that can be implemented into ED screening programs. Brief motivational interviewing interventions may reduce alcohol use, but evidence for reductions of other substances is limited due to insufficient research. Both screening and interventions are feasible and acceptable in the ED setting with the appropriate resources. Increased training and the use of emerging technology can provide emergency physicians with opportunities to incorporate these tools into practice to when treating adolescents. Linkage to outpatient care for adolescents with substance use is understudied. The research on adult patient ED interventions and linkage to care is more robust and can provide insights for future ED studies among adolescents. CONCLUSION: ED-based adolescent substance use screening and interventions are necessary, feasible, and acceptable, but understudied. Future studies, focusing on optimizing ED interventions and linkage to care, are important next steps in determining the best care for adolescents with substance use who present to the ED.

Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells.

MicroRNAs (miRNAs) are crucial for normal embryonic stem (ES) cell self-renewal and cellular differentiation, but how miRNA gene expression is controlled by the key transcriptional regulators of ES cells has not been established. We describe here the transcriptional regulatory circuitry of ES cells that incorporates protein-coding and miRNA genes based on high-resolution ChIP-seq data, systematic identification of miRNA promoters, and quantitative sequencing of short transcripts in multiple cell types. We find that the key ES cell transcription factors are associated with promoters for miRNAs that are preferentially expressed in ES cells and with promoters for a set of silent miRNA genes. This silent set of miRNA genes is co-occupied by Polycomb group proteins in ES cells and shows tissue-specific expression in differentiated cells. These data reveal how key ES cell transcription factors promote the ES cell miRNA expression program and integrate miRNAs into the regulatory circuitry controlling ES cell identity.

Cardiopulmonary Resuscitation Induced Posterior Rib Fractures in Nontraumatic Pediatric Deaths.

ABSTRACT: Posterior rib fractures are considered suspicious for nonaccidental injury when observed in infants without significant trauma history or underlying bone disease. The biomechanical mechanism postulated for causing posterior rib fractures is anterior/posterior compression of the chest with posterior levering of the rib head over the transverse process of the vertebra creating a focal area of stress. The recommended "2-thumb" cardiopulmonary resuscitation method involves the administrator placing both thumbs on the sternum of the patient, encircling the chest with the hands, and placing the finger tips lateral to the spine. From this position, the administrator compresses the chest in an anterior/posterior direction by pressing on the sternum. Theoretically, the 2-thumb method should focus all force on the sternum while the back is supported by the fingers limiting posterior levering of the ribs and reducing the risk of posterior rib fractures. However, posterior rib fractures have been found during the autopsy of infants who received 2-thumb cardiopulmonary resuscitation, had no traumatic history, had a nontraumatic cause of death, and had no indication of underlying bone disease. This case study series presents the demographics, birth histories, circumstances surrounding death, and autopsy findings of four such medical examiner cases.

Fatal Sodium Nitrite Poisoning: Key Considerations for Prehospital Providers.

Sodium nitrite is a powerful oxidizing agent that causes hypotension and limits oxygen transport and delivery in the body through the formation of methemoglobin. Clinical manifestations can include cyanosis, hypoxia, altered consciousness, dysrhythmias, and death. The majority of reports on sodium nitrite poisonings have been the result of unintentional exposures. We report a case of an intentional fatal overdose of sodium nitrite. A 17-year-old female reportedly drank approximately one tablespoon of sodium nitrite in a self-harm attempt. The patient was hypotensive and cyanotic upon EMS arrival. The patient decompensated rapidly into a bradycardic arrest during transport despite intubation, push-dose epinephrine, and intravenous fluid resuscitation. In the Emergency Department (ED), she received methylene blue and packed red cells but could not be resuscitated despite a prolonged effort. EMS professionals should consider sodium nitrite toxicity in patients with a suspected overdose who present with a cyanotic appearance, pulse oximetry that remains around 85% despite oxygen, and dark brown blood seen on venipuncture. Early prehospital contact with the Poison Control Center and ED prenotification in poisoned patients is encouraged.

