Predicting Emission Wavelengths in Benzobisoxazole-Based OLEDs with Gradient Boosted Ensemble Models.

We demonstrate the use of gradient-boosted ensemble models that accurately predict emission wavelengths in benzobis[1,2-d:4,5-d']oxazole (BBO) based fluorescent emitters. We have curated a database of 50 molecules from previously published data by the Jeffries-EL group using density functional theory (DFT) computed ground and excited state features. We consider two machine learning (ML) models based on (i) whole cruciform molecules and (ii) their constituent fragment molecules. Both ML models provide accurate predictions with root-mean-square errors between 30 and 36 nm, competitive with state-of-the-art deep learning models trained on orders of magnitude more molecules, and this accuracy holds even when tested on four new BBO emitters unseen by the models. We also provide an interpretable feature importance analysis and discuss the relevant relationships between DFT and changes in predicted emission wavelength.

Off the wall: incidental paraspinal and pelvic muscle pathology on abdominopelvic imaging.

As the use of cross-sectional abdominal and pelvic imaging has increased exponentially in the past several decades, incidental musculoskeletal findings have become commonplace. These are often unrelated to the indication for the examination and are frequently referred to as the "radiologist's blind spot" on these studies. The differential diagnosis for abnormalities of the paraspinal and pelvic musculature is, in many cases, quite different from the anterior abdominal wall muscles. Furthermore, due to their relatively deep location, pathology involving the former muscle groups is more likely to be clinically occult, often presenting only incidentally when the patient undergoes cross-sectional imaging. Effective treatment of diseases of these muscles is dependent on adherence to a diverse set of diagnostic and treatment algorithms. The purpose of this review article is to familiarize the radiologist with the unique pathology of these often-overlooked muscles of the abdomen and pelvis.

Navigating the Unexpected: Right Aortic Arch Unveiled During Left Heart Catheterization.

A right aortic arch (RAA) is an extremely rare congenital anomaly with seven identified variants. While most variants are asymptomatic, those with a vascular ring can be associated with severe symptoms. We present an incidental RAA finding during left heart catheterization (LHC) in a 68-year-old female with multiple morbidities presented with worsening angina. Her echocardiogram was significant for inferolateral wall akinesia, prompting LHC. The procedure was challenging with an unexpected course of the guide wire distally behind the cardiac shadow. Pressure tracing confirmed arterial access and contrast injection revealed RAA. A subsequent aortic computed tomography angiography (CTA) confirmed RAA with mirror-image branching. Abnormal origin and angle of aortic arch branches pose challenges in choosing the proper access. We used the right radial artery approach, but the left radial approach may be superior in providing a more proximal access and avoiding the abnormal origin of the right subclavian artery (RSA). Choosing the appropriate angiographic view is also of utmost importance, and the right anterior oblique view provided better visualization in our case. Aortic arch anomalies are confirmed by a CTA or magnetic resonance angiography (MRA) of the aorta. This case underscores the importance of identifying the aortic arch anomalies and the imposed challenges during the LHC.

Analysis of driver behavior at grade-separated intersections to support design.

Understanding driver behaviors in varied traffic scenarios is critical to the design of safe and efficient roadways and traffic control device. This research presents an analysis of driver cognitive workload, situation awareness (SA) and performance for three different scenarios, including a standard intersection and contraflow grade-separated intersections (C-GSI) and quadrant GSI (Q-GSI) with lane assignment sign manipulations. The study used a simulator-based driving experiment with application of the NASA Task Load Index and Situation Awareness Global Assessment Technique to assess the influence of the scenarios on driver behavioral responses. The findings reveal challenges for drivers navigating the C-GSI, characterized by diminished SA and elevated workload. These states were associated with behaviors such as delayed lane changes, missed opportunities for appropriate lane changes, heightened acceleration behavior within deceleration segments, and frequent speeding. In contrast, while drivers in the Q-GSI scenario faced elevated workloads, their SA remained steady, largely due to lane-specific signs facilitating early lane changes. Although the Q-GSI led to increased speed variability and slight increases in deceleration, the use of supplementary speed signage revealed a promising alternative to the S-intersection. Correlation analysis highlighted a significant relationship between mental workload and acceleration responses, indicating that increased acceleration was associated with higher mental workload. In addition, a significant negative correlation between driver perceived performance and absolute lane deviations indicated that drivers with higher self-assessed performance were more accurate in lane-keeping. The study underscores the need for GSIs and signage designs that support driver SA, manage cognitive workload to improve driver performance and increase road safety.

