The Ring-Closing Reaction of Cyclopentadiene Probed with Ultrafast X-ray Scattering.

The dynamics of cyclopentadiene (CP) following optical excitation at 243 nm was investigated by time-resolved pump-probe X-ray scattering using 16.2 keV X-rays at the Linac Coherent Light Source (LCLS). We present the first ultrafast structural evidence that the reaction leads directly to the formation of bicyclo[2.1.0]pentene (BP), a strained molecule with three- and four-membered rings. The bicyclic compound decays via a thermal backreaction to the vibrationally hot CP with a time constant of 21 ± 3 ps. A minor channel leads to ring-opened structures on a subpicosecond time scale.

Plumbing mysterious RNAs in "dark genome" for the conquest of human diseases.

Next-generation sequencing has revealed that less than 2% of transcribed genes are translated into proteins, with a large portion transcribed into noncoding RNAs (ncRNAs). Among these, long noncoding RNAs (lncRNAs) represent the largest group and are pervasively transcribed throughout the genome. Dysfunctions in lncRNAs have been found in various diseases, highlighting their potential as therapeutic, diagnostic, and prognostic targets. However, challenges, such as unknown molecular mechanisms and nonspecific immune responses, and issues of drug specificity and delivery present obstacles in translating lncRNAs into clinical applications. In this review, we summarize recent publications that have explored lncRNA functions in human diseases. We also discuss challenges and future directions for developing lncRNA treatments, aiming to bridge the gap between functional studies and clinical potential and inspire further exploration in the field.

Implementation of Video Blood Pressure Visits in the Veterans Health Administration.

Introduction: Almost half of veterans (44.6%) seen in the U.S. Department of Veterans Affairs outpatient setting are diagnosed with hypertension (HTN). Because of the widespread nature of HTN, use of virtual visits has the potential to improve blood pressure (BP) management. This evaluation assessed the effectiveness of video blood pressure visits (VBPVs) in the management of HTN in veterans enrolled in Veterans Health Administration primary care. Methods: The program was implemented within the existing veteran-centered medical home. VBPVs are scheduled where the nurse observes veterans taking their BP and provides teaching or counseling. A national training curriculum was delivered to local nurse champions through Microsoft Teams. We analyzed improvement in BP over a 2-year period. We also captured actions taken by nurses during the VBPV by searching the electronic notes. Ratings of training and comments were summarized using feedback forms completed after training. Results: In total, 81,476 veterans participated in VBPVs over 2 years. Of those, 44,682 veterans had an existing ICD-10 code related to HTN. Of the 18,078 veterans who had a pre- and post-VBPV BP, the average change to systolic measurement was -10.6 mm Hg (range -82 to 78). Average change to diastolic measurement was -4.61 mm Hg (range -59 to 55). Most interventions addressed medication management (77%). Nurses' evaluations of the program were positive. Conclusions: Video visits provide reliable and convenient veteran-centered care. Such visits enable care when unanticipated interruptions occur such as the coronavirus disease 2019 pandemic. In addition to medication management, nurse-led interventions such as counseling on lifestyle changes can be effective in HTN management.

Understanding integrated HPV testing and treatment of pre-cancerous cervical cancer in Burkina Faso, Cote d'Ivoire, Guatemala and Philippines: study protocol.