The management of the poisoned patient using a novel emergency department-based resuscitation and critical care unit (ResCCU).

OBJECTIVES: The Resuscitation & Critical Care Unit (ResCCU) is a novel ED-based ICU designed to provide early critical care services. This study sought to identify characteristics of poisoned patients treated in the ResCCU. METHODS: We conducted a retrospective, single-center case study of poisoned patients over the age of 18 years old over a 16-month period. Patient demographics, drug concentrations, and severity of illness scores were extracted from electronic medical records. Patients were divided into two groups, those who required short term ICU level care (< 24 h) and prolonged ICU care (> 24 h). RESULTS: A total of 58 ED visits with a tox-related illness were analyzed. There were 24 women (41%) and 34 men (59%). There were 42 patients (72%) who required short term ICU level care and 16 patients (28%) who required prolonged ICU care. In the short-term ICU group, 13 patients (31%) were discharged home directly from the ResCCU, 29 patients (69%) were sent to the inpatient floor, and 1 of the admitted floor patients expired. There were no patients admitted to the floor that required a step-up to the inpatient ICU. 56 patients (97%) were alive at post-admit day 7 and 28, and only 8 (14%) were re-admitted within 30 days. CONCLUSIONS: Patients who were treated in the ED-based ICU for toxicology-related illnesses were frequently able to be either discharged home or admitted to a regular floor after their initial stabilization and treatment, and none that were sent to the floor required an ICU step-up.

The Importance of Ligand-Induced Backdonation in the Stabilization of Square Planar d10 Nickel π-Complexes.

The electronic nature of Ni π-complexes is underexplored even though these complexes have been widely postulated as intermediates in organometallic chemistry. Herein, the geometric and electronic structure of a series of nickel π-complexes, Ni(dtbpe)(X) (dtbpe=1,2-bis(di-tert-butyl)phosphinoethane; X=alkene or carbonyl containing π-ligands), is probed using a combination of 31 P NMR, Ni K-edge XAS, Ni Kß XES, and DFT calculations. These complexes are best described as square planar d10 complexes with π-backbonding acting as the dominant contributor to M-L bonding to the π-ligand. The degree of backbonding correlates with 2 JPP from NMR and the energy of the Ni 1s→4pz pre-edge in the Ni K-edge XAS data, and is determined by the energy of the π*ip ligand acceptor orbital. Thus, unactivated olefinic ligands tend to be poor π-acids whereas ketones, aldehydes, and esters allow for greater backbonding. However, backbonding is still significant even in cases in which metal contributions are minor. In such cases, backbonding is dominated by charge donation from the diphosphine, which allows for strong backdonation, although the metal centre retains a formal d10 electronic configuration. This ligand-induced backbonding can be formally described as a 3-centre-4-electron (3c-4e) interaction, in which the nickel centre mediates charge transfer from the phosphine σ-donors to the π*ip ligand acceptor orbital. The implications of this bonding motif are described with respect to both structure and reactivity.

Platinum-mediated B-H methoxylation of bis(pyrazolyl)borate.

A new bis(pyrazolyl)dihydridoborato diphenylplatinum(ii) complex was found to react with methanol to form H2 and a new diphenylplatinum(ii) complex supported by bis(pyrazolyl)dimethoxyborate. When performed in CD3OD, in addition to the expected installation of OCD3 fragments on the B-center and concomitant formation of H-D, deuteration of PtII(C6H5)2 fragments was observed. In contrast, dissolution of the bis(pyrazolyl)dimethoxyborato diphenylplatinum(ii) complex in CD3OD led to neither deuteration of PtII(C6H5)2 fragments nor substitution of B-bound methoxy fragments. A mechanism discussing the role of the PtII-center is presented.

Role of Phosphine Sterics in Strained Aminophosphine Chelate Formation.

The preparation of four-membered aminophosphine (PN) chelates from common metal precursors has largely evaded realization because of the ring strain associated with these species. We report a straightforward approach to the synthesis of such PN metallacycles using simple α-PN ligands analogous to the popular class of small-bite-angle diphosphinomethane ligands. It is demonstrated that bulky phosphine substituents are important to the formation of these chelates.