Challenges & barriers for real-time integration of drones in emergency cardiac care: Lessons from the United States, Sweden, & Canada.

Importance: Out-of-hospital cardiac arrest (OHCA) is a leading cause of morbidity and mortality in the US and Europe (∼600,000 incident events annually) and around the world (∼3.8 million). With every minute that passes without cardiopulmonary resuscitation or defibrillation, the probability of survival decreases by 10%. Preliminary studies suggest that uncrewed aircraft systems, also known as drones, can deliver automated external defibrillators (AEDs) to OHCA victims faster than ground transport and potentially save lives. Objective: To date, the United States (US), Sweden, and Canada have made significant contributions to the knowledge base regarding AED-equipped drones. The purpose of this Special Communication is to explore the challenges and facilitators impacting the progress of AED-equipped drone integration into emergency medicine research and applications in the US, Sweden, and Canada. We also explore opportunities to propel this innovative and important research forward. Evidence review: In this narrative review, we summarize the AED-drone research to date from the US, Sweden, and Canada, including the first drone-assisted delivery of an AED to an OHCA. Further, we compare the research environment, emergency medical systems, and aviation regulatory environment in each country as they apply to OHCA, AEDs, and drones. Finally, we provide recommendations for advancing research and implementation of AED-drone technology into emergency care. Findings: The rates that drone technologies have been integrated into both research and real-life emergency care in each country varies considerably. Based on current research, there is significant potential in incorporating AED-equipped drones into the chain of survival for OHCA emergency response. Comparing the different environments and systems in each country revealed ways that each can serve as a facilitator or barrier to future AED-drone research. Conclusions and relevance: The US, Sweden, and Canada each offers different challenges and opportunities in this field of research. Together, the international community can learn from one another to optimize integration of AED-equipped drones into emergency systems of care.

Cochlear zinc signaling dysregulation is associated with noise-induced hearing loss, and zinc chelation enhances cochlear recovery.

Exposure to loud noise triggers sensory organ damage and degeneration that, in turn, leads to hearing loss. Despite the troublesome impact of noise-induced hearing loss (NIHL) in individuals and societies, treatment strategies that protect and restore hearing are few and insufficient. As such, identification and mechanistic understanding of the signaling pathways involved in NIHL are required. Biological zinc is mostly bound to proteins, where it plays major structural or catalytic roles; however, there is also a pool of unbound, mobile (labile) zinc. Labile zinc is mostly found in vesicles in secretory tissues, where it is released and plays a critical signaling role. In the brain, labile zinc fine-tunes neurotransmission and sensory processing. However, injury-induced dysregulation of labile zinc signaling contributes to neurodegeneration. Here, we tested whether zinc dysregulation occurs and contributes to NIHL in mice. We found that ZnT3, the vesicular zinc transporter responsible for loading zinc into vesicles, is expressed in cochlear hair cells and the spiral limbus, with labile zinc also present in the same areas. Soon after noise trauma, ZnT3 and zinc levels are significantly increased, and their subcellular localization is vastly altered. Disruption of zinc signaling, either via ZnT3 deletion or pharmacological zinc chelation, mitigated NIHL, as evidenced by enhanced auditory brainstem responses, distortion product otoacoustic emissions, and number of hair cell synapses. These data reveal that noise-induced zinc dysregulation is associated with cochlear dysfunction and recovery after NIHL, and point to zinc chelation as a potential treatment for mitigating NIHL.

An association between Dnmt1 and Wnt in the production of oocytes in the whitefly Bemisia tabaci.