BACKGROUND: Many low- and-middle-income countries are disproportionately burdened by cervical cancer, resulting in high morbidity and mortality. HPV-DNA testing coupled with treatment with thermal ablation is a recommended screening and precancer treatment strategy, but not enough is known about how this can be effectively implemented in the context of integrated services. The (Scale Up Cervical Cancer Elimination by Secondary prevention Strategy, (SUCCESS) project is conducting a study to understand this approach, integrated into existing women's health services in Burkina Faso, Cote d'Ivoire, Guatemala, and the Philippines (2020-2024). METHODS: A hybrid effectiveness-implementation type III mixed-methods observational study design is used to assess feasibility, acceptability, and costs of integrated service delivery in 10 sites per country, selected considering urban/rural location, facility level, onsite/offsite laboratories, and health services type. In each country, a sample size of 2227 women aged 25-49 years will be enrolled with about 20% being women living with HIV. The primary outcome is proportion of HPV positive women completing precancer treatment, if eligible, within three months of screening. Data collection and analysis includes; facility and client exit surveys, key informant and client interviews, registries and project records extractions, and costing data analysis. Analysis includes descriptive statistics, context description, thematic analysis, and document analysis. Quantitative analyses will be stratified by participant's HIV status. DISCUSSION: Recruitment of study participants started in April 2022 (Burkina Faso and Côte d'Ivoire) and August 2022 (Guatemala and the Philippines). Enrolment targets for women screened, client exit, in-depth and key informant interviews conducted were reached in Burkina Faso and Cote d'Ivoire in November 2022. Guatemala and Philippines are expected to complete enrolment by June 2023. Follow-up of study Participants 12-months post-treatment is ongoing and is expected to be completed for all countries by August 2024. In LMICs, integrating cervical cancer secondary prevention services into other health services will likely require specific rather than incidental recruitment of women for screening. Reconfiguration of laboratory infrastructure and planning for sample management must be made well in advance to meet induced demand for screening. Trail Registration ClinicalTrials.Gov ID: NCT05133661 (24/11/2021).

Fluoroscopic Imaging for the Interventional Echocardiographer.

Procedural guidance during structural heart disease (SHD) interventions is achieved with both two-dimensional and three-dimensional transesophageal echocardiography as well as real-time fluoroscopic imaging. Although both image the cardiac anatomy, they are based on different principles of image acquisition. In the era of multimodality imaging with coregistration of anatomic landmarks and simultaneous real-time display, it is essential to have cross-disciplinary imaging knowledge. Besides improving communication, it also enhances patient care and, possibly, outcomes. In this study, the authors used a novel fluoroscopic phantom cardiac model with enhanced structural markers to display the basic fluoroscopic images used during SHD interventions. The projected images enhance the understanding of the orientation and relationship among intracardiac structures as seen on fluoroscopy. In this study, the authors present the basic fluoroscopic views for SHD interventions and the anatomic relationship for intracardiac structures using a custom-made phantom fluoroscopic heart model.

Development of BET inhibitors as potential treatments for cancer: A new carboline chemotype.

We describe our efforts to introduce structural diversity to a previously described triazole-containing N1-carboline series of bromodomain and extra-terminal (BET) inhibitors. N9 carbolines were designed to retain favorable binding interactions that the N1-carbolines possess. A convergent synthetic route enabled modifications to reduce clearance, enhance physicochemical properties, and improve the overall in vitro profile. This work led to the identification of a potent BET inhibitor, (S)-2-{8-fluoro-5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-7-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-3-yl}propan-2-ol (10), a compound with enhanced oral exposure in mice. Subsequent evaluation in a mouse triple-negative breast cancer tumor model revealed efficacy at 4 mg/kg of N9-carboline 10.

Development and validation of an aetiology in delirium diagnostic support tool.

BACKGROUND: recognition of the multifactorial causes of delirium represents a clinical challenge. OBJECTIVES: to develop and show proof of principle of a diagnostic support tool (DST) for identification of causes of delirium. METHODS: stage 1-development of the aetiology in delirium-diagnostic support tool (AiD-DST); stage 2-validation of the AiD-DST against reference standard diagnosis, based on clinical assessment from two independent consultant geriatricians. RESULTS: a series of eight steps AiD-DST were formulated by an expert group to identify possible causes of delirium. Forty inpatients admitted to a general medical unit with a consultant physician/geriatrician diagnosis of delirium were recruited, consented and reviewed against the AiD-DST. Mean age was 85.1 (standard deviation 7.9) years and 26 (65%) of participants were female. Participants had multiple chronic co-morbidities [median Charlson Comorbidity Index 7; interquartile range (IQR 6-9)] and median number of medications was 8 (IQR 6-11.75). Median number of causes of delirium detected on AiD-DST was 3 (IQR 3-4) versus 5 (IQR 3-6) using the reference standard diagnosis, with sensitivity of 88.8% (95% confidence interval, 81.6-93.9%) and specificity of 71.8% (63-79.5%). CONCLUSIONS: the aetiology in delirium DST shows promise in the identification of cause(s) in delirium.