Understanding Ni(II)-Mediated C(sp3)-H Activation: Tertiary Ureas as Model Substrates.

We report a mechanistic study of C(sp3)-H bond activation mediated by nickel. Cyclometalated Ni(II) ureate [(PEt3)Ni(κ3- C,N,N-(CH2)N(Cy)(CO)N((N)-quinolin-8-yl))] was synthesized and isolated from the urea precursor, (Me)(Cy)N(CO)N(H)(quinolin-8-yl), via C(sp3)-H activation. We investigated the effects of solvents and base additives on the rate of C-H activation. Kinetic isotope effect experiments showed that C-H activation is rate determining. Through deuterium labeling and protonation studies, we also showed that C-H activation can be reversible. We extended this reaction to a range of ureas with primary and secondary C(sp3)-H bonds, which activate readily to form analogous nickelated products. Finally, we showed that carboxylate additives assist with both ligand dissociation and initial N-H bond activation, consistent with a concerted metalation-deprotonation mechanism.

Recent advances in well-defined, late transition metal complexes that make and/or break C-N, C-O and C-S bonds.

Chemical transformations that result in either the formation or cleavage of carbon-heteroatom bonds are among the most important processes in the chemical sciences. Herein, we present a review on the reactivity of well-defined, late-transition metal complexes that result in the making and breaking of C-N, C-O and C-S bonds via fundamental organometallic reactions, i.e. oxidative addition, reductive elimination, insertion and elimination reactions. When appropriate, emphasis is placed on structural and spectroscopic characterization techniques, as well as mechanistic data.

1,3-N,O-Complexes of late transition metals. Ligands with flexible bonding modes and reaction profiles.

1,3-N,O-Chelating ligands are ubiquitous in nature owing to their occurrence as α-chiral amino acids in metalloproteins. These structural units also display diverse coordination modes, which lend themselves to applications in catalysis as well as novel fundamental stoichiometric reactivity, including the activation of inert bonds. This review comments on recent developments in N,O-ligated late transition metal complexes with an emphasis on preparation, characterization, and reactivity.

Spirituality and Post-Stroke Aphasia Recovery.

The role of spirituality in post-stroke aphasia recovery has been ignored despite its potential contribution to positive health outcomes, particularly stroke recovery. The present study examines the spiritual experience of adults with aphasia in an effort to better understand the role of one's spirituality in the aphasia recovery process. Thirteen adults with aphasia completed a modified spirituality questionnaire and participated in semi-structured interviews. All participants considered themselves spiritual and reported improvements in communication during post-stroke recovery. Two themes related to spirituality that emerged from the interviews were (a) a greater power being in control of events and (b) a greater power as helper.

Catalytic Functionalization of Styrenyl Epoxides via 2-Nickela(II)oxetanes.

Low-valent nickel is shown to preferentially isomerize mono- or disubstituted epoxides into their corresponding aldehydes. Experiments with tetrasubstituted epoxides demonstrate that these reactions proceed via reactive 2-nickelaoxetane intermediates, and that the oxidative addition step likely occurs with retention of configuration. The monosubstituted aldehyde isomerization products were found to rapidly react with HBpin to form boronate esters. These hydroboration reactions could be performed catalytically.

Toward anti-Markovnikov 1-Alkyne O-Phosphoramidation: Exploiting Metal-Ligand Cooperativity in a 1,3-N,O-Chelated Cp*Ir(III) Complex.

Metal-ligand cooperation between iridium(III) and a 1,3-N,O-chelating phosphoramidate ligand has been used to develop a protocol for the intermolecular O-phosphoramidation of 1-alkynes. This selective C-O bond-forming reaction differs from that of standard amidation reactions, highlighting the ability to control N- or O-functionalization based on judicious choice of N,O-chelating ligand and metal center. Advances toward the development of catalytic anti-Markovnikov O-phosphoramidation using iridium(III), including characterization of rare reactive intermediates that invoke 1,3-bidentate donor ligand hemilability, are disclosed.