The function of DNA methylation in insects and the DNA methyltransferase (Dnmt) genes that influence methylation remains uncertain. We used RNA interference to reduce the gene expression of Dnmt1 within the whitefly Bemisia tabaci (Hemiptera:Aleyrodidae; Gennadius), a hemipteran species that relies on Dnmt1 for proper gametogenesis. We then used RNA-seq to test an a priori hypothesis that meiosis-related genetic pathways would be perturbed. We generally did not find an overall effect on meiosis-related pathways. However, we found that genes in the Wnt pathway, genes associated with the entry into meiosis in vertebrates, were differentially expressed. Our results are consistent with Dnmt1 knockdown influencing specific pathways and not causing general transcriptional response. This is a finding that is also seen with other insect species. We also characterised the methylome of B. tabaci and assessed the influence of Dnmt1 knockdown on cytosine methylation. This species has methylome characteristics comparable to other hemipterans regarding overall level, enrichment within gene bodies, and a bimodal distribution of methylated/non-methylated genes. Very little differential methylation was observed, and difference in methylation were not associated with differences in gene expression. The effect on Wnt presents an interesting new candidate pathway for future studies.

Offspring overcome poor parenting by being better parents.

The evolutionary repercussions of parental effects-the impact of the developmental environment provided by parents on offspring-are often discussed as static effects that can have negative influences on offspring fitness that may even persist across generations. However, individuals are not passive recipients and may mitigate the persistence of parental effects through their behaviour. Here, we tested how the burying beetle, Nicrophorus orbicollis, a species with complex parental care, responded to poor parenting. We cross-fostered young and manipulated the duration of parental care received and measured the impact on traits of both F1 and F2 offspring to experimentally extricate the effect of poor parenting from other parental effects. As expected, reducing parental care negatively affected traits that are ecologically important for burying beetles, including F1 offspring development time and body size. However, F1 parents that received reduced care as larvae spent more time feeding F2 offspring than parents that received full care as larvae. As a result, both the number and mass of F2 offspring were unaffected by the developmental experience of their parents. Our results show that flexible parental care may be able to overcome poor developmental environments and limit negative parental effects to a single generation.

LOXHD1 is indispensable for coupling auditory mechanosensitive channels to the site of force transmission.

Hearing is initiated in hair cells by the mechanical activation of ion channels in the hair bundle. The hair bundle is formed by stereocilia organized into rows of increasing heights interconnected by tip links, which convey sound-induced forces to stereocilia tips. The auditory mechanosensitive channels are complexes containing at least four protein-subunits - TMC1/2, TMIE, CIB2, and LHFPL51-16 - and are located at the tips of shorter stereocilia at a yet-undetermined distance from the lower tip link insertion point17. While multiple auditory channel subunits appear to interact with the tip link, it remains unknown whether their combined interaction alone can resist the high-frequency mechanical stimulations owing to sound. Here we show that an unanticipated additional element, LOXHD1, is indispensable for maintaining the TMC1 pore-forming channel subunits coupled to the tip link. We demonstrate that LOXHD1 is a unique element of the auditory mechanotransduction complex that selectively affects the localization of TMC1, but not its close developmental paralogue TMC2. Taking advantage of our novel immunogold scanning electron microscopy method for submembranous epitopes (SUB-immunogold-SEM), we demonstrate that TMC1 normally concentrates within 100-nm of the tip link insertion point. In LOXHD1's absence, TMC1 is instead mislocalized away from this force transmission site. Supporting this finding, we found that LOXHD1 interacts selectively in vitro with TMC1 but not with TMC2 while also binding to channel subunits CIB2 and LHFPL5 and tip-link protein PCDH15. SUB-immunogold-SEM additionally demonstrates that LOXHD1 and TMC1 are physically connected to the lower tip-link complex in situ. Our results show that the TMC1-driven mature channels require LOXHD1 to stay coupled to the tip link and remain functional, but the TMC2-driven developmental channels do not. As both tip links and TMC1 remain present in hair bundles lacking LOXHD1, it opens the possibility to reconnect them and restore hearing for this form of genetic deafness.

IUPHAR Review - Bivalent and bifunctional opioid receptor ligands as novel analgesics.

Though efficacious in managing chronic, severe pain, opioid analgesics are accompanied by significant adverse effects including constipation, tolerance, dependence, and respiratory depression. The life-threatening risks associated with µ opioid receptor agonist-based analgesics challenges their use in clinic. A rational approach to combatting these adverse effects is to develop agents that incorporate activity at a second pharmacologic target in addition to µ opioid receptor activation. The promise of such bivalent or bifunctional ligands is the development of an analgesic with an improved side effect profile. In this review, we highlight ongoing efforts in the development of bivalent and bifunctional analgesics that combine µ agonism with efficacy at κ and δ opioid receptors, the nociceptin opioid peptide (NOP) receptor, σ receptors, and cannabinoid receptors. Several examples of bifunctional analgesics in preclinical and clinical development are highlighted, as are strategies being employed toward the rational design of novel agents.