Workflow of Ultrasound-Guided Arterial Access.

Arterial line cannulations frequently are performed in various clinical settings to facilitate hemodynamic monitoring and metabolic assessments. Palpation-guided technique generally is performed due to the superficial nature of the peripheral arteries; however, this approach may be challenging in patients with obesity, edema, and hypotension. Difficult line placements are a significant contributor of reduced operating room efficiency due to time delays seen in procedural workflow. Real-time ultrasound guidance is shown to improve success rates of arterial cannulation and reduction in multiple attempts, leading to time efficiency and less likelihood of arterial spasms or hematoma formation. In this report, the authors demonstrate the workflow of ultrasound-guided arterial line cannulation, outline the features of their institutional multi-modal training project for quality improvement, and evaluate the possible effect of the initiative on surgical delays seen with difficult line placements.

Retrieval cues fail to influence contextualized evaluations.

Initial evaluations generalise to new contexts, whereas counter-attitudinal evaluations are context-specific. Counter-attitudinal information may not change evaluations in new contexts because perceivers fail to retrieve counter-attitudinal cue-evaluation associations from memory outside the counter-attitudinal learning context. The current work examines whether an additional, counter-attitudinal retrieval cue can enhance the generalizability of counter-attitudinal evaluations. In four experiments, participants learned positive information about a target person, Bob, in one context, and then learned negative information about Bob in a different context. While learning the negative information, participants wore a wristband as a retrieval cue for counter-attitudinal Bob-negative associations. Participants then made speeded as well as deliberate evaluations of Bob while wearing or not wearing the wristband. Internal meta-analysis failed to find a reliable effect of the counter-attitudinal retrieval cue on speeded or deliberate evaluations, whereas the context cues influenced speeded and deliberate evaluations. Counter to predictions, counter-attitudinal retrieval cues did not disrupt the generalisation of first-learned evaluations or the context-specificity of second-learned evaluations (Experiments 2-4), but the counter-attitudinal retrieval cue did influence evaluations in the absence of context cues (Experiment 1). The current work provides initial evidence that additional counter-attitudinal retrieval cues fail to disrupt the renewal and generalizability of first-learned evaluations.

The Impact of Ambient Environmental Exposures to Microbial Products on Asthma Outcomes from Birth to Childhood.

PURPOSE OF REVIEW: Asthma is a chronic respiratory condition with increasing domestic and worldwide prevalence that burdens individuals and the healthcare system with high costs associated with long-term treatments and acute emergency room (ER) visits. It can be triggered by ambient microbes, including bacteria, viruses, and fungi. In this review, we examine the outcomes of asthma patients in relation to environmental exposures to ambient microbe products, focusing on whether exposure leads to asthma development from birth to childhood and if particular microbes are associated with worsened asthma exacerbations. RECENT FINDINGS: Bacterial endotoxin is more prominent in homes with pets and may cause cytokine cascades that lead to asthma exacerbation. However, some studies have demonstrated a protective effect with early exposure. Patients with positive Aspergillus skin testing are more prone to moderate-severe or severe-uncontrolled asthma. Fungal sensitization is also associated with earlier onset of asthma and demonstrates a dose-dependent relationship of symptom severity and duration. Among viruses, rhinovirus has the greatest association with decreased lung function, severe asthma, and asthma-related hospital admissions. Distribution of microbial products and associated asthma symptoms depends on the geographical climate. Genetic variations among individuals also mitigate the effects of microbial products on asthma development and symptom severity. Microbial products of bacteria, fungi, and viruses are associated with the development of asthma, more severe asthma symptoms, and worse outcomes. However, some early exposure studies have also demonstrated a protective effect. Bacterial and fungal products are related to decreased lung function and earlier onset of asthma. Viral products are related to asthma-associated hospital admissions; and the climate and patient genetics can also temper or intensify the relationships between microbial products, asthma development, and asthma symptom severity. Further research should focus on the effects of early microbe exposure and its interaction with human immune systems and asthma-related outcomes.