Nitro-benzylideneoxymorphone, a bifunctional mu and delta opioid receptor ligand with high mu opioid receptor efficacy.

Introduction: There is a major societal need for analgesics with less tolerance, dependence, and abuse liability. Preclinical rodent studies suggest that bifunctional ligands with both mu (MOPr) and delta (DOPr) opioid peptide receptor activity may produce analgesia with reduced tolerance and other side effects. This study explores the structure-activity relationships (SAR) of our previously reported MOPr/DOPr lead, benzylideneoxymorphone (BOM) with C7-methylene-substituted analogs. Methods: Analogs were synthesized and tested in vitro for opioid receptor binding and efficacy. One compound, nitro-BOM (NBOM, 12) was evaluated for antinociceptive effects in the warm water tail withdrawal assay in C57BL/6 mice. Acute and chronic antinociception was determined, as was toxicologic effects on chronic administration. Molecular modeling experiments were performed using the Site Identification by Ligand Competitive Saturation (SILCS) method. Results: NBOM was found to be a potent MOPr agonist/DOPr partial agonist that produces high-efficacy antinociception. Antinociceptive tolerance was observed, as was weight loss; this toxicity was only observed with NBOM and not with BOM. Modeling supports the hypothesis that the increased MOPr efficacy of NBOM is due to the substituted benzylidene ring occupying a nonpolar region within the MOPr agonist state. Discussion: Though antinociceptive tolerance and non-specific toxicity was observed on repeated administration, NBOM provides an important new tool for understanding MOPr/DOPr pharmacology.

The role of Dmnt1 during spermatogenesis of the insect Oncopeltus fasciatus.

BACKGROUND: The function of DNA methyltransferase genes of insects is a puzzle, because an association between gene expression and methylation is not universal for insects. If the genes normally involved in cytosine methylation are not influencing gene expression, what might be their role? We previously demonstrated that gametogenesis of Oncopeltus fasciatus is interrupted at meiosis following knockdown of DNA methyltransferase 1 (Dnmt1) and this is unrelated to changes in levels of cytosine methylation. Here, using transcriptomics, we tested the hypothesis that Dmnt1 is a part of the meiotic gene pathway. Testes, which almost exclusively contain gametes at varying stages of development, were sampled at 7 days and 14 days following knockdown of Dmnt1 using RNAi. RESULTS: Using microscopy, we found actively dividing spermatocysts were reduced at both timepoints. However, as with other studies, we saw Dnmt1 knockdown resulted in condensed nuclei after mitosis-meiosis transition, and then cellular arrest. We found limited support for a functional role for Dnmt1 in our predicted cell cycle and meiotic pathways. An examination of a priori Gene Ontology terms showed no enrichment for meiosis. We then used the full data set to reveal further candidate pathways influenced by Dnmt1 for further hypotheses. Very few genes were differentially expressed at 7 days, but nearly half of all transcribed genes were differentially expressed at 14 days. We found no strong candidate pathways for how Dnmt1 knockdown was achieving its effect through Gene Ontology term overrepresentation analysis. CONCLUSIONS: We, therefore, suggest that Dmnt1 plays a role in chromosome dynamics based on our observations of condensed nuclei and cellular arrest with no specific molecular pathways disrupted.

Insect homolog of oxytocin/vasopressin associated with parenting of males but not females in a subsocial beetle.

Parental care is thought to evolve through modification of behavioral precursors, which predicts that mechanistic changes occur in the genes underlying those traits. The duplicated gene system of oxytocin/vasopressin has been broadly co-opted across vertebrates to influence parenting, from a preduplication ancestral role in water balance. It remains unclear whether co-option of these genes for parenting is limited to vertebrates. Here, we experimentally tested for associations between inotocin gene expression and water balance, parental acceptance of offspring, and active parenting in the subsocial beetle Nicrophorus orbicollis, to test whether this single-copy homolog of the oxytocin/vasopressin system has similarly been co-opted for parental care in a species with elaborate parenting. As expected, inotocin was associated with water balance in both sexes. Inotocin expression increased around sexual maturation in both males and females, although more clearly in males. Finally, inotocin expression was not associated with acceptance of larvae, but was associated with a transition to male but not female parenting. Moreover, level of offspring provisioning behavior and gene expression were positively correlated in males but uncorrelated in females. Our results suggest a broad co-option of this system for parenting that may have existed prior to gene duplication.

Axially Chiral Cannabinoids: Design, Synthesis, and Cannabinoid Receptor Affinity.

The resorcinol-terpene phytocannabinoid template is a privileged scaffold for the development of diverse therapeutics targeting the endocannabinoid system. Axially chiral cannabinols (axCBNs) are unnatural cannabinols (CBNs) that bear an additional C10 substituent, which twists the cannabinol biaryl framework out of planarity creating an axis of chirality. This unique structural modification is hypothesized to enhance both the physical and biological properties of cannabinoid ligands, thus ushering in the next generation of endocannabinoid system chemical probes and cannabinoid-inspired leads for drug development. In this full report, we describe the philosophy guiding the design of axCBNs as well as several synthetic strategies for their construction. We also introduce a second class of axially chiral cannabinoids inspired by cannabidiol (CBD), termed axially chiral cannabidiols (axCBDs). Finally, we provide an analysis of axially chiral cannabinoid (axCannabinoid) atropisomerism, which spans two classes (class 1 and 3 atropisomers), and provide first evidence that axCannabinoids retain─and in some cases, strengthen─affinity and functional activity at cannabinoid receptors. Together, these findings present a promising new direction for the design of novel cannabinoid ligands for drug discovery and exploration of the complex endocannabinoid system.

Renal Mass Imaging with MRI Clear Cell Likelihood Score: A User's Guide.

Small solid renal masses (SRMs) are frequently detected at imaging. Nearly 20% are benign, making careful evaluation with MRI an important consideration before deciding on management. Clear cell renal cell carcinoma (ccRCC) is the most common renal cell carcinoma subtype with potentially aggressive behavior. Thus, confident identification of ccRCC imaging features is a critical task for the radiologist. Imaging features distinguishing ccRCC from other benign and malignant renal masses are based on major features (T2 signal intensity, corticomedullary phase enhancement, and the presence of microscopic fat) and ancillary features (segmental enhancement inversion, arterial-to-delayed enhancement ratio, and diffusion restriction). The clear cell likelihood score (ccLS) system was recently devised to provide a standardized framework for categorizing SRMs, offering a Likert score of the likelihood of ccRCC ranging from 1 (very unlikely) to 5 (very likely). Alternative diagnoses based on imaging appearance are also suggested by the algorithm. Furthermore, the ccLS system aims to stratify which patients may or may not benefit from biopsy. The authors use case examples to guide the reader through the evaluation of major and ancillary MRI features of the ccLS algorithm for assigning a likelihood score to an SRM. The authors also discuss patient selection, imaging parameters, pitfalls, and areas for future development. The goal is for radiologists to be better equipped to guide management and improve shared decision making between the patient and treating physician. © RSNA, 2023 Quiz questions for this article are available in the supplemental material. See the invited commentary by Pedrosa in this issue.

A Comprehensive Guide to Sodium Glucose Cotransport Inhibitors.

Sodium-glucose cotransport 2 inhibitors (SGLT2i) are a class of drugs initially approved by the Food and Drug Association (FDA) as antihyperglycemic agents for patients with type 2 diabetes mellitus (DM). However, lately, these agents (Canagliflozin, Empagliflozin, Ertugliflozin, Sotagliflozin, and Dapagliflozin) have become better known for their cardiovascular (CV) and reno-protective effects. In this comprehensive review and analysis, we display the advancement of Sodium Glucose Cotransport Inhibitors have shown in cardiology, specifically heart failure in a concise, yet thorough manner.

The role of Dnmt1 in oocyte development.