Interdisciplinary Collaboration in Medication-Related Falls Prevention in Older Adults.

The older adult population continues to steadily increase. Largely attributed to longer life spans and aging of the Baby Boomer generation, continued growth of this population is expected to affect a multitude of challenging public health concerns. Specifically, falls in older adults are prevalent but overlooked concerns. Health care providers are well-positioned to provide valuable interventions in this aspect. An interdisciplinary, team-based approach of health care providers is required to maximize falls prevention through patient-centered and collaborative care. The current article highlights the implications of inappropriate medication use and the need to improve care coordination to tackle this public health issue affecting older adults. [Journal of Gerontological Nursing, 44(4), 11-15.].

Elevated Levels of Microbial Translocation Markers and CCL2 Among Older HIV-1-Infected Men.

The aging of the human immunodeficiency virus type 1 (HIV-1)-infected population obligates a focus on the interaction between aging, comorbid conditions, and HIV-1. We recruited a cohort of HIV-1-infected men aged ≤ 35 years or ≥ 50 years who were receiving fully suppressive antiretroviral therapy (ART). We analyzed plasma markers of inflammation; T-cell activation, exhaustion, proliferation; and innate cellular subsets and functional capacity. Levels of lipopolysaccharide and the plasma marker of chemokine (C-C motif) ligand 2 were significantly elevated in older HIV-infected men despite comparable cellular phenotypes. Compared with similarly age-stratified uninfected subjects, older HIV-1-infected adults were also more frequently in the upper quartile of soluble CD14 expression.

Diagnosis and management of hearing loss in elderly patients.

BACKGROUND: Hearing loss is the most common sensory deficit in elderly patients, and is often under-recognised and poorly managed. It is essential for all clinicians to have awareness and knowledge in this field to enable the institution of early and appropriate care. OBJECTIVE: The goal of this article is to review the causes, diagnosis and management of hearing loss as it applies to elderly patients. The review describes a useful approach that clinicians can apply to daily practice. DISCUSSION: For elderly patients presenting with hearing loss, the basic assessment should include history, physical examination and pure tone audiometry. Management depends on the cause and type of hearing loss, and options include medical therapy, surgery and amplification. In the absence of a simple and correctable cause, consider referring patients to an otolaryngologist for further assessment.

Embryonic ablation of osteoblast Smad4 interrupts matrix synthesis in response to canonical Wnt signaling and causes an osteogenesis-imperfecta-like phenotype.

To examine interactions between bone morphogenic protein (BMP) and canonical Wnt signaling during skeletal growth, we ablated Smad4, a key component of the TGF-ß-BMP pathway, in Osx1(+) cells in mice. We show that loss of Smad4 causes stunted growth, spontaneous fractures and a combination of features seen in osteogenesis imperfecta, cleidocranial dysplasia and Wnt-deficiency syndromes. Bones of Smad4 mutant mice exhibited markers of fully differentiated osteoblasts but lacked multiple collagen-processing enzymes, including lysyl oxidase (Lox), a BMP2-responsive gene regulated by Smad4 and Runx2. Accordingly, the collagen matrix in Smad4 mutants was disorganized, but also hypomineralized. Primary osteoblasts from these mutants did not mineralize in vitro in the presence of BMP2 or Wnt3a, and Smad4 mutant mice failed to accrue new bone following systemic inhibition of the Dickkopf homolog Dkk1. Consistent with impaired biological responses to canonical Wnt, ablation of Smad4 causes cleavage of ß-catenin and depletion of the low density lipoprotein receptor Lrp5, subsequent to increased caspase-3 activity and apoptosis. In summary, Smad4 regulates maturation of skeletal collagen and osteoblast survival, and is required for matrix-forming responses to both BMP2 and canonical Wnt.

Postnatal ablation of osteoblast Smad4 enhances proliferative responses to canonical Wnt signaling through interactions with ß-catenin.