The whitefly Bemisia tabaci is a globally important crop pest that is difficult to manage through current commercially available methods. While RNA interference (RNAi) is a promising strategy for managing this pest, effective target genes remain unclear. We suggest DNA methyltransferase 1 (Dnmt1) as a potential target gene due to its effect on fecundity in females in other taxa of insects. We investigated the role of Dnmt1 in B. tabaci using RNAi and immunohistochemistry to confirm its potential conserved function in insect reproduction, which will define its usefulness as a target gene. Using RNAi to downregulate Dnmt1 in female B. tabaci, we show that Dnmt1 indeed has a conserved role in reproduction, as knockdown interfered with oocyte development. Females in which Dnmt1 was knocked down had greatly reduced fecundity and fertility; this supports Dnmt1 as a suitable target gene for RNAi-mediated pest management of B. tabaci.

Control of stereocilia length during development of hair bundles.

Assembly of the hair bundle, the sensory organelle of the inner ear, depends on differential growth of actin-based stereocilia. Separate rows of stereocilia, labeled 1 through 3 from tallest to shortest, lengthen or shorten during discrete time intervals during development. We used lattice structured illumination microscopy and surface rendering to measure dimensions of stereocilia from mouse apical inner hair cells during early postnatal development; these measurements revealed a sharp transition at postnatal day 8 between stage III (row 1 and 2 widening; row 2 shortening) and stage IV (final row 1 lengthening and widening). Tip proteins that determine row 1 lengthening did not accumulate simultaneously during stages III and IV; while the actin-bundling protein EPS8 peaked at the end of stage III, GNAI3 peaked several days later-in early stage IV-and GPSM2 peaked near the end of stage IV. To establish the contributions of key macromolecular assemblies to bundle structure, we examined mouse mutants that eliminated tip links (Cdh23v2J or Pcdh15av3J), transduction channels (TmieKO), or the row 1 tip complex (Myo15ash2). Cdh23v2J/v2J and Pcdh15av3J/av3J bundles had adjacent stereocilia in the same row that were not matched in length, revealing that a major role of these cadherins is to synchronize lengths of side-by-side stereocilia. Use of the tip-link mutants also allowed us to distinguish the role of transduction from effects of transduction proteins themselves. While levels of GNAI3 and GPSM2, which stimulate stereocilia elongation, were greatly attenuated at the tips of TmieKO/KO row 1 stereocilia, they accumulated normally in Cdh23v2J/v2J and Pcdh15av3J/av3J stereocilia. These results reinforced the suggestion that the transduction proteins themselves facilitate localization of proteins in the row 1 complex. By contrast, EPS8 concentrates at tips of all TmieKO/KO, Cdh23v2J/v2J, and Pcdh15av3J/av3J stereocilia, correlating with the less polarized distribution of stereocilia lengths in these bundles. These latter results indicated that in wild-type hair cells, the transduction complex prevents accumulation of EPS8 at the tips of shorter stereocilia, causing them to shrink (rows 2 and 3) or disappear (row 4 and microvilli). Reduced rhodamine-actin labeling at row 2 stereocilia tips of tip-link and transduction mutants suggests that transduction's role is to destabilize actin filaments there. These results suggest that regulation of stereocilia length occurs through EPS8 and that CDH23 and PCDH15 regulate stereocilia lengthening beyond their role in gating mechanotransduction channels.

One genome, multiple phenotypes: decoding the evolution and mechanisms of environmentally induced developmental plasticity in insects.

Plasticity in developmental processes gives rise to remarkable environmentally induced phenotypes. Some of the most striking and well-studied examples of developmental plasticity are seen in insects. For example, beetle horn size responds to nutritional state, butterfly eyespots are enlarged in response to temperature and humidity, and environmental cues also give rise to the queen and worker castes of eusocial insects. These phenotypes arise from essentially identical genomes in response to an environmental cue during development. Developmental plasticity is taxonomically widespread, affects individual fitness, and may act as a rapid-response mechanism allowing individuals to adapt to changing environments. Despite the importance and prevalence of developmental plasticity, there remains scant mechanistic understanding of how it works or evolves. In this review, we use key examples to discuss what is known about developmental plasticity in insects and identify fundamental gaps in the current knowledge. We highlight the importance of working towards a fully integrated understanding of developmental plasticity in a diverse range of species. Furthermore, we advocate for the use of comparative studies in an evo-devo framework to address how developmental plasticity works and how it evolves.