Canonical Wnt (cWnt) signaling through ß-catenin regulates osteoblast proliferation and differentiation to enhance bone formation. We previously reported that osteogenic action of ß-catenin is dependent on BMP signaling. Here, we further examined interactions between cWnt and BMP in bone. In osteoprogenitors stimulated with BMP2, ß-catenin localizes to the nucleus, physically interacts with Smad4, and is recruited to DNA-binding transcription complexes containing Smad4, R-Smad1/5 and TCF4. Furthermore, Tcf/Lef-dependent transcription, Ccnd1 expression and proliferation all increase when Smad4, 1 or 5 levels are low, whereas TCF/Lef activities decrease when Smad4 expression is high. The ability of Smad4 to antagonize transcription of Ccnd1 is dependent on DNA-binding activity but Smad4-dependent transcription is not required. In mice, conditional deletion of Smad4 in osterix(+) cells increases mitosis of cells on trabecular bone surfaces as well as in primary osteoblast cultures from adult bone marrow and neonatal calvaria. By contrast, ablation of Smad4 delays differentiation and matrix mineralization by primary osteoblasts in response to Wnt3a, indicating that loss of Smad4 perturbs the balance between proliferation and differentiation in osteoprogenitors. We propose that Smad4 and Tcf/Lef transcription complexes compete for ß-catenin, thus restraining cWnt-dependent proliferative signals while favoring the matrix synthesizing activity of osteoblasts.

Sequential action of ATPase, ATP, ADP, Pi and dsDNA in procapsid-free system to enlighten mechanism in viral dsDNA packaging.

Many cells and double-stranded DNA (dsDNA) viruses contain an AAA(+) ATPase that assembles into oligomers, often hexamers, with a central channel. The dsDNA packaging motor of bacteriophage phi29 also contains an ATPase to translocate dsDNA through a dodecameric channel. The motor ATPase has been investigated substantially in the context of the entire procapsid. Here, we report the sequential action between the ATPase and additional motor components. It is suggested that the contact of ATPase to ATP resulted in its conformational change to a higher binding affinity toward dsDNA. It was found that ATP hydrolysis led to the departure of dsDNA from the ATPase/dsDNA complex, an action that is speculated to push dsDNA to pass the connector channel. Our results suggest that dsDNA packaging goes through a combined effort of both the gp16 ATPase for pushing and the channel as a one-way valve to control the dsDNA translocation direction. Many packaging models have previously been proposed, and the packaging mechanism has been contingent upon the number of nucleotides packaged per ATP relative to the 10.5 bp per helical turn for B-type dsDNA. Both 2 and 2.5 bp per ATP have been used to argue for four, five or six discrete steps of dsDNA translocation. Combination of the two distinct roles of gp16 and connector renews the perception of previous dsDNA packaging energy calculations and provides insight into the discrepancy between 2 and 2.5 bp per ATP.

Binomial distribution for quantification of protein subunits in biological nanoassemblies and functional nanomachines.

Living systems produce ordered structures and nanomachines that inspire the development of biomimetic nanodevices such as chips, MEMS, actuators, sensors, sorters, and apparatuses for single-pore DNA sequencing, disease diagnosis, drug or therapeutic RNA delivery. Determination of the copy numbers of subunits that build these machines is challenging due to small size. Here we report a simple mathematical method to determine the stoichiometry, using phi29 DNA-packaging nanomotor as a model to elucidate the application of a formula ∑M=0(Z)((Z)M)p(Z-M)q(M), where p and q are the percentage of wild-type and inactive mutant in the empirical assay; M is the copy numbers of mutant and Z is the stoichiometry in question. Variable ratios of mutants and wild-type were mixed to inhibit motor function. Empirical data were plotted over the theoretical curves to determine the stoichiometry and the value of K, which is the number of mutant needed in each machine to block the function, all based on the condition that wild-type and mutant are equal in binding affinity. Both Z and K from 1-12 were investigated. The data precisely confirmed that phi29 motor contains six copies (Z) of the motor ATPase gp16, and K=1. From the clinical editor: To determine copy numbers of subunits that form nanomachines in living organisms is a daunting task due to the complexities and the inherently small sizes associated with such systems. In this paper, a simple mathematical method is described how to determine the stoichiometry of copies in biomimetic nanodevices, using phi29 DNA-packaging nanomotor as a